Effect of age on cardiovascular responses to static muscular contraction in beagles GEORGE

C. HAIDET

Department of Internal Medicine, Dallas, Texas 75235-9034

University

of Texas Southwestern

HAIDET,GEURGEC.E~~~C~~~~~~~~ cardiovascularresponses contraction in beagles. J. Appl. Physiul. 73(6): 2320-2327, 1992.~Induced muscular contraction in anesthetized animals results in significant hemodynamic and regional blood flow (RBF) changes.Although reflex cardiovascular responsesinitiated in contracting musclehave been firmly established, little is known about the effects of age on these responses.Becauseother reflex responsesthat involve sympathetic activation appear to be attenuated with age, it was hypothesizedthat reflex efferent cardiovascular responsesthat normally occur during muscularcontraction would be impaired in senescent dogs. Therefore, hemodynamic and RBF responsesto induced static hindlimb contraction (HLC) were evaluated in 8- to 14- and 2- to 3-yr-old beaglesduring cu-chloraloseanesthesia.Must baselinehemodynamicparameterswere similar in both groups, but heart rate was significantly (P < 0.05) higher in old dogs. During HLC, heart rate and blood pressure increased in the young and old dogs. However, increasesin stroke volume and cardiac output were greater in old dogs, combined with a reduction in systemic vascular resistance not observedin young dogs.No age-relateddifference in baselineRBF (microspheres)was observed in six of eight abdominal regional circulations and in each of four skeletal muscle groups. During HLC, RBF reductions occurred in six uf eight abdominal organs in young and old dogs. However, the reduction in RBF and concomitant increasein vascular resistance in all eight abdominalregionscombinedwas almosttwice asgreat in young vs. old dogs.In noncontracting skeletal muscle, RBF decreasedand vascular resistance increased four times more In young vs. old dogs. By contrast, there were no age-relateddifferencesin RBF increasesto contracting muscle. Thus, cardiac output, aswell asblood flow to contracting muscle groups, is maintained with age during HLC in the beagle. However, an age-related attenuation in reflex-mediated vasoconstriction appearsto occur in circulations that are not metabolically active. Hence, somebut not all reflex cardiovascular responsesto HLC appearto be impaired with agein the beagle. to static muscular

blood flow; dogs;hemodynamics;isometric exercise; reflexes

THE ACUTE cardiovascular

responses to static exercise are thought to be mediated by a series of complex interactions between neural, humoral, and hormonal influences. Substantial evidence suggests that central neural impulses, afferent reflex responses originating in contracting muscle, and metabolic products of muscular contraction each may contribute to the reflex efferent responses to muscular contraction (15,17,18). By contrast, few studies have evaluated the effects of age on cardiovascular reflexes. Those studies that have been performed 2320

Medical

Center,

suggest that aging is associated with impaired arterial and cardiopulmonary reflexes, dependent in part on the effects of reflex sympathetic stimulation (5,6,11,12,24). However, the effects of age on reflex responses to static muscular contraction, also dependent in part on reflex sympathetic activation, have not been clearly elucidated (22). Studies in anesthetized animals have provided significant insights into the mechanisms responsible for the reflex responses to static muscular contraction. These studies have been particularly helpful because they have contributed to the understanding of the role of the peripheral factors that contribute to these responses (18). Dogs have frequently been used in these studies to evaluate factors that contribute to both the afferent and efferent responses to static muscular contraction (3,7,8,16). In these experiments, static muscular contraction has been induced via electrical stimulation of the severed peripheral ends of ventral spinal nerve roots, producing cardiovascular responses similar to those that occur during static exercise. This technique eliminates the role of central neural impulses in the initiation of the cardiovascular responses to muscular contraction. However, this experimental methodology has not been used to evaluate the effects of aging on the cardiovascular responses to static muscular contraction. In fact, there are no published reports of the effects of age on afferent or efferent responses to muscular contraction in conscious or in anesthetized animals. In the present study, therefore, the effects of age on cardiovascular (i.e., hemodynamic and regional blood flow) responses to induced static muscular contraction were evaluated by comparing these responses in older and in younger beagles. Other reflex cardiovascular responses that are dependent, at least in part, on reflex sympathetic activation appear to be impaired with age in the dog. Therefore, the following hypotheses were tested. Reflex efferent cardiovascular responses that normally occur during muscular contraction would be impaired with age in the dog and would result in 1) an attenuation in the normal cardiac output response (3, 7,8,16); 2) an attenuation in the normal increase in blood flow to contracting skeletal muscles that occurs during muscular contraction in dogs (4,7,8); and 3) an attenuated reduction in blood flow in abdominal regional circulations, normally mediated by reflex vasoconstriction in these areas (4, 7,8).

0161~7567792 $2.00 Copyright 0 1992 the AmericanPhysiological Society

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AGING

AND RESPONSES

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METHODS

The experimental procedures used in this study were reviewed and approved by the University of Texas Southwestern Medical Center Animal Resources Committee and conformed with institutional and National Institutes of Health Guidelines. Animal selection. Eighteen senescent (8-14 yr old) beagles (old) and 18 younger mature (2-3 yr old) beagles (young) were used in this study. Older beagles weighed 10.76 t 0.36 kg, and younger dogs weighed 10.20 t 0.31 kg. All dogs were obtained from sources where accurate and complete birth and health records could be supplied for each animal, All animals were free of infectious diseases. Surgical instrumentation. Anesthesia was induced with thiopental sodium (35 mg/kg iv) and then maintained by the intravenous administration of a 10% solution of achloralose in polyethylene glycol (40-80 mg/kg). Additional doses of a-chloralose (5-10 mg/kg) were given hourly to maintain anesthesia. Animals were ventilated by a Harvard ventilator after endotracheal intubation. Arterial blood gases were monitored periodically during surgical instrumentation, as well as during the experimental protocol. Arterial blood gases and pH were measured using a blood gas and pH analyzer (ABL-3 AcidBase Laboratory, Radiometer). Ventilation was modified as required to maintain the arterial PO, > 80 Torr and PCO, between 30 and 40 Torr. Arterial pH was maintained between 7.35 and 7.45 by the administration of intravenous sodium bicarbonate as required. A catheter was inserted into the external jugular vein and advanced into the pulmonary artery for dye injections during cardiac output determinations. In addition, catheters were inserted via both brachiai arteries and advanced into the thoracic aorta for arterial blood pressure monitoring and blood sampling. A left ventricular or left atria1 catheter was inserted in retrograde fashion via the common carotid artery for microsphere injections. A lumbar laminectomy was performed and ventral spinal nerve roots were carefully exposed and isolated as previously described (3, 7, 8, 16). Each animal was then raised above the operating table in the prone position and fixed at the hips, as well as at the spinous process of the L, vertebra, with a modified Eccles Canberra frame to ensure immobility of the spine. In addition, the ipsilatera1 hindlimb was fixed with clamps to prevent movement during static hindlimb contraction. Ventral spinal nerve roots L, and L, were sectioned close to their exit from the spinal cord: The distal portions of these nerves were placed across bipolar silver chloride stimulating electrodes. To maintain viability of the nerve preparation and to prevent drying, mineral oil maintained at 37OC was pooled over the exposed spinal cord and nerve roots. An electronic stimulator (model SSS, Grass Instruments) was used to induce static hindlimb contraction for 1 min during blood flow determinations and was repeated ~30 min later for 2 min during the evaluation of the cardiac output response to muscle contraction in both groups of dogs. A cathodal stimulus of 0.2-ms duration, 40 Hz, and 5-10 times motor threshold voltage was used to induce static hindlimb contrac-

CONTRACTION

2321

tion during regional blood flow and cardiac output determinations. The stimulus duration and voltage used were each at least 10 times less than those durations and voltages reported to produce sympathetic efferent responses in mixed nerves (14, 26). Hemodynamic measurements. Each study was performed aft !er an overnight fast. The temperatu re of the laboratory was controlled and w pasthe same for al .l studies at 22.S23.7OC. Hemodynamic variables were measured in all dogs before induced muscular contraction, as well as during l-2 min of induced static hindlimb contraction. Arterial blood pressure was monitored via one thoracic aortic catheter connected to a fluid- filled transducer (Statham model P5O, Gould). Heart rate was measured from the aortic pressure tracing. These values were recorded on an oscillbgraph (model 28005, Gould). Cardiac output was measured by the dye-dilution technique with use of a cardiac output computer and recorder (model CO-lOR, Waters Instruments). Stroke volume was calculated as the ratio of cardiac output, to a concurrently measured heart rate. Systemic vascular resistance (SVR), reported in peripheral resistance units (mmHg 1-l min), was calculated as the ratio of mean arterial pressure to cardiac output. Measurement of regional blood flow. Regional blood flows were measured by use of the radioactive microsphere technique (13) as previously described (10, 19). Microspheres were placed in a sonicator and shaken for 260 min before injection to assure that microsphere aggregates were broken up. Microspheres (2-4 X 106, 15 pm diam, total activity 20-40 &i) were injected via a left ventricular or left atria1 catheter and flushed with 20 ml of 37°C saline. Microspheres were injected during a baseline control period with concurrent hemodynamic measurements before induced static hindlimb contraction. Microspheres were also injected at the peak of the pressor response during a 60-s isometric contraction, within 15-30 s of the onset of muscular contraction. Beginning with the injection of microspheres, reference arterial blood samples were obtained from an aortic catheter (13). Microspheres with the following gamma-emitting radioactive labels were randomly chosen: *6Sc 85Sr, ‘13Sn, 57Co, and g5Nb= After the completion of the Study, each dog was killed with an overdose of intravenous pentobarb&l sodium. Tissue samples were obtained from each dog, and tissue radioactivity was measured with a multichannel gamma scintillation counter (model 233862, Packard Instruments). Regional blood flows were calculated by the reference sample method (13). Adequate mixing of microspheres was verified for each injection by demonstrating ~20% difference between blood flows to paired organ samples. Four muscles of the hindlimb (gastrocnemius, semimembranosus, semitendinosus, and biceps femoris) were chosen for muscle blood flow statistical analysis in this study, after blood flow data for each skeletal muscle in the hindlimb were examined in pilot studies that I performed. These four muscles were chosen because they were the only muscles in the hindlimb that consistently contracted and also consistently demonstrated increased blood flow during induced static hindlimb contraction. Blood flow value&to these muscles in the ipsilateral limb l

l

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AGING AND RESPONSES - Cardiac

Output

Heart

TO MUSCULAR

Rate

- Stroke

CONTRACTION Volume

170

t

T

/ ----s -P t ~ c/ I

I

CONTROL

- Mean

‘I

STATE

Arterial

Pressure

I CONTROL

STATIC

Systemic Vascular Resistance

CONTROL

1 STATIC

FIG. 1. Hemodynamic variables determined during baseline (control) and induced static muscular contraction (static) in 18 older beagles (old) and 18 younger mature beagles (young). Values are means k SE. PRU, peripheral resistance unit (mmHg 1-l * min). * P < 0.05, control vs. static. t P < 0.05, old vs. young, response to static. $ P < 0.05, old vs. young, control values. l

f

1 STATIC

CONTROL

STATIC

have been designated as %untracting.” Blood flow values to the same muscles of the contralateral limb were used as a control and have been designated as “noncontracting.” Data analysis. Statistical analyses of the reduced data included calculation of means + SE and the application of analysis of variance (ANOVA) techniques for withinand between-group analyses (23). Combined blood flow responses to the group of eight abdominal organs, as well as to the group of four contracting and four noncontracting muscles, were also evaluated by ANOVA. Betweengroup (old vs. young) comparisons during resting control were determined using the unpaired t test technique, except in instances in which requirements for normality were not present, when the Wilcoxon rank-sum technique was applied. The 0.05 probability level was selected to determine statistical significance. RESULTS

Effect of ageon hemodynamic responsesto static muscular contraction. Hemodynamic variables obtained in older

and younger mature beagles during baseline (control) and static hindlimb contraction (static) are presented in Fig. 1. Baseline cardiac output (l/min) was similar in the older and in the younger mature beagles. However, the cardiac output response to static hindlimb contraction was significantly greater in the older group than in the younger group. Baseline heart rate (beats/min) was also greater in the older than in the younger dogs. However, the increase in heart rate in response to isometric exercise was similar in both groups of beagles. Baseline stroke volume (ml/beat) was not significantly different in the two groups. However, the stroke volume response

to static hindlimb contraction was greater in the older than in the younger beagles. Baseline mean arterial pressure (mmHg) was similar in the older and younger dogs (Fig. 1). In addition, similar significant increases in mean arterial pressure in response to induced hindlimb contraction were observed in both groups. Furthermore, there were no significant agerelated differences in systolic or diastolic arterial blood pressures at baseline, as well as during static contraction. Baseline values for SVR (mmHg l min = peripheral resistance unit) were not significantly different in the old and young dogs. The changes in SVR in response to static hindlimb contraction were significantly different in the two groups, however, with a reduction occurring in the older dogs vs. a small increase in the younger beagles. 1-l

l

Effect of age on regional blood floLo responses to static hindlimb contraction. There were no significant differ-

ences in any of the baseline blood flows to skeletal muscle. Absolute blood flows (ml. 100 g tissue-‘. min-‘) to each of the four muscles were not significantly different with respect to age, as well as to whether the muscle was subsequently designated as contracting or noncontracting (Fig. 2). In addition, age-related similarities and differences in calculated regional vascular resistance at baseline, as well as during static muscular contraction, were generally similar to the age-related similarities and differences reported for regional blood flows in each skeletal muscle group because of the marked similarity in mean arterial pressure in the young and old dogs at baseline and during muscle contraction. During induced static muscular contraction, there was a significant increase in blood flow to each of four skeletal muscle groups evaluated in the contracting limb in the older and in the younger dogs (Fig. 2). To further

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AGfNG

Gastrocnemius

0 Young

T

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Gastrocnemius

AND RESPONSES

TO MUSCULAR

Semitendinosus

Semimembranosus

Biceps

2323

CONTRACTION Femoris

60

- CONTROL

STATIC

- CONTROL

- CONTROL

Semitendinosus

Semimembranosus 16 -

STATIC

16 -

I

Biceps

STATIC

Femoris

77 10 -

FIG. 2. Regional blood flows to skeletal muscle groups during baseline (control) and induced static muscular contraction (static) in ipsilateral (contracting) limb (top) and contralateral (noncontracting) limb (bottom) in 18 older beagles (old) and 18 younger mature beagles (Goung). Values are means t SE. * P < 0.05, control vs. static. T P < 0.05, old vs. young, response to static. (No significant age-related differences for control values.)

9878-

l Old

CONTROL

STATIC

CONTROL

STATIC

6-

CONTROL

STATIC

compare the combined effect of blood flow changes in all four contracting muscles during induced muscular contraction, the significance of the blood flow response (from baseline to static muscular contraction) was determined for all four contracting muscles. In each dog, baseline blood flows to all four muscles were added together, as were blood flow values obtained during muscular contraction. The pooled values (baseline and muscular contraction) in each dw were then directly compared in both the younger and the older age groups. As expected, there was a significant change in the combined blood flow response from baseline to muscular contraction to all four contracting muscles in both the younger (49 & 6 to 152 -t 14 ml e100 g-l min-l) and the older (51 t 7 to 189 t 24 ml 4100 g-l min-l) beagles. The sum of the changes in blood flow (muscular contraction-baseline) was then determined for all four muscles in each dog, and these pooled blood flow responses were directly compared in the older and younger dogs. The mean increase in blood flow to all four contracting muscles was not significantly different in the older (138 t 21 ml 100 g-l. min-‘) vs. the younger dogs (103 t 12 ml 100 g-l min-‘). By contrast, blood flows to the individual muscle groups in the noncontracting limb either decreased or did not change during induced static hindlimb contraction (Fig. 2) in the older and in the younger dogs. Blood flow decreased significantly in the semimembranosus in both old and young beagles. However, the extent of blood flow reduction to the gastrocnemius was significantly greater in the younger vs. older dogs. The overall blood flow response to the group of four muscles in the noncontracting limb was also evaluated to further compare the combined effect of blood flow changes in all four noncontracting muscles duri ng induced must ula .r contraction. In each dog, the blood flow values obtained in all four l

l

l

l

l

CONTROL

STATIC

noncontracting muscles were summed at baseline, as well as during induced muscular contraction. Then, the significance of the pooled blood flow response to all four noncontracting muscles (muscular contraction vs. baseline) was determined in both the younger and older dogs. Blood flow decreased in all four noncontracting muscles from 39 & 3 to 25 t 4 ml 100 g-l min-l in the younger dogs vs. from 43 t 6 to 40 t 5 ml 100 8-l. min-l in the older dogs, with a pooled change in blood flow in the noncontracting muscles of -3 * 7 ml. 100 g-l min-’ in the older dogs vs. -14 t 4 ml. 100 8-l. min-l in the younger dogs. This represents a significant reduction in the combined blood flow response from baseline to muscular contraction in all four noncontracting muscles in the younger dogs vs. no significant change from baseline in the older dogs. Regional blood flow values obtained during baseline (control) as well as during induced static muscular contraction (static) for eight abdominal regions (including the kidney) are presented in Fig. 3. Age-related similarities and differences in calculated regional vascular resistance at baseline and during static muscular contraction were generally similar to the age-related similarities and differences reported for regional blood flows in each abdominal organ because of the marked similarity in mean arterial pressure in the young and old dogs at baseline and during muscular contraction. Baseline blood flows were not significantly different in both groups of dogs in the stomach, large intestine, pancreas, and spleen. Furthermore, in each of these four regional circulations, significant blood flow reductions occurred in the older and younger dogs in response to static muscular contraction. In the kidney, baseline blood flow was 30% lower in the old dogs compared with the young dogs (Fig. 3). However, the blood flow response to static muscular contracl

l

l

l

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AGING AND RESPONSES TO MUSCULAR CONTRACTION -

Large Intestine

Small Int

_

Stomach

Kidney

-T-

\ l

‘9 *

Old

FIG. 3. Blood flow to individual abdominal organs during baseline (control) and induced static muscular contraction (static) in 18 older beagles (old) and 18 younger mature beagles (young). Values are means t SE. * P < 0.05, control vs. static. t P < 0.05, old vs. young, response to static. $ P c 0.05, old vs. young, control values.

0 Young STATIC

CONTROL

-

STATIC

CONTROL

CONTROL

Adrenal

Pancreas

STATfC

80

Spleen 180

t

‘I CONTROL

STATIC

CONTROL

STATIC

CONTROL

STATIC

tion was not significantly different in the two groups. Unlike in the kidney, baseline blood flow in the liver (via hepatic artery) was higher in the older than in the younger beagles. However, as in the kidney and in six of the eight splanchnic regions evaluated, a reduction in hepatic blood flow occurred during static muscular contraction in both groups, with similar significant reductions observed in both the older and in the younger dogs. In the adrenal, baseline blood flow was not different in the older and younger beagles (Fig. 3). However, there was a significant age-related difference in the blood flow response to static hindlimb contraction. As in the adrenal, no age- related difference in baseline blood flow was observed in the small intestine. Furthermore, the blood flow response to static hindlimb contraction was not statistically different in the young and old dogs because of the variability in blood flow responses in the small intestine. The overall blood flow response to all eight abdominal organs was also evaluated in the older and in the younger dogs to further compare the combined effect of blood flow changes that occurred during muscular contraction in all eight abdominal organs evaluated in this study. In each dog, blood flow values obtained in each of the eight abdominal organs were summed at baseline, as well as during induced muscular contraction. Then, the significance of the pooled blood flow response to all eight I abdominal organs (mu scular contraction vs. baseline) was determined in the younger and older dogs. There was a significant change in the combined blood flow response from baseline to muscular contraction to all eight abdominal organs in both the older (783 t 61 to 667 t45 ml. 100 g -I. min-I) and in the younger (875 t 97 to 628 t 77 ml. 100 g-l min-‘) dogs. Then, the sum of the changes in blood flow from baseline to induced muscular contracl

STATIC

CONTROL

r

Liver

I

I

CONTROL

STATIC

0I

tion was calculated for each of the eight abdominal circulations in each dog, and these pooled blood flow responses were directly compared in the older vs. younger dogs. Although the pooled reduction in blood flow was significantly changed from baseline in both the older (-116 t 49 ml. 100 g-l min-I) and in the younger (-247 t 44 ml 100 g-l smin-‘) dogs, there was an agerelated difference in the combined blood flow response to the group of all eight abdominal organs. The change that occurred in the younger dogs was significantly more profound than the change that occurred in the older dogs. In both the older and the younger mature beagles, there were no differences in absolute blood flow to the heart at baseline in the older dogs vs. younger dogs (266 t 31 vs. 195 t 26 ml. 100 8-l. min-l). In addition, myocardial blood flow was unchanged during induced muscular contraction in both the old (246 t 26 ml 100 g -I min-‘) and young (194 t 23 ml 100 8-l. min-‘) dogs. l

l

l

l

l

DISCUSS1ON

Effect of age on hemodynamic responsesto static muscular contraction. The normal left ventricle responds to the

increased afterload that usually Occurs during static muscular contraction with only a small increase in diastolic pressure (l&22). There is a concomitant increase in the contractile state of the myocardium that appears to be mediated, at least in part, by reflex activation of the adrenergic nervous system and resultant ,&adrenergic stimulation (18, 22). These findings suggest that the Frank Starling mechanism normally is not required to meet the imposed stress that reflexly occurs during static muscular contraction (22). Thus, because inotropic and chronotropic responses both appear to be attenuated in the myocardium of the aging beagle (25,28), the relative

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AGING AND RESPONSES

TO MUSCULAR CONTRACTION

increase in heart rate and stroke volume, with resultant augmentation of the cardiac output response to static muscular contraction in the older vs. the younger beagles in this study, was unexpected. These augmented responses to hindlimb contraction may be related to an age-related reduction in left ventricular afterload, reflected by the reduction in SVR observed in the older dogs during induced muscular contraction. In addition, a possible contribution from augmented left ventricular filling during muscular contraction cannot be excluded because left ventricular dimensions were not measured during this study. The observed increase in heart rate during induced hindlimb contraction in both groups of dogs in this study is similar to the increases noted previously in dogs (3, 7, 8,16). Thus the heart rate response to muscular contraction in this study was not altered with age. By contrast, an age-related attenuation in the heart rate response to static exercise has been observed in conscious humans (18,22). However, the percentage, as well as the absolute, increase in heart rate observed in this and other studies in unconscious dogs, in which reflex cardiovascular responses have been initiated in the periphery, is less than the increases in heart rate that have been reported during static exercise in conscious humans (22). During static muscular contraction, a modest increase in cardiac output, in conjunction with the combined effects of reflex and metabolically mediated vasoconstriction and vasodilation in different regional beds, appears to be responsible for the maintenance of SVR and the associated pressor response to tetanic muscular contraction in anesthetized dogs (18, 20, 21). Pressor responses to static muscular contraction in both groups of dogs in this study are similar to those previously reported in mongrel dogs (4, 7Y8, 16). Furthermore, SVR was maintained in the younger dogs in this study, as previously observed (4,7,8). However, SVR decreased significantly in the older beagles, despite appropriate increases in arterial pressure, heart rate, stroke volume, and cardiac output. Regional blood flow and resistance results (discussed later) suggest that attenuated reflex-mediated vasoconstriction in abdominal circulations and in noncontracting muscles, in conjunction with preserved vasodilation in contracting muscles, contributes to the observed reduction in SVR observed in the older dogs. By contrast, the reduction in SVR that occurs after elimination of the afferent limb of the exercise pressor reflex is not associated with a significant change in arterial pressure, heart rate, cardiac output, or renal blood flow (7, 18). Thus the reduction in SVR that occurred in the older dogs in this study does not appear to have resulted from an age-related absence of input from muscle afferents. Effect of age on regional blood flow responses to static muscular contraction. Blood flow to contracting muscles

increases significantly during induced static hindlimb contraction in the dog (4,7,8). This response appears to result from vasodilation in contracting muscle, in conjunction with vasoconstriction in nonessential beds, combined with a modest increase in cardiac output (18, 20,21). The increases in blood flow to contracting muscle in both young and old dogs in this study are similar to those increases that have been reported in mongrel dogs of undetermined age (4, 7, S)= The absolute and percent

2325

increases in blood flow, as well as the reductions in regional vascular resistance in contracting muscle, were similar in the older and younger beagles in this study, as well as in another study in conscious young and old beagles in which skeletal muscle blood flow responses during maximal dynamic exercise were evaluated (9, 10). Thus, vasodilation that occurs in skeletal muscle during static muscular contraction, as well as during dynamic exercise, appears to be well maintained with advanced age in the beagle. In this study, microspheres were injected ~15 s into muscle contraction; thus it is unlikely that muscle fatigue contributed to the increase in muscle blood flow observed during hindfimb contraction in both groups of dogs. Likewise, the stimulation protocol in this study utilized stimulus duration and voltages that do not produce sympathetic stimulation in mixed nerves (14, 26). Therefore, sympathetic-mediated vasodilation, resulting from the stimulation protocol used, would not appear to have contributed to the increases in skeletal blood flow that occurred during induced muscular contraction. Finally, a recent study has demonstrated that type I fiber percent and area do not change with age in the beagle (lo), making it unlikely that age-related differences in skeletal muscle composition contributed to the skeletal muscle blood flow results presented in this study. In the younger beagles in this study, blood flow decreased significantly in two of four muscle groups in the noncontracting limb and tended (P = 0.07) to be reduced in a third group (semitendinosus). By contrast, a significant reduction in blood flow was only observed in one of the muscles of the noncontracting limb in the older beagles. Furthermore, the reduction in blood flow to the group of four noncontracting muscles was approximately four times greater in the younger than in the older dogs. In addition, vascular resistance in these muscles was 75% higher in the younger beagles than in the older dogs. These results suggest that the vasoconstrictor response in noncontracting muscle that occurs secondary to reflex increases in the sympathoadrenal drive (1,20) appears to be attenuated with age. The results of this study also demonstrate that there is a reduction in blood flow and an increase in vascular resistance in most abdominal organs, regardless of age, during muscular contraction in the anesthetized dog, heretofore not evaluated. Of equal significance, however, is the fact that these changes appear to have been more profound in the younger than in the older dogs. The combined reduction in normalized blood flow to all eight abdominal organs was twice as large and the increase in vascular resistance 70% greater in the younger compared with the older dogs in this study. Thus the overall vasoconstrictor response in the abdominal organs evaluated was significantly attenuated during muscular contraction in the aged beagle. This response appears to be mediated by sympathoadrenal mechanisms (4,7), activated by stimulation of muscle afferents (2,20), and associated with increased sympathetic nerve activity (27). Renal function is somewhat diminished with age in the dog (9) and is associated with a tendency for baseline blood flow to the kidney to be reduced in the conscious senescent beagle (10). Therefore, the age-related 30%

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2326

AGING

AND RESPONSES

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difference in baseline renal blood flow and 40% difference in baseline renal vascular resistance observed in this study were not unexpected. Despite baseline differences, blood flow to the kidney decreased by -25% and vascular resistance increased w 50% during induced hindlimb contraction, regardless of age. These responses to static muscular contraction are similar to those previously reported in mongrel dogs (4, 7) and appear to be mediated, at least in part, by cu-adrenergic stimulation (7) associated with an increase in renal sympathetic nerve activity stimulated by mechanoreceptor-induced reflexes from contracting skeletal muscle (27). Thus the combined effects of ar-adrenergic stimulation and other mechanisms that contribute to vasoconstriction in the kidney (e.g., prostaglandins, renin/angiotensin) are maintained with age in the kidney of the dog. Myocardial blood flow was 36% greater at baseline in the older dogs than in the younger dogs in this study and was associated with a 17% higher estimated myocardial 0, demand (heart rate X systolic blood pressure). During static hindlimb contraction, however, myocardial blood flow did not increase in either group, despite 16 and 21% increases in the estimated myocardial 0, demand that resulted from induced muscular contraction in the older and younger beagles, respectively. This failure to increase myocardial blood flow during static muscular contraction has been observed by others using similar methodology to this study (7) and appears to result from reflex cu-adrenergic-mediated coronary vasoconstriction (3). These findings may have important clinical implications if similar responses are present during static exercise in conscious aging humans who have a relatively high prevalence of underlying atherosclerotic coronary artery disease. Summary. This study is the first to evaluate the effects of age on the reflex hemodynamic and regional blood flow responses that originate in contracting muscle. In summary, the principal new findings in this investigation in the beagle include the following. 1) The cardiac output response to induced muscle contraction is maintained with age in the dog and is actually augmented rather than attenuated. 2) Reflex sympathetic-mediated vasoconstriction in the group of circulations that comprise the splanchnic region, as well as in noncontracting skeletal muscle groups, is attenuated with age and appears to be primarily responsible for the observed reduction in SVR that occurs during muscular contraction in the older beagles. 3) Blood flow to contracting muscle is well maintained with age in the dog during induced hindlimb contraction. 4) The results of this study confirm and extend the findings from other studies that have examined the reflex responses to induced muscular contraction in anesthetized mongrel dogs (3, 4, 7, 8, 15, 16) and other animals (17, 18) of undetermined age. Finally, additional studies will be required to determine the mechanism(s) responsible for the age-related attenuation in reflex-mediated vasoconstriction that appears to occur in metabolically quiescent abdominal regions, as well as in noncontracting skeletal muscles, during static hindlimb contraction in the aging dog. The author thanks Juan Baez, Brian Gentile, James Jones, and Ken Rybicki for technical assistance and helpful advice; George Ordway for generously providing the use of the lab; and Tom Rector for expert

CONTRACTION

assistance with the data analysis used. Also, special acknowledgment is given to Drs. Seymour Eisenberg and Jere Mitchell for encouragement, advice, and support. This study was supported in part by the Southland Finance Company Chair in Geriatric Medicine and by the Lawson and Rogers Lacy Research Fund in Cardiovascular Diseases. G. C. Haidet is the recipient of National Heart, Lung, and Blood Institute Clinical Investigator Award HL-01550 and of the American Heart Association Texas Affiliate Grants-in-Aid 85G-076 and 87G-105. Address for reprint requests: G. C. Haidet, Dept. of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St. SE, Minneapolis, MN 55455. Received 24 October 1991; accepted in final form 8 July 1992. REFERENCES F, M., D. D. HEISTAD, Reflex control of the peripheral

1. ABBOUD,

A. L. MARK, AND P. G. SCHMID. circulation. Prog. Cardiouasc. Dis.

28: 371-403, 1976. 2. ABBOUD, F. M., A.

L. MARK, AND M. D. THAMES. Modulation of the somatic reflex by carotid baroreceptors and by cardiopulmonary afferents in animals and in humans. Ct’rc. Res. 48, Suppl. I:

1131-1137, 3. AUNG-DIN,

4.

5.

6.

7.

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