Adrenergic vasoconstriction limits coronary blood flow during exercise in hypertrophied left ventricle ROBERT
J. BACHE,
DAVID
C. HOMANS,
Cardiovascular Division, Department Minneapolis, Minnesota 55455
AND
of Medicine,
XUE-ZHENG
University
DA1
of Minnesota,
BACHE, ROBERT J., DAVID C. HOMANS, AND XUE-ZHENG DAI. Adrenergic vasoconstriction limits coronary blood flow durleft ventricle. Am. J. Physiol. 260 ing exercise in hypertrophied
gested that adrenergic coronary vasoconstriction can limit myocardial oxygen uptake during exercise. Previous observations suggest that perfusion of the (Heart Circ. Physiol. 29): H1489-H1494, 1991.-This study chronically pressure-overloaded, hypertrophied left venwas carried out to test the hypothesis that cw-adrenergic vasotricle may be inadequate to meet the increased myocarconstriction limits coronary blood flow (CBF) during exercise dial oxygen demands during exercise (2, 7). In dogs with in the chronically pressure overloaded, hypertrophied left venleft ventricular hypertrophy produced by banding the tricle. Studies were performed in dogs in which left ventricular hypertrophy had been produced by banding the ascending aorta ascending aorta, Hittinger et al. (18) found that exercise at 9 wk of age. Left circumflex Foronary artery blood flow and resulted in both systolic and diastolic contractile dysmyocardial O2 consumption (MVO~) were examined at rest and function, suggesting that coronary blood flow was insufduring treadmill exercise during control conditions, after selec- ficient to meet myocardial demands. Because of the tive cul-adrenergic blockade with prazosin, and after nonselec- finding that adrenergic vasoconstrictor activity limits tive a-adrenergic blockade with phentolamine. All studies were coronary blood flow during exercise in the normal heart, performed after ,&adrenergic blockade with propranolol. During control conditions CBF and Mv02 increased progressively dur- this study was performed to determine whether adrenergic vasoconstriction also restrains the increase in coroing exercise, while coronary sinus O2tension decreased. Neither nary blood flow that occurs in the chronically pressureprazosin nor phentolamine altered CBF at rest but, in comparleft ventricle during exercise. ison with control measurements, both agents significantly in- overloaded, hypertrophied creased CBF during exercise and abolished the decrease in Because previous reports have suggested that both postcoronary sinus O2 tension that normally occurred during exer- junctional a!1- and az-adrenoceptor activation can cause cise. Both prazosin and phentolamine caused similar significant coronary vasoconstriction, the effects of selective cyl- and increases of MOON relative to the heart rate times systolic left combined cyl- and a2-adrenergic blockade were evaluated. ventricular pressure during exercise, indicating that the in- Because nonselective a-adrenergic blockade interrupts creased CBF produced by these agents enhanced MVo2. Similar negative feedback control of norepinephrine release by findings after prazosin and phentolamine indicate that adre- blocking prejunctional cxa-adrenergic receptors, thereby nergic restraint of CBF during exercise resulted principally of the from arl-adrenergic vasoconstrictions with little additional con- leading to increased @-adrenergic stimulation heart, studies were performed after @-adrenergic blocktribution from postjunctional aa-adrenergic mechanisms. ade with propranolol (20). myocardial blood flow; coronary sinus oxygen pressure; prazosin; phentolamine; p-adrenergic blockade
IN
THE
NORMAL
HEART,
adrenergic
vasoconstrictor
ac-
tivity has been shown to oppose metabolic coronary vasodilation during exercise (12, 13, 16, 25, 28). As the result of adrenergic constriction, the increase in coronary blood flow that occurs during exercise is less than required to meet the increased myocardial oxygen demands, resulting in increased oxygen extraction by the heart, with a decrease of coronary venous oxygen content (12, 13, 16, 28). This increase in myocardial oxygen extraction during exercise may be prevented by either nonselective a-adrenergic blockade with phentolamine or by selective cul-adrenergic blockade with prazosin (5, l2,13, 16). Gwirtz et al. (12) found that during treadmill exercise, intracoronary administration of the selective al-adrenergic antagonist prazosin caused an increase in coronary blood flow that resulted in a significant increase in myocardial oxygen consumption. This finding sug0363-6135/91
$1.50
Copyright
METHODS
Studies were performed in seven mongrel dogs in which left ventricular hypertrophy was produced by banding the ascending aorta. At 9 wk of age the dogs were anesthetized with pentobarbital sodium (25-30 mg/kg iv), ventilated with a respirator, and underwent right thoracotomy through the third intercostal space using sterile surgical technique. The ascending aorta, -1.5 cm above the aortic valve, was dissected free and encircled with a polyethylene band, 2.5 mm in width. While left ventricular and distal aortic pressures were simultaneously measured, the band was tightened until a 20- to 25-mmHg peak systolic pressure -gradient was achieved across the area of constriction. The thoracotomy was then repaired, the pneumothorax evacuated with a chest tube, and the animal allowed to recover. The dogs were subsequently maintained in enclosed runs on a standard laboratory diet. At 3 mo of age, the animals were trained to run on a motor-driven treadmill. Thereafter, animals
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were not exercised on the treadmill until 1 wk before chronic instrumentation surgery, when they underwent a period of retraining on the treadmill for -20 min twice daily. At lo-12 mo of age, animals were returned to the laboratory, anesthetized with pentobarbital sodium (3035 mg/kg iv), intubated, and ventilated with a respirator. By means of sterile surgical procedure, a left thoracotomy was performed in the fifth intercostal space. A polyvinyl chloride (PVC) catheter (3.0 mm OD) was introduced into the left internal thoracic artery and advanced into the ascending aorta. The pericardium was then opened, and a similar catheter was introduced into the right atrium via the atria1 appendage and manipulated into the coronary sinus until the tip could be palpated to 22.5 cm beyond the coronary sinus ostium. A similar catheter was inserted into the left ventricular cavity through a stab wound in the apical dimple and secured with a purse-string suture. A final catheter was placed into the left atrium via the atria1 appendage and secured with a purse-string suture. The proximal left circumflex coronary artery was mobilized, and an electromagnetic flowmeter probe (Howell Instrument, Oxnard, CA) was placed around the vessel. A hydraulic occluder constructed of PVC tubing (2.7 mm OD) was positioned around the artery distal to the flowmeter probe but proximal to any arterial branches. The catheters and flowmeter leads were tunneled subcutaneously to exit at the base of the neck. The pericardium was loosely closed, the thoracotomy repaired, and the dog allowed to recover. Exercise on the treadmill was resumed -1 wk after surgery, and studies were performed -2 wk after surgery when the animals were free from fever, anemia, or other evidence of ill health. Studies were performed with the dogs standing on the platform of a motor-driven treadmill. Aortic and left ventricular catheters were connected to Statham P23 ID pressure transducers at midchest level. The flowmeter leads were connected to a Statham model SP2202 electromagnetic flowmeter for measurement of left circumflex coronary blood flow. The zero flow baseline was established with 2-3 s total occlusions of the left circumflex coronary artery. Data were recorded on a HewlettPackard model 8800 eight-channel direct writing oscillograph. Before the study was started, the dogs underwent a 5 min period of warm-up exercise during which the exercise level was progressively increased to 6.0 km/h at a 15% grade. A 15.min rest period was allowed after warm-up exercise. During this time, propranolol (0.15 mg/kg iv) was administered. The adequacy of P-adrenergic blockade was assessed by examining the response of heart rate to isoproterenol (0.2 pg/kg iv) before and after propran0101. Hemodynamic variables were continuously monitored to ensure that steady-state conditions of heart rate and blood pressures existed before the study. Immediately before exercise was started, aortic and coronary sinus blood samples (1.0 ml) were withdrawn anaerobically for measurement of Paz, Pco~, pH, and hemoglobin, while hemodynamic measurements were obtained. Exercise was then begun at a rate of 5 km/h at a 1% grade. Two minutes after exercise was started. aortic and cor-
VENTRICULAR
HYPERTROPHY
onary sinus blood samples were withdrawn, while coronary blood flow and all pressures were recorded. After 3 min of exercise, the speed and grade of the treadmill were increased to 6 km/h at a 15% grade. Arterial and coronary sinus blood samples, as well as measurements of coronary blood flow and all pressures were obtained during the 3rd min of this exercise stage. Exercise was then discontinued, and the response to isoproterenol was examined again to assess the completeness of P-adrenergic blockade. After a l-h rest period, the response of arterial pressure to the arl-adrenergic agonist phenylephrine (2-6 pg/kg iv) was examined. The selective cul-adrenergic antagonist prazosin (100 pg/kg iv) was then administered to six dogs. In addition, a supplemental dose of propranolol (0.1 mg/kg iv) was administered and the response to isoproterenol again observed. The completeness of cyladrenergic blockade was assessed by repeating the dose of phenylephrine while observing the response of arterial pressure. The exercise protocol was then repeated, with hemodynamic measurements and coronary sinus and arterial blood sampling performed at rest and during the two exercise stages. Dogs were then allowed to rest for 1 h. After this time, propranolol (0.1 mg/kg) was again administered intravenously to six dogs. Nonselective cyadrenergic blockade was produced by administration of phentolamine (2.0 mg/kg in 5 dogs and 1.0 mg/kg in 1 dog). Measurements at rest and during the two exercise stages were repeated after administration of phentolamine. After the conclusion of exercise, the completeness of a-adrenergic blockade was tested by administration of phenylephrine as previously described, while the completeness of ,&adrenergic blockade was examined by administration of isoproterenol. Blood specimens were maintained in ice-cold syringes until completion of each exercise protocol; measurements of Po2, Pco~, and pH were performed with an Instrumentation Laboratory model 113 blood gas analyzer that was calibrated with known gas mixtures. Blood hemoglobin content was estimated by the cyanmethemoglobin method. Arterial and coronary sinus oxyhemoglobin saturations were estimated from the blood pH, POT, and temperature, using the oxygen dissociation curve for dog blood (26). Blood oxygen content was calculated as follows: O2 content (ml/dl): hemoglobin (g/dl) x 1.34x O2 saturation (%/lOO) + PoB (Torr) X 0.0031. An index of myocardial oxygen consumption was computed as follows: O2 consumption (ml) = left circumflex coronary artery blood flow (ml/min) X [O, content difference between aortic and coronary sinus blood (ml/dl)]/lOO. measurements were Data analysis. Hemodynamic taken directly from the strip chart recordings. A minimum of five beats were averaged for each measurement. Hemodynamic data, blood gas measurements, and myocardial oxygen consumption data were compared using analysis of variance for repeated measures. The change in each variable from rest to exercise level 1 and from rest to exercise level 2 were determined, and the effects of prazosin and phentolamine on the responses to exercise were examined using analysis of variance for repeated measures. A value of P < 0.05 was reauired for
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statistical significance. When a significant value was found, individual comparisons were made using the Scheffe method.
during the second exercise level (P < 0.05). During control conditions, left ventricular end-diastolic pressure increased significantly during the first exercise level (P < 0.05),with a further significant increase at the second level of exercise. After prazosin, left ventricular endRESULTS diastolic pressure was not significantly different from Mean left ventricular weight for the seven dogs was control at rest or during the first level of exercise but 140.3t 13.6 g, while mean body weight was 16.4 t 1.3 was significantly less than control during the second kg. The mean left ventricular-to-body weight ratio was exercise stage. Similarly, after phentolamine left ventricular end-diastolic pressure was not significantly different 8.8 * 1.0g/kg. In a previous report from this laboratory, from control at rest or during the first exercise stage but the left ventricular-to-body weight ratio of normal adult mongrel dogs was found to be 4.3 -I- 0.2 g/kg (6). Thus was significantly less than control during the second the mean left ventricular-to-body weight ratio of the level of exercise (P < 0.05). animals used in this study was 105%greater than normal. Coronary blood flow, coronary sinus oxygen tension, Hemodynamic data are shown in Table 1. During and myocardial oxygen consumption are shown in Table control conditions, resting heart rates ranged from 96 to 2. During resting conditions, blood flow through the left 120 beats/min. Neither prazosin nor phentolamine sig- circumflex coronary artery ranged from 32 to 68 ml/min nificantly altered resting heart rates. During control (mean, 52 $- 4.5). Coronary blood flow increased 45 t conditions, heart rate increased significantly during the 11% during the first stage of exercise (P < O.Ol),with a first exercise stage, with a further significant increase further 27 t 4% increase during the second exercise stage during the second level of exercise. Heart rate was not (P < 0.01). Neither prazosin nor phentolamine signifisignificantly different from normal after prazosin during cantly altered coronary blood flow during resting condieither exercise level or after phentolamine during the tions. The increase in coronary blood flow in response to first exercise stage. However, after phentolamine heart exercise was significantly greater than control during rates were significantly faster than control during the exercise stage 2 after prazosin (P < 0.05) and during both second stage of exercise (P < 0.05). Mean aortic pressure exercise stages after phentolamine (each P < 0.01).Corranged from 65 to 100 mmHg during resting control onary blood flow was significantly greater than control conditions and did not change significantly in response during both exercise stages after prazosin and after phento exercise. Mean and diastolic aortic pressures tended tolamine (each P < 0.05). During control conditions to be lower after a-adrenergic blockade during resting coronary sinus oxygen tension decreased significantly conditions and was significantly less than control during from rest to the second stage of exercise (P < 0.02). In exercise after both prazosin and phentolamine (P < contrast to control conditions, coronary sinus oxygen 0.05). tension did not change significantly in response to exDuring control resting conditions, left ventricular sys- ercise after either prazosin or phentolamine. Thus the tolic pressure ranged from 198 to 290 mmHg (Table 1). change in coronary sinus oxygen tension during the second level of exercise was significantly less than conLeft ventricular systolic pressure increased significantly trol after both prazosin and phentolamine (P < 0.05). during the first level of exercise (P < 0.05),with a further During control conditions, myocardial oxygen consignificant increase at the second exercise level (P < sumption increased 39 t 8% from rest to the first exercise 0.05). Prazosin did not significantly alter left ventricular stage (P < O.Ol),with an additional 33 t 5% increase (P systolic pressure at rest or during either exercise level. After phentolamine, left ventricular systolic pressure was < 0.01) at the second level of exercise (Table 2). Neither not different from control at rest or during the first phentolamine nor prazosin significantly altered myocarexercise level but was significantly greater than control dial oxygen consumption at rest. However, the change in
Rest
Exl Al
EX2 A2
107 &5 165 *9f+58 6 203 +7t +96 t4
110 &6 172 +8t +61 &6 204 +7t +94 t6
116 k4 189 +8t +89 zk5 235 *9*t$ +119 *9*$
108/71 &8/5 108/61 +7/4 o/-10 +4/3 115/58 +6/3 +7/-13 +3/3
95165 *8/2 93144 +9/4 -21-21 +2/3 109/46 +6/2 +14/-19 +2/4
Values are means & SE. Con, control (n = 7); Praz, rest to exercise stage 1 (Ed); A2, difference from rest rest. $ P < 0.05 compared with prazosin.
91/60 &6/4 92143 rt7/6 +1/-17 2214 107146 k6/4 +16/-15 +3/4
83 t4 79 k4 -4 t2 79 t3 -4 t3
78 t4 64 +4*t -13 t3” 72 t3* -6 t3
71 t5* 64 *5*t -7 k2 69 k4* -2 t2
228 t14 269 +14t +41 *lo 308 +20t +80 t16
208 *21 272 +22-f +64 t22 310 +19t +102 t29
207 t11 288 +24t +81 t18” 348 +21*Q +141 +17”$
6 t1 10 +rt +4 z?zl 13 ,+1t +7 t1
6
6
tl
t2
9 *1t +4 t1 10 *l*t +5 *1
8 +1 +2 t2 11 +1*t +5 rtl
prazosin (n = 6); Phen, phentolamine (n = 6); LV, left ventricular; Al, difference to exercise sbge 2 (Ed). * P < 0.05 compared with control. 7 P < 0.05 compared
from with
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TABLE 2. Coronary blood flow, coronary sinus PO,, and myocardial oxygen consumption at rest and during 2 stages of treadmill exercise during control conditions, after a+drenergic blockade with prazosin, and after nonselective a-adrenergic blockade with phentolamine Coronary Eiercise Stage
Blood Flow, ml/min
Con
Rest Exl
Praz
52k4.5 73*4.5t +21&3.6
Al
Ex2
87&6.7t
A2
Coronary
+35*3.6
59k7.1 92+,11.8*t +33&6.2* 116*14.0*t +57&7.8*
Phen
Con
53k5.9 107+12.6*t +54+7.6’s 127+13.0*t 74t7.8”
Sinus P02, Torr Praz
18.1k1.5 17.0t1.5 -1.kkO.6 15.2*1.1t -2.9t0.8
Myocardial Con
Phen
19.OH.3 17.4kO.9 -1.5t0.9 18.Okl.O” -l.o~l.z*
18.5t1.0 18.6t1.1 +0.1*1.5 19.0*1.9* t0.5t1.8”
Values are means k SE. Con, control (n = 7); Praz, prazosin (n = 6); Phen, (Exl); AZ, difference from rest to exercise stage 2 (Ex2). * P < 0.05 compared
O2 Consumption, ml/min Praz
6.12t0.72 8.28&0.76-f +2.16t0.44 10.31~0.91~ +4.20t0.79
6.56k0.72 10.83+1.50*t +4.27t0.96* 12.80+1.79*t +6.24&0.99*
Phen 6.18k0.76 12.30*1.32*t +6.12+0.78*$ 14.38+1.81*7 +8.20t1.34*
phentolamine (n = 6); Al, difference from rest to exercise stage 1 with control. -t P < 0.05 compared with rest. $ P < 0.05 compared
wtih prazosin.
myocardial oxygen consumption was significantly greater than control after both prazosin and phentolamine during both exercise stages (each P < 0.05). The change in myocardial oxygen consumption from rest to exercise stage 1 was greater after phentolamine than after prazosin (P < 0.02) but not for exercise stage 2. As shown in Fig. 1, during control conditions, the increase in myocardial oxygen consumption was directly proportional to the increases in heart rate and the heart rate times left ventricular systolic pressure (rate-pressure product). The slopes of both of these relationships were significantly increased by prazosin, so that increases in heart rate and rate-pressure product produced greater increases of myocardial oxygen consumption after prazosin than during control conditions (P c 0.05). Phentolamine also increased the slopes of both of these relationships, but this did not achieve statistical significance. DISCUSSION
The present study demonstrates that a-adrenergic vasoconstriction limits coronary blood flow during exercise in the chronically pressure overloaded, hypertrophied left ventricle. The concept that adrenergic vasoconstriction can oppose metabolic coronary vasodilation during exercise was originally proposed by Murray and Vatner (25). Using normal dogs pretreated with propran-
-
0 y = 0.0447x A y - 0.0628% n y = 0.0782x
+ 1.15 - 0.20 - 2.90
I
4
I I
I I
I I
125
175
225
Heart
Rate
(beats/min)
0101, these investigators found that left circumflex coronary artery blood flow during exercise was 17% higher after nonselective cr-adrenergic blockade with phentolamine than during control conditions. The effect of CYadrenergic blockade appeared greater in the present study, with coronary blood flow during exercise stage 2 being 33% higher than control after prazosin and 46% greater than control after phentolamine. The greater effect of ar-adrenergic blockade in this study suggests that adrenergic restraint of coronary blood flow during exercise is greater in hypertrophied than in normal hearts. This may be because exercise represents a greater stress in hypertrophied hearts, because of the exaggerated increase in left ventricular systolic pressure that occurs during exercise in the presence of left ventricular outflow obstruction. Thus, in the normal dogs studied by Murray and Vatner (25), left ventricular systolic pressure increased 10 t 8 mmHg in response to exercise, whereas in the present study left ventricular systolic pressure increased 80 t 16 mmHg during exercise stage 2. The greater exercise-imposed stress in the present study may have resulted in greater activation of the sympathetic nervous system in the animals with hypertrophy. The greater increase in coronary blood flow during exercise after cu-adrenergic blockade was not merely luxuriant flow, because it resulted in a significant increase in myocardial oxygen consumption. This finding suggests
I
0 y = 0.000100x
+ 3.84
--
A y - 0.000162x l y = 0.000173x
+ 2.81 + 2.63 FIG. 1. Myocardial oxygen consumption plotted against heart rate (A) and heart rate times systolic left ventricular pressure product (B) at rest and during 2 exercise stages. Data are shown during control conditions (circles), after prazosin (100 pg/kg iv; triangles), and after phentolamine (l-2 mg/kg iv; squares). Slopes of both relationships were increased after prazosin (P < 0.05).
0
II
I I
I I
25
50
75
Rate-Pressure
Product
100 x 1 Om3
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that myocardial oxygen consumption during exercise was limited by adrenergic restraint of coronary blood flow. Abnormal perfusion in the hypertrophied heart generally has been attributed to structural alterations of the coronary vasculature (24). Hypertrophy of cardiac myocytes results in vascular rarefaction, and this is believed to be responsible for impairment of minimum vascular resistance during maximum coronary vasodilation (1, 6, 24). The present findings imply that in addition to structural abnormalities of the coronary vasculature, adrenergic vasoconstriction may also limit coronary blood flow during exercise. It generally has been assumed that local metabolic factors outweigh central control of the coronary resistance vessels. However, recent studies have demonstrated that ar-adrenergic vasoconstriction may limit blood flow even during coronary hypoperfusion. In open chest normal dogs, Liang and Jones (22) found that after decreasing coronary perfusion pressure sufficiently to reduce coronary blood flow and decrease myocardial oxygen consumption, al-adrenergic blockade with prazosin caused a significant increase in blood flow that was associated with an increase in myocardial oxygen consumption, demonstrating that adrenergic vasoconstriction had contributed to the impairment of myocardial oxygen delivery. In chronically instrumented exercising dogs in which a stenosis reduced distal coronary pressure to 40 mmHg and decreased myocardial blood flow to 37% of control, Laxson et al. (21) found that intracoronary prazosin caused a 50 t 14% increase in blood flow with no change in perfusion pressure. The increase in blood flow produced by prazosin caused improvement of systolic shortening in the area perfused by the stenotic coronary artery. These studies indicate that in the normal heart, adrenergic coronary vasoconstriction may oppose metabolic vasodilation, even during hypoperfusion sufficient to reduce myocardial oxygen consumption and impair contractile performance. In the pressure-overloaded hypertrophied left ventricle, exercise results in redistribution of blood flow toward the epimyocardium with relative subendocardial underperfusion (2,7). Although al-adrenergic blockade caused an increase in coronary artery blood flow during exercise, the effect of cw-adrenergic blockade on the transmural distribution of perfusion was not determined. This may be of importance, because Feigl (10) has suggested that ar-adrenergic activity may cause preferential vasoconstriction of resistance vessels in the subepicardium, thereby diverting blood to the subendocardium. This could be of importance in the hypertrophied heart where subendocardial underperfusion is especially likely to occur during exercise. Further studies will be needed to determine the effect of cx-adrenergic blockade on the transmural distribution of perfusion during exercise in the hypertrophied heart. Previous studies in normal hearts have yielded conflicting data regarding the relative importance of postjunctional a!1- and az-adrenoceptors in mediating adrenergic coronary vasoconstriction. Several investigators have reported that coronary vasoconstriction produced by intra-arterial norepinephrine or by electrical stimulation of cardiac sympathetic nerves was only slightly blunted bv al-adrenergic blockade with prazosin but was
VENTRICULAR
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HYPERTROPHY
attenuated
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(15, 19). In contrast, adrenergic coronary vasoconstriction during exercise in normal dogs appears to be mediated principally by arl-adrenoceptors. Thus Strader et al. (27) and Dai et al. (9) demonstrated that in normal dogs coronary blood flow during exercise was increased by intracoronary administration of prazosin but not by the selective ar2-adrenergic antagonists idazoxan or yohimbine. The present data demonstrate that adrenergic restraint of coronary blood flow during exercise in the hypertrophied heart is also mediated principally by aladrenoceptors. In agreement with previous studies in normal dogs, neither prazosin nor phentolamine caused a significant increase of coronary blood flow or coronary sinus oxygen tension during resting conditions (5, 9). Similarly, Chilian et al. (8), using epicardial application of phenol to produce regional sympathectomy in normal dogs, found no difference in blood flow between sympathectomized and normal myocardial areas during resting conditions. The failure of a-adrenergic blockade to increase coronary blood flow during resting conditions in the present study indicates that adrenergic vasoconstriction does not limit resting coronary blood flow in the hypertrophied heart. The present study was carried out under conditions of P-adrenergic blockade with propranolol. This was done to blunt ,&adrenergic stimulation that may occur after nonselective a-adrenergic blockade. Prejunctional cy2adrenoceptors inhibit central sympathetic outflow and modulate norepinephrine release by noradrenergic nerve terminals (20, 23). By blocking prejunctional cx2-adrenoceptors, phentolamine interrupts negative feedback control of norepinephrine release (20). The resultant increase in P-adrenergic stimulation could cause increased myocardial oxygen consumption with a secondary increase in coronary blood flow (13, 17). Although the dose of propranolol used in the present study antagonized the response to isoproterenol and blunted the normal increase in heart rate during exercise, heart rate during the second stage of exercise was significantly faster after phentolamine than during control conditions. This suggests that the dose of propranolol used did not completely block the increased P-adrenergic activity produced by phentolamine. Unfortunately, larger doses of propranolol could not be used because they resulted in inability to complete the exercise protocol in these animals with left ventricular hypertrophy. Clearly, the faster heart rates during exercise after phentolamine would have contributed to the observed increase in myocardial oxygen consumption. To take into account the effects of the faster heart rate after phentolamine, myocardial oxygen consumption was plotted relative to heart rate and the heart rate times left ventricular systolic pressure product. This demonstrated that the increase in myocardial oxygen consumption during exercise after phentolamine was greater than expected for the change in heart rate or rate-pressure product. In addition, although prazosin caused no change in heart rate or rate-pressure product, myocardial oxygen uptake was 24 t 7% higher during the second level of exercise after prazosin than during control exercise. This finding supports the concept that adrenereic coronarv vasoconstriction limited
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myocardial oxygen consumption during exercise. Despite differing effects on heart rate and the ratepressure product, prazosin and phentolamine caused similar shifts of the relationship with myocardial oxygen consumption to a new line with a slope greater than control. The finding that both agents caused similar relative increases in myocardial oxygen consumption implies that the sympathetic restraint of coronary vasodilation during exercise resulted principally from cyladrenergic coronary vasoconstriction. If postjunctional az-adrenoceptors had also contributed to coronary vasoconstriction during exercise, then phentolamine should have caused further upward displacement of the curve relating coronary blood flow to the rate-pressure product above that produced by prazosin. This did not occur, indicating that after cul-adrenergic blockade, the addition of az-blockade did not cause further coronary vasodilation. In summary, this study demonstrates that adrenergic coronary vasoconstriction opposes coronary vasodilation during exercise in the chronically pressure overloaded, hypertrophied left ventricle. Restraint of coronary blood flow during exercise was principally the result of cyladrenoceptor-mediated coronary vasoconstriction with little additional effect from postjunctional cw2-adrenergic mechanisms. The data indicate that restraint of coronary blood flow by adrenergic vasoconstriction can limit myocardial oxygen delivery during exercise in the chronically hypertrophied left ventricle. The authors acknowledge expert technical assistance provided by Todd Pavek, Melanie Crampton, Paul Lindstrom, and Eugene Sublett. This work was supported by National Heart, Lung, and Blood Institute Grants HL-21872, HL-20598, and HL-34701. Address for reprint requests: R. J. Bathe, Box 338 UMHC, Univ. of Minnesota, Minneapolis, MN 55455. Received 5 February 1990; accepted in final form 19 December 1990. REFERENCES D., R. W. ANDERSON, D. G. PARRISH, X. DAI, AND R. J. Persistence of regional left ventricular dysfunction following exercise-induced myocardial ischemia in conscious dogs. J. Clin. Invest. 77: 66-73, 1986. 2. BACHE, R. J., D. ALYONO, X. DAI, T. R. VROBEL, D. G. PARRISH, AND D. C. HOMANS. Myocardial blood flow during exercise in left ventricular hypertrophy produced by aortic banding and perinephritic hypertension. Circulation 76: 835-842, 1987. 3. BACHE, R. J., C. E. ARENTZEN, A. B. SIMON, AND T. R. VROBEL. Abnormalities in myocardial hypertrophy: metabolic evidence for myocardial ischemia. Circulation 69: 409-417, 1984. 4. BACHE, R. J., AND X. DAI. Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis. J. Am. CoLZ. Cardiol. 15: 11571. ALYONO, BACHE.
1164,199O. 5. BACHE, R.
J., X. DAI, C. A. HERZOG, AND J. S. SCHWARTZ. Effects of nonselective and selective alphal-adrenergic blockade on coronary blood flow during exercise. Circ. Res. 61: 11-36-11-41, 1987. 6. BACHE, R. J., T. R. VROBEL, C. E. ARENTZEN, AND W. S. RING. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy. Circ. Res. 49: 742-750, 1981. 7. BACHE, R. J., T. R. VROBEL, W. S. RING, R. W. EMERY, AND R. W. ANDERSON. Regional mvocardial blood flow during exercise in
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dogs with chronic left ventricular
hypertrophy.
87, 1981. 8. CHILIAN,
W. M., R. B. BOATWRIGHT, T. JR. Evidence against significant resting tor tone in the conscious dog. Circ. Res. 9. DAI, X.-Z., E. SUBLETT, P. LINDSTROM, HOMANS, AND R. J. BACHE. Coronary selective cyl and acz-adrenergic blockade. Circ. Physiol. 25): H1148-H1155, 1989. 10. FEIGL, E. 0. The paradox of adrenergic 11. 12.
Circulation GOODWIN, Cardiovasc. GWIRTZ,
76: 737-745,
AND D. M. GRIGGS, sympathetic vasoconstric49: 866-876, 1981. J. S. SCHWARTZ, D. C. flow during exercise after
SHOJI,
Am. J. Physiol.
256 (Heart
coronary vasoconstriction.
1987.
J. R. Hypertrophic Dis.
Circ. Res. 48: 76-
disease of the myocardium.
Prog.
16: 199-238,1973. S. P. OVERN,
P. A., H. J. MASS, AND C. E. JONES. alAdrenergic constriction limits coronary flow and cardiac function in running dogs. Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H1117-H1126,1986. 13. GWIRTZ, P. A., AND H. L. STONE. Coronary blood flow and myocardial oxygen consumption after alpha-adrenergic blockade during submaximal exercise. J. Pharmucol. Exp. Ther. 217: 92-98, 1981. 14. HARRIS, C. N., W. S. ARONOW, D. D. PARKER, AND M. A. KAPLAN. Treadmill stress in left ventricular hypertrophy. Chest 63: 353357,1973. 15. HEUSCH,
G., A. DEUSSEN, J. SCHIPKE, AND V. THAMER. Alphaland alpha2-adrenoceptor mediated vasoconstrictor of large and Phurmucol. small canine coronary arteries in vivo. J. Cardiovusc.
6: 961-968,1984. 16. HEYNDRICKX,
G. R., P. MUYLAERT, AND J. L. PANNIER. a-Adrenergic control of oxygen delivery to myocardium during exercise in conscious dogs. Am. J. Physiol. 242 (Heart Circ. Physiol. 11): H805-
H809,1982. 17. HEYNDRICKX, LEUSEN. Role
G. R., J. P. VILAINE, E. J. MOERMAN, AND I. of prejunctional alphan-adrenergic receptors in the of myocardial performance during exercise in conscious
regulation dogs. Circ. Res. 54: 683-693, 1984. 18. HITTINGER, L., R. P. SHANNON, S. KOHIN, W. T. MANDERS, P. KELLY, AND S. F. VATNER. Exercise induced subendocardial dysfunction in dogs with left ventricular hypertrophy. Circ. Res. 66: 329-343,199o. 19. HOLTZ, J.,
M. SAEED, 0. SOMMER, AND E. BASSENGE. Norepinephrine constricts the canine coronary vascular bed via postsynaptic alpha;?-adrenoceptors. Eur. J. Phurmucol. 82: 199-202,
1982. 20. LANGER,
S. Z. Pre-synaptic receptors and their role in the regulation of transmitter release. Br. J. Phurmacol. 60: 481-497, 1977. 21. LAXSON, D. D., X. DAI, D. C. HOMANS, AND R. J. BACHE. The role of cyl- and cuz-adrenergic receptors in mediating coronary vasoconstriction in hypoperfused ischemic myocardium during exercise. Circ. Res. 65: 1688-1697, 1989. 22. LIANG, I. Y. S., AND C. E. JONES. Alphal-adrenergic blockade increases coronary blood flow during coronary hypoperfusion. Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H1070-H1077, 1985. 23. MCCALL, R. B., M. R. SCHUETTE, S. J. HUMPHREY, R. A. LAHTI, AND C. BARSUHN. Evidence for a central sympathoexcitatory action of alpha2-adrenergic antagonists. J. Phurmacol. Exp. Ther. 224: 501-507,1983. 24. MUELLER, T. M., W. BARNES, AND
left ventricular
M. L. MARCUS, R. E. KERBER, J. A. YOUNG, R. F. M. ABBOUD. Effect of renal hypertension and hypertrophy with coronary circulation of dogs. Circ.
Res. 42: 543-550, 1978. MURRAY, R. A., AND S. F. VATNER.
a-Adrenoceptor attenuation of the coronary vascular response to severe exercise in the conscious dog. Circ. Res. 45: 654-660, 1979. 26. REEVES, R. B., J. S. PARK, G. N. LAPENNAS, AND A. J. OLSZOWKA. Oxygen affinity and Bohr coefficients in dog blood. J. Appl. Physiol. 25.
53: 87-95,1982. STRADER, R.,
C. E. JONES, AND P. A. GWIRTZ. Comparative effects of cyl- and cuz-adrenoceptors in modulation of coronary flow during exercise. J. Pharmacol. Exp. Ther. 246: 772-778, 1988. 28. VON RESTORFF, W., E. HORLING, J. HOLTZ, AND E. BASSENGE. Exercise-induced augmentation of myocardial oxygen extraction in spite of normal coronary dilator capacity in dogs. PfZuegers Arch. 27.
373: 181-185.1977.
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J. BACHE,
DAVID
C. HOMANS,
Cardiovascular Division, Department Minneapolis, Minnesota 55455
AND
of Medicine,
XUE-ZHENG
University
DA1
of Minnesota,
BACHE, ROBERT J., DAVID C. HOMANS, AND XUE-ZHENG DAI. Adrenergic vasoconstriction limits coronary blood flow durleft ventricle. Am. J. Physiol. 260 ing exercise in hypertrophied
gested that adrenergic coronary vasoconstriction can limit myocardial oxygen uptake during exercise. Previous observations suggest that perfusion of the (Heart Circ. Physiol. 29): H1489-H1494, 1991.-This study chronically pressure-overloaded, hypertrophied left venwas carried out to test the hypothesis that cw-adrenergic vasotricle may be inadequate to meet the increased myocarconstriction limits coronary blood flow (CBF) during exercise dial oxygen demands during exercise (2, 7). In dogs with in the chronically pressure overloaded, hypertrophied left venleft ventricular hypertrophy produced by banding the tricle. Studies were performed in dogs in which left ventricular hypertrophy had been produced by banding the ascending aorta ascending aorta, Hittinger et al. (18) found that exercise at 9 wk of age. Left circumflex Foronary artery blood flow and resulted in both systolic and diastolic contractile dysmyocardial O2 consumption (MVO~) were examined at rest and function, suggesting that coronary blood flow was insufduring treadmill exercise during control conditions, after selec- ficient to meet myocardial demands. Because of the tive cul-adrenergic blockade with prazosin, and after nonselec- finding that adrenergic vasoconstrictor activity limits tive a-adrenergic blockade with phentolamine. All studies were coronary blood flow during exercise in the normal heart, performed after ,&adrenergic blockade with propranolol. During control conditions CBF and Mv02 increased progressively dur- this study was performed to determine whether adrenergic vasoconstriction also restrains the increase in coroing exercise, while coronary sinus O2tension decreased. Neither nary blood flow that occurs in the chronically pressureprazosin nor phentolamine altered CBF at rest but, in comparleft ventricle during exercise. ison with control measurements, both agents significantly in- overloaded, hypertrophied creased CBF during exercise and abolished the decrease in Because previous reports have suggested that both postcoronary sinus O2 tension that normally occurred during exer- junctional a!1- and az-adrenoceptor activation can cause cise. Both prazosin and phentolamine caused similar significant coronary vasoconstriction, the effects of selective cyl- and increases of MOON relative to the heart rate times systolic left combined cyl- and a2-adrenergic blockade were evaluated. ventricular pressure during exercise, indicating that the in- Because nonselective a-adrenergic blockade interrupts creased CBF produced by these agents enhanced MVo2. Similar negative feedback control of norepinephrine release by findings after prazosin and phentolamine indicate that adre- blocking prejunctional cxa-adrenergic receptors, thereby nergic restraint of CBF during exercise resulted principally of the from arl-adrenergic vasoconstrictions with little additional con- leading to increased @-adrenergic stimulation heart, studies were performed after @-adrenergic blocktribution from postjunctional aa-adrenergic mechanisms. ade with propranolol (20). myocardial blood flow; coronary sinus oxygen pressure; prazosin; phentolamine; p-adrenergic blockade
IN
THE
NORMAL
HEART,
adrenergic
vasoconstrictor
ac-
tivity has been shown to oppose metabolic coronary vasodilation during exercise (12, 13, 16, 25, 28). As the result of adrenergic constriction, the increase in coronary blood flow that occurs during exercise is less than required to meet the increased myocardial oxygen demands, resulting in increased oxygen extraction by the heart, with a decrease of coronary venous oxygen content (12, 13, 16, 28). This increase in myocardial oxygen extraction during exercise may be prevented by either nonselective a-adrenergic blockade with phentolamine or by selective cul-adrenergic blockade with prazosin (5, l2,13, 16). Gwirtz et al. (12) found that during treadmill exercise, intracoronary administration of the selective al-adrenergic antagonist prazosin caused an increase in coronary blood flow that resulted in a significant increase in myocardial oxygen consumption. This finding sug0363-6135/91
$1.50
Copyright
METHODS
Studies were performed in seven mongrel dogs in which left ventricular hypertrophy was produced by banding the ascending aorta. At 9 wk of age the dogs were anesthetized with pentobarbital sodium (25-30 mg/kg iv), ventilated with a respirator, and underwent right thoracotomy through the third intercostal space using sterile surgical technique. The ascending aorta, -1.5 cm above the aortic valve, was dissected free and encircled with a polyethylene band, 2.5 mm in width. While left ventricular and distal aortic pressures were simultaneously measured, the band was tightened until a 20- to 25-mmHg peak systolic pressure -gradient was achieved across the area of constriction. The thoracotomy was then repaired, the pneumothorax evacuated with a chest tube, and the animal allowed to recover. The dogs were subsequently maintained in enclosed runs on a standard laboratory diet. At 3 mo of age, the animals were trained to run on a motor-driven treadmill. Thereafter, animals
0 1991 the American
Physiological
Society
H1489
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H1490
ADRENERGIC
EFFECTS
IN
LEFT
were not exercised on the treadmill until 1 wk before chronic instrumentation surgery, when they underwent a period of retraining on the treadmill for -20 min twice daily. At lo-12 mo of age, animals were returned to the laboratory, anesthetized with pentobarbital sodium (3035 mg/kg iv), intubated, and ventilated with a respirator. By means of sterile surgical procedure, a left thoracotomy was performed in the fifth intercostal space. A polyvinyl chloride (PVC) catheter (3.0 mm OD) was introduced into the left internal thoracic artery and advanced into the ascending aorta. The pericardium was then opened, and a similar catheter was introduced into the right atrium via the atria1 appendage and manipulated into the coronary sinus until the tip could be palpated to 22.5 cm beyond the coronary sinus ostium. A similar catheter was inserted into the left ventricular cavity through a stab wound in the apical dimple and secured with a purse-string suture. A final catheter was placed into the left atrium via the atria1 appendage and secured with a purse-string suture. The proximal left circumflex coronary artery was mobilized, and an electromagnetic flowmeter probe (Howell Instrument, Oxnard, CA) was placed around the vessel. A hydraulic occluder constructed of PVC tubing (2.7 mm OD) was positioned around the artery distal to the flowmeter probe but proximal to any arterial branches. The catheters and flowmeter leads were tunneled subcutaneously to exit at the base of the neck. The pericardium was loosely closed, the thoracotomy repaired, and the dog allowed to recover. Exercise on the treadmill was resumed -1 wk after surgery, and studies were performed -2 wk after surgery when the animals were free from fever, anemia, or other evidence of ill health. Studies were performed with the dogs standing on the platform of a motor-driven treadmill. Aortic and left ventricular catheters were connected to Statham P23 ID pressure transducers at midchest level. The flowmeter leads were connected to a Statham model SP2202 electromagnetic flowmeter for measurement of left circumflex coronary blood flow. The zero flow baseline was established with 2-3 s total occlusions of the left circumflex coronary artery. Data were recorded on a HewlettPackard model 8800 eight-channel direct writing oscillograph. Before the study was started, the dogs underwent a 5 min period of warm-up exercise during which the exercise level was progressively increased to 6.0 km/h at a 15% grade. A 15.min rest period was allowed after warm-up exercise. During this time, propranolol (0.15 mg/kg iv) was administered. The adequacy of P-adrenergic blockade was assessed by examining the response of heart rate to isoproterenol (0.2 pg/kg iv) before and after propran0101. Hemodynamic variables were continuously monitored to ensure that steady-state conditions of heart rate and blood pressures existed before the study. Immediately before exercise was started, aortic and coronary sinus blood samples (1.0 ml) were withdrawn anaerobically for measurement of Paz, Pco~, pH, and hemoglobin, while hemodynamic measurements were obtained. Exercise was then begun at a rate of 5 km/h at a 1% grade. Two minutes after exercise was started. aortic and cor-
VENTRICULAR
HYPERTROPHY
onary sinus blood samples were withdrawn, while coronary blood flow and all pressures were recorded. After 3 min of exercise, the speed and grade of the treadmill were increased to 6 km/h at a 15% grade. Arterial and coronary sinus blood samples, as well as measurements of coronary blood flow and all pressures were obtained during the 3rd min of this exercise stage. Exercise was then discontinued, and the response to isoproterenol was examined again to assess the completeness of P-adrenergic blockade. After a l-h rest period, the response of arterial pressure to the arl-adrenergic agonist phenylephrine (2-6 pg/kg iv) was examined. The selective cul-adrenergic antagonist prazosin (100 pg/kg iv) was then administered to six dogs. In addition, a supplemental dose of propranolol (0.1 mg/kg iv) was administered and the response to isoproterenol again observed. The completeness of cyladrenergic blockade was assessed by repeating the dose of phenylephrine while observing the response of arterial pressure. The exercise protocol was then repeated, with hemodynamic measurements and coronary sinus and arterial blood sampling performed at rest and during the two exercise stages. Dogs were then allowed to rest for 1 h. After this time, propranolol (0.1 mg/kg) was again administered intravenously to six dogs. Nonselective cyadrenergic blockade was produced by administration of phentolamine (2.0 mg/kg in 5 dogs and 1.0 mg/kg in 1 dog). Measurements at rest and during the two exercise stages were repeated after administration of phentolamine. After the conclusion of exercise, the completeness of a-adrenergic blockade was tested by administration of phenylephrine as previously described, while the completeness of ,&adrenergic blockade was examined by administration of isoproterenol. Blood specimens were maintained in ice-cold syringes until completion of each exercise protocol; measurements of Po2, Pco~, and pH were performed with an Instrumentation Laboratory model 113 blood gas analyzer that was calibrated with known gas mixtures. Blood hemoglobin content was estimated by the cyanmethemoglobin method. Arterial and coronary sinus oxyhemoglobin saturations were estimated from the blood pH, POT, and temperature, using the oxygen dissociation curve for dog blood (26). Blood oxygen content was calculated as follows: O2 content (ml/dl): hemoglobin (g/dl) x 1.34x O2 saturation (%/lOO) + PoB (Torr) X 0.0031. An index of myocardial oxygen consumption was computed as follows: O2 consumption (ml) = left circumflex coronary artery blood flow (ml/min) X [O, content difference between aortic and coronary sinus blood (ml/dl)]/lOO. measurements were Data analysis. Hemodynamic taken directly from the strip chart recordings. A minimum of five beats were averaged for each measurement. Hemodynamic data, blood gas measurements, and myocardial oxygen consumption data were compared using analysis of variance for repeated measures. The change in each variable from rest to exercise level 1 and from rest to exercise level 2 were determined, and the effects of prazosin and phentolamine on the responses to exercise were examined using analysis of variance for repeated measures. A value of P < 0.05 was reauired for
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ADRENERGIC
EFFECTS
IN
LEFT
VENTRICULAR
H1491
HYPERTROPHY
statistical significance. When a significant value was found, individual comparisons were made using the Scheffe method.
during the second exercise level (P < 0.05). During control conditions, left ventricular end-diastolic pressure increased significantly during the first exercise level (P < 0.05),with a further significant increase at the second level of exercise. After prazosin, left ventricular endRESULTS diastolic pressure was not significantly different from Mean left ventricular weight for the seven dogs was control at rest or during the first level of exercise but 140.3t 13.6 g, while mean body weight was 16.4 t 1.3 was significantly less than control during the second kg. The mean left ventricular-to-body weight ratio was exercise stage. Similarly, after phentolamine left ventricular end-diastolic pressure was not significantly different 8.8 * 1.0g/kg. In a previous report from this laboratory, from control at rest or during the first exercise stage but the left ventricular-to-body weight ratio of normal adult mongrel dogs was found to be 4.3 -I- 0.2 g/kg (6). Thus was significantly less than control during the second the mean left ventricular-to-body weight ratio of the level of exercise (P < 0.05). animals used in this study was 105%greater than normal. Coronary blood flow, coronary sinus oxygen tension, Hemodynamic data are shown in Table 1. During and myocardial oxygen consumption are shown in Table control conditions, resting heart rates ranged from 96 to 2. During resting conditions, blood flow through the left 120 beats/min. Neither prazosin nor phentolamine sig- circumflex coronary artery ranged from 32 to 68 ml/min nificantly altered resting heart rates. During control (mean, 52 $- 4.5). Coronary blood flow increased 45 t conditions, heart rate increased significantly during the 11% during the first stage of exercise (P < O.Ol),with a first exercise stage, with a further significant increase further 27 t 4% increase during the second exercise stage during the second level of exercise. Heart rate was not (P < 0.01). Neither prazosin nor phentolamine signifisignificantly different from normal after prazosin during cantly altered coronary blood flow during resting condieither exercise level or after phentolamine during the tions. The increase in coronary blood flow in response to first exercise stage. However, after phentolamine heart exercise was significantly greater than control during rates were significantly faster than control during the exercise stage 2 after prazosin (P < 0.05) and during both second stage of exercise (P < 0.05). Mean aortic pressure exercise stages after phentolamine (each P < 0.01).Corranged from 65 to 100 mmHg during resting control onary blood flow was significantly greater than control conditions and did not change significantly in response during both exercise stages after prazosin and after phento exercise. Mean and diastolic aortic pressures tended tolamine (each P < 0.05). During control conditions to be lower after a-adrenergic blockade during resting coronary sinus oxygen tension decreased significantly conditions and was significantly less than control during from rest to the second stage of exercise (P < 0.02). In exercise after both prazosin and phentolamine (P < contrast to control conditions, coronary sinus oxygen 0.05). tension did not change significantly in response to exDuring control resting conditions, left ventricular sys- ercise after either prazosin or phentolamine. Thus the tolic pressure ranged from 198 to 290 mmHg (Table 1). change in coronary sinus oxygen tension during the second level of exercise was significantly less than conLeft ventricular systolic pressure increased significantly trol after both prazosin and phentolamine (P < 0.05). during the first level of exercise (P < 0.05),with a further During control conditions, myocardial oxygen consignificant increase at the second exercise level (P < sumption increased 39 t 8% from rest to the first exercise 0.05). Prazosin did not significantly alter left ventricular stage (P < O.Ol),with an additional 33 t 5% increase (P systolic pressure at rest or during either exercise level. After phentolamine, left ventricular systolic pressure was < 0.01) at the second level of exercise (Table 2). Neither not different from control at rest or during the first phentolamine nor prazosin significantly altered myocarexercise level but was significantly greater than control dial oxygen consumption at rest. However, the change in
Rest
Exl Al
EX2 A2
107 &5 165 *9f+58 6 203 +7t +96 t4
110 &6 172 +8t +61 &6 204 +7t +94 t6
116 k4 189 +8t +89 zk5 235 *9*t$ +119 *9*$
108/71 &8/5 108/61 +7/4 o/-10 +4/3 115/58 +6/3 +7/-13 +3/3
95165 *8/2 93144 +9/4 -21-21 +2/3 109/46 +6/2 +14/-19 +2/4
Values are means & SE. Con, control (n = 7); Praz, rest to exercise stage 1 (Ed); A2, difference from rest rest. $ P < 0.05 compared with prazosin.
91/60 &6/4 92143 rt7/6 +1/-17 2214 107146 k6/4 +16/-15 +3/4
83 t4 79 k4 -4 t2 79 t3 -4 t3
78 t4 64 +4*t -13 t3” 72 t3* -6 t3
71 t5* 64 *5*t -7 k2 69 k4* -2 t2
228 t14 269 +14t +41 *lo 308 +20t +80 t16
208 *21 272 +22-f +64 t22 310 +19t +102 t29
207 t11 288 +24t +81 t18” 348 +21*Q +141 +17”$
6 t1 10 +rt +4 z?zl 13 ,+1t +7 t1
6
6
tl
t2
9 *1t +4 t1 10 *l*t +5 *1
8 +1 +2 t2 11 +1*t +5 rtl
prazosin (n = 6); Phen, phentolamine (n = 6); LV, left ventricular; Al, difference to exercise sbge 2 (Ed). * P < 0.05 compared with control. 7 P < 0.05 compared
from with
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H1492
ADRENERGIC
EFFECTS
IN LEFT
VENTRICULAR
HYPERTROPHY
TABLE 2. Coronary blood flow, coronary sinus PO,, and myocardial oxygen consumption at rest and during 2 stages of treadmill exercise during control conditions, after a+drenergic blockade with prazosin, and after nonselective a-adrenergic blockade with phentolamine Coronary Eiercise Stage
Blood Flow, ml/min
Con
Rest Exl
Praz
52k4.5 73*4.5t +21&3.6
Al
Ex2
87&6.7t
A2
Coronary
+35*3.6
59k7.1 92+,11.8*t +33&6.2* 116*14.0*t +57&7.8*
Phen
Con
53k5.9 107+12.6*t +54+7.6’s 127+13.0*t 74t7.8”
Sinus P02, Torr Praz
18.1k1.5 17.0t1.5 -1.kkO.6 15.2*1.1t -2.9t0.8
Myocardial Con
Phen
19.OH.3 17.4kO.9 -1.5t0.9 18.Okl.O” -l.o~l.z*
18.5t1.0 18.6t1.1 +0.1*1.5 19.0*1.9* t0.5t1.8”
Values are means k SE. Con, control (n = 7); Praz, prazosin (n = 6); Phen, (Exl); AZ, difference from rest to exercise stage 2 (Ex2). * P < 0.05 compared
O2 Consumption, ml/min Praz
6.12t0.72 8.28&0.76-f +2.16t0.44 10.31~0.91~ +4.20t0.79
6.56k0.72 10.83+1.50*t +4.27t0.96* 12.80+1.79*t +6.24&0.99*
Phen 6.18k0.76 12.30*1.32*t +6.12+0.78*$ 14.38+1.81*7 +8.20t1.34*
phentolamine (n = 6); Al, difference from rest to exercise stage 1 with control. -t P < 0.05 compared with rest. $ P < 0.05 compared
wtih prazosin.
myocardial oxygen consumption was significantly greater than control after both prazosin and phentolamine during both exercise stages (each P < 0.05). The change in myocardial oxygen consumption from rest to exercise stage 1 was greater after phentolamine than after prazosin (P < 0.02) but not for exercise stage 2. As shown in Fig. 1, during control conditions, the increase in myocardial oxygen consumption was directly proportional to the increases in heart rate and the heart rate times left ventricular systolic pressure (rate-pressure product). The slopes of both of these relationships were significantly increased by prazosin, so that increases in heart rate and rate-pressure product produced greater increases of myocardial oxygen consumption after prazosin than during control conditions (P c 0.05). Phentolamine also increased the slopes of both of these relationships, but this did not achieve statistical significance. DISCUSSION
The present study demonstrates that a-adrenergic vasoconstriction limits coronary blood flow during exercise in the chronically pressure overloaded, hypertrophied left ventricle. The concept that adrenergic vasoconstriction can oppose metabolic coronary vasodilation during exercise was originally proposed by Murray and Vatner (25). Using normal dogs pretreated with propran-
-
0 y = 0.0447x A y - 0.0628% n y = 0.0782x
+ 1.15 - 0.20 - 2.90
I
4
I I
I I
I I
125
175
225
Heart
Rate
(beats/min)
0101, these investigators found that left circumflex coronary artery blood flow during exercise was 17% higher after nonselective cr-adrenergic blockade with phentolamine than during control conditions. The effect of CYadrenergic blockade appeared greater in the present study, with coronary blood flow during exercise stage 2 being 33% higher than control after prazosin and 46% greater than control after phentolamine. The greater effect of ar-adrenergic blockade in this study suggests that adrenergic restraint of coronary blood flow during exercise is greater in hypertrophied than in normal hearts. This may be because exercise represents a greater stress in hypertrophied hearts, because of the exaggerated increase in left ventricular systolic pressure that occurs during exercise in the presence of left ventricular outflow obstruction. Thus, in the normal dogs studied by Murray and Vatner (25), left ventricular systolic pressure increased 10 t 8 mmHg in response to exercise, whereas in the present study left ventricular systolic pressure increased 80 t 16 mmHg during exercise stage 2. The greater exercise-imposed stress in the present study may have resulted in greater activation of the sympathetic nervous system in the animals with hypertrophy. The greater increase in coronary blood flow during exercise after cu-adrenergic blockade was not merely luxuriant flow, because it resulted in a significant increase in myocardial oxygen consumption. This finding suggests
I
0 y = 0.000100x
+ 3.84
--
A y - 0.000162x l y = 0.000173x
+ 2.81 + 2.63 FIG. 1. Myocardial oxygen consumption plotted against heart rate (A) and heart rate times systolic left ventricular pressure product (B) at rest and during 2 exercise stages. Data are shown during control conditions (circles), after prazosin (100 pg/kg iv; triangles), and after phentolamine (l-2 mg/kg iv; squares). Slopes of both relationships were increased after prazosin (P < 0.05).
0
II
I I
I I
25
50
75
Rate-Pressure
Product
100 x 1 Om3
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ADRENERGIC
EFFECTS
IN
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that myocardial oxygen consumption during exercise was limited by adrenergic restraint of coronary blood flow. Abnormal perfusion in the hypertrophied heart generally has been attributed to structural alterations of the coronary vasculature (24). Hypertrophy of cardiac myocytes results in vascular rarefaction, and this is believed to be responsible for impairment of minimum vascular resistance during maximum coronary vasodilation (1, 6, 24). The present findings imply that in addition to structural abnormalities of the coronary vasculature, adrenergic vasoconstriction may also limit coronary blood flow during exercise. It generally has been assumed that local metabolic factors outweigh central control of the coronary resistance vessels. However, recent studies have demonstrated that ar-adrenergic vasoconstriction may limit blood flow even during coronary hypoperfusion. In open chest normal dogs, Liang and Jones (22) found that after decreasing coronary perfusion pressure sufficiently to reduce coronary blood flow and decrease myocardial oxygen consumption, al-adrenergic blockade with prazosin caused a significant increase in blood flow that was associated with an increase in myocardial oxygen consumption, demonstrating that adrenergic vasoconstriction had contributed to the impairment of myocardial oxygen delivery. In chronically instrumented exercising dogs in which a stenosis reduced distal coronary pressure to 40 mmHg and decreased myocardial blood flow to 37% of control, Laxson et al. (21) found that intracoronary prazosin caused a 50 t 14% increase in blood flow with no change in perfusion pressure. The increase in blood flow produced by prazosin caused improvement of systolic shortening in the area perfused by the stenotic coronary artery. These studies indicate that in the normal heart, adrenergic coronary vasoconstriction may oppose metabolic vasodilation, even during hypoperfusion sufficient to reduce myocardial oxygen consumption and impair contractile performance. In the pressure-overloaded hypertrophied left ventricle, exercise results in redistribution of blood flow toward the epimyocardium with relative subendocardial underperfusion (2,7). Although al-adrenergic blockade caused an increase in coronary artery blood flow during exercise, the effect of cw-adrenergic blockade on the transmural distribution of perfusion was not determined. This may be of importance, because Feigl (10) has suggested that ar-adrenergic activity may cause preferential vasoconstriction of resistance vessels in the subepicardium, thereby diverting blood to the subendocardium. This could be of importance in the hypertrophied heart where subendocardial underperfusion is especially likely to occur during exercise. Further studies will be needed to determine the effect of cx-adrenergic blockade on the transmural distribution of perfusion during exercise in the hypertrophied heart. Previous studies in normal hearts have yielded conflicting data regarding the relative importance of postjunctional a!1- and az-adrenoceptors in mediating adrenergic coronary vasoconstriction. Several investigators have reported that coronary vasoconstriction produced by intra-arterial norepinephrine or by electrical stimulation of cardiac sympathetic nerves was only slightly blunted bv al-adrenergic blockade with prazosin but was
VENTRICULAR
markedly
HYPERTROPHY
attenuated
H1493
by tug-blockade with rauwolscine
(15, 19). In contrast, adrenergic coronary vasoconstriction during exercise in normal dogs appears to be mediated principally by arl-adrenoceptors. Thus Strader et al. (27) and Dai et al. (9) demonstrated that in normal dogs coronary blood flow during exercise was increased by intracoronary administration of prazosin but not by the selective ar2-adrenergic antagonists idazoxan or yohimbine. The present data demonstrate that adrenergic restraint of coronary blood flow during exercise in the hypertrophied heart is also mediated principally by aladrenoceptors. In agreement with previous studies in normal dogs, neither prazosin nor phentolamine caused a significant increase of coronary blood flow or coronary sinus oxygen tension during resting conditions (5, 9). Similarly, Chilian et al. (8), using epicardial application of phenol to produce regional sympathectomy in normal dogs, found no difference in blood flow between sympathectomized and normal myocardial areas during resting conditions. The failure of a-adrenergic blockade to increase coronary blood flow during resting conditions in the present study indicates that adrenergic vasoconstriction does not limit resting coronary blood flow in the hypertrophied heart. The present study was carried out under conditions of P-adrenergic blockade with propranolol. This was done to blunt ,&adrenergic stimulation that may occur after nonselective a-adrenergic blockade. Prejunctional cy2adrenoceptors inhibit central sympathetic outflow and modulate norepinephrine release by noradrenergic nerve terminals (20, 23). By blocking prejunctional cx2-adrenoceptors, phentolamine interrupts negative feedback control of norepinephrine release (20). The resultant increase in P-adrenergic stimulation could cause increased myocardial oxygen consumption with a secondary increase in coronary blood flow (13, 17). Although the dose of propranolol used in the present study antagonized the response to isoproterenol and blunted the normal increase in heart rate during exercise, heart rate during the second stage of exercise was significantly faster after phentolamine than during control conditions. This suggests that the dose of propranolol used did not completely block the increased P-adrenergic activity produced by phentolamine. Unfortunately, larger doses of propranolol could not be used because they resulted in inability to complete the exercise protocol in these animals with left ventricular hypertrophy. Clearly, the faster heart rates during exercise after phentolamine would have contributed to the observed increase in myocardial oxygen consumption. To take into account the effects of the faster heart rate after phentolamine, myocardial oxygen consumption was plotted relative to heart rate and the heart rate times left ventricular systolic pressure product. This demonstrated that the increase in myocardial oxygen consumption during exercise after phentolamine was greater than expected for the change in heart rate or rate-pressure product. In addition, although prazosin caused no change in heart rate or rate-pressure product, myocardial oxygen uptake was 24 t 7% higher during the second level of exercise after prazosin than during control exercise. This finding supports the concept that adrenereic coronarv vasoconstriction limited
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H1494
ADRENERGIC
EFFECTS
IN LEFT
myocardial oxygen consumption during exercise. Despite differing effects on heart rate and the ratepressure product, prazosin and phentolamine caused similar shifts of the relationship with myocardial oxygen consumption to a new line with a slope greater than control. The finding that both agents caused similar relative increases in myocardial oxygen consumption implies that the sympathetic restraint of coronary vasodilation during exercise resulted principally from cyladrenergic coronary vasoconstriction. If postjunctional az-adrenoceptors had also contributed to coronary vasoconstriction during exercise, then phentolamine should have caused further upward displacement of the curve relating coronary blood flow to the rate-pressure product above that produced by prazosin. This did not occur, indicating that after cul-adrenergic blockade, the addition of az-blockade did not cause further coronary vasodilation. In summary, this study demonstrates that adrenergic coronary vasoconstriction opposes coronary vasodilation during exercise in the chronically pressure overloaded, hypertrophied left ventricle. Restraint of coronary blood flow during exercise was principally the result of cyladrenoceptor-mediated coronary vasoconstriction with little additional effect from postjunctional cw2-adrenergic mechanisms. The data indicate that restraint of coronary blood flow by adrenergic vasoconstriction can limit myocardial oxygen delivery during exercise in the chronically hypertrophied left ventricle. The authors acknowledge expert technical assistance provided by Todd Pavek, Melanie Crampton, Paul Lindstrom, and Eugene Sublett. This work was supported by National Heart, Lung, and Blood Institute Grants HL-21872, HL-20598, and HL-34701. Address for reprint requests: R. J. Bathe, Box 338 UMHC, Univ. of Minnesota, Minneapolis, MN 55455. Received 5 February 1990; accepted in final form 19 December 1990. REFERENCES D., R. W. ANDERSON, D. G. PARRISH, X. DAI, AND R. J. Persistence of regional left ventricular dysfunction following exercise-induced myocardial ischemia in conscious dogs. J. Clin. Invest. 77: 66-73, 1986. 2. BACHE, R. J., D. ALYONO, X. DAI, T. R. VROBEL, D. G. PARRISH, AND D. C. HOMANS. Myocardial blood flow during exercise in left ventricular hypertrophy produced by aortic banding and perinephritic hypertension. Circulation 76: 835-842, 1987. 3. BACHE, R. J., C. E. ARENTZEN, A. B. SIMON, AND T. R. VROBEL. Abnormalities in myocardial hypertrophy: metabolic evidence for myocardial ischemia. Circulation 69: 409-417, 1984. 4. BACHE, R. J., AND X. DAI. Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis. J. Am. CoLZ. Cardiol. 15: 11571. ALYONO, BACHE.
1164,199O. 5. BACHE, R.
J., X. DAI, C. A. HERZOG, AND J. S. SCHWARTZ. Effects of nonselective and selective alphal-adrenergic blockade on coronary blood flow during exercise. Circ. Res. 61: 11-36-11-41, 1987. 6. BACHE, R. J., T. R. VROBEL, C. E. ARENTZEN, AND W. S. RING. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy. Circ. Res. 49: 742-750, 1981. 7. BACHE, R. J., T. R. VROBEL, W. S. RING, R. W. EMERY, AND R. W. ANDERSON. Regional mvocardial blood flow during exercise in
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