Effects of catecholamines alkalosis in dogs
during
respiratory
RONALD W. YAKAITIS, TERRY L. DODGE, AND JOHN D. THOMAS Department of Anesthesiology, University of Arizona Medical Center, Tucson, and Department of Anesthesiology, Medical University of South Carolina, Charleston, South Carolina 29401
W., TERRY L. DODGE, AND JOHN II, catecholamines during respiratory alkahis in dogs. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(4): 581-584, 1978. -The effects of three catecholamines (epinephrine, 2 pg. kg-l. min-l; isoproterenol, 0.2 pg kg-l. min--l; dopamine, 10 pg kg-l min-l) were compared in dogs during 1) normal acid-base balance, 2) respiratory alkalosis, and 3) respiratory alkalosis with normal pH. Fifteen dogs were divided into three groups according to the drug administered. Each dog was anesthetized with chloralose and urethan, intubated, and mechanically ventilated. Hypocarbia was induced by hyperventilation with air; simultaneous infusion of 0.3 M lactic acid produced a “compensated” alkalosis. Cardiovascular variables measured were heart rate, mean arterial blood pressure, left ventricular dP/dt, right atria1 pressure, and cardiac output (thermodilution technique); peripheral vascular resistance was calculated. Measurements in each acid-base state were made immediately before drug administration and at the point of greatest change during drug infusion. Among the three agents, the respective magnitudes of beta-receptor stimulation were essentially equal during normal acid-base and purely alkalotic conditions* This suggests that respiratory alkalosis does not appreciably affect beta receptors. Respiratory alkalosis with normal pH accentuated isoproterenol’s beta-receptor activity; conversely, epinephrine and dopamine exhibited significant negative chronotropic effects. YAKATTXS, RONALD THOMAS. Effects of
l
acid-base
l
balance;
epinephrine;
l
dopamine;
isoproterenol
VASCULAR EFFECTS of respiratory alkalos$ are relatively distinct within the cerebral circulation (9). Outside the brain, the variability of cardiovascular responsesto this acid-base abnormality derives primarily from differences in investigative methodology. The more consistent effects of respiratory alkalosis, in both animals and man, appear to be tachycardia, increased myocardial contractility, and decreased peripheral vascular resistance (11, 15, 16). Generally, respiratory alkalosis produced alterations resembling those following beta-adrenergic receptor stimulation. Although a number of investigators (1-3, 10) have found hypercarbia to significantly inhibit the chronotropic, inotropic, and pressor responses to epinephrine, little is known about the influence of respiratory alkalosis on the cardiovascular effects of sympathomimetic amines. After inducing sympathetic and parasympathetic blockade in intact dogs, Bendixen et al. (3) demonstrated OOZl-8987/78/0000-0000$01.25
Copyright
0 1978
the American
Physiological
Arizona
85724;
that the degree of positive myocardial contractile response to epinephrine was inversely related to arterial partial pressure of carbon dioxide (Pa,,,). Greenburg (8) found that isoproterenol significantly potentiated the chronotropic and hypotensive prdperties of pure respiratory alkalosis. The present study was undertaken to expand the observations of previous investigators and evaluate, in the dog, the cardiovascular effects of several sympathomimetic amines infused during states of 1) acid-base balance, 2) respiratory alkalosis, and 3) hypocapnia with normal pH. METHODS
Mongrel dogs weighing 15-20 kg were anesthetized with choloralose, 50 mg/kg, and urethan, 750 mg/kg. The dogs were intubated, connected to a Harvard pump respirator, and ventilated with air at an initial tidal volume of 25 ml/kg. The respiratory rate was adjusted to maintain PacOzat 35-45 Torr. One femoral artery was cannulated to obtain samples for blood gas determinations, and to measure arterial blood pressure through a Statham P23DB pressure transducer. A Statham SF1 catheter-tip transducer was inserted through the opposite femoral artery into the left ventricle. The signal from this catheter was split and sent through both a Statham P23DB pressure transducer and a passive R-C differentiator. This divided signal provided continual measurement of, respectively, left ventricular pressure and the first derivative of intraventricular pressure rise (LV dP/&). A femoral vein was cannulated for the purpose of fluid and drug administration. Through the right jugular vein a Swan-Ganz 7F thermodilution catheter was advanced into the pulmonary artery. One lumen was connected to a Statham P23DB transducer to permit measurement of right atria1 pressure. The catheter was also attached to an Eds Lab 9510 cardiac output computer to determine cardiac output using the thermodilution technique. Lead II of the electrocardiogram (ECG) was continuously monitored. All pressures, LV dP/dt, and the ECG were displayed and recorded on an Electronics for Medicine DR8 Research Recorder. Acid-base balance was defined as a pH of 7.35-7.45 and a PacOz of 35-45 Torr; it was established by adjustment of ventilation and sodium bicarbonate infusion, if necessary. Arterial PO, was maintained at 80-110 Torr throughout the study. The following cardioSociety
581
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.081.226.078) on January 16, 2019.
582
YAKAITIS,
vascular variables were directly recorded: heart rate (HR), mean arterial pressure (MAP), right atria1 pressure (RAP), cardiac output (CO), maximum left ventricular dP/dt (max LV dP/dt), and left intraventricular pressure (LVP), Peripheral vascular resistance (PVR), denoted in peripheral resistance units, was calculated by subtracting right atria1 pressure from mean arterial pressure and dividing by cardiac output. As a quantitative assessment of myocardial contractility, left ventricular dP/dt was divided by an isovolumetric ventricular pressure ((dP/dt)/CPIP) common to contractions in both the control state and following pharmacologic intervention, This measurement has been described previously (4) and is relatively unaffected by moderate changes in preload and afterload. No less than 1 h after initial anesthetization, control measurements were recorded. The animals were divided into three groups of five dogs each. Group A received epinephrine intravenously at an infusion rate of 2 pg kg-’ min-l; group B was given isoproterenol at a rate of 0.2 pgm kg-l . min-I; and dogs in group C were infused with dopamine at a rate of 10 pg kg-l min? Infusion rates were chosen to elicit predominately betaadrenergic receptor stimulation by these amines+ Arterial blood gas values and all the aforementioned cardiovascular variables were remeasured after stabilization of maximal changes in blood pressure and heart rate. Drug infusion was then discontinued, and a 30-min interim wad allowed before proceeding to the next phase. Respiratory alkalosis was induced by hyperventilation to a PaCO, of lo-15 Torr. After stabilization, base-line cardiovascular functions were measured, and infusion of the appropriate drug restarted. Variables were measured during drug administration as previously described. After another 30-min hiatus, a 0.3 M lactic acid infusion was started to return the pH to 7.357.45; hyperventilation was continued to maintain Pco2 at lo-15 Torr. Once again, cardiovascular measurements were recorded before and during administration of the prescribed drug. Intraand intergroup drug response differences during the three acid-base states were analyzed with the Student paired and unpaired ttests. l
l
l
Table 1 shows the mean Pcoz and pH values induced within each drug group during each acid-base state. Values were comparable between the groups studied. Acid-base balance (NAB) (Table 2). Under normocarbic conditions, all three amines produced effects characteristic of beta-adrenergic receptor stimulation: increased heart rate, cardiac output, and estimated myocardial contractile force; decreased peripheral vascular resistance; and relatively undisturbed mean arterial pressure* Statistically, these alterations were least significant with dopamine. Respiratory alkalosis (RAL). In all three drug groups, the induction of respiratory alkalosis produced significant increases in heart rate, and generally enhanced myocardial contractile force (Table 3). Mean arterial pressure and peripheral vascular resistance
AND
THOMAS
1, Mean PacO,,and pH values induced during drug infusion
TABLE
Group
h-,, PH NAB alkalosis
A, Epinephrine
Group
B, Isoproterenol
Group
C, Dopamine
NAB
RAL
RALH
NAB
RAL
RALH
NAB
RAL
RALH
40 7.36
13 7.59
14 7.43
41 7.36
13 7.59
13 7.42
39 7.37
12 7.62
12 7.42
balance;
RAL
= normal acid-base with normal pH.
= respiratory
alkalosis;
RALH
= respiratory
TABLE 2. Cardiovascular effects of sympathomimetic amines during acid-base balance Epinephrine, 2 pgkg “.rnin-’ ~~ Control Drug HR, beatslmin MAP,
Torr
PVR, pru CO, llmin (dPldt)/CPIP
l
RESULTS
DODGE,
Values value.
142 k 10.3 119 k4.0 1.2 kO.11 6.2 20.51 23.8 24.0
Isoproterenol, 0.2 pg-kg-‘emin
164 210.3 117 25.8 0.8 20.04 8.8 ~0.64' 35.6 +5.4*
* Significantly are means 2 SE. pru = peripheral resistance units.
Control
Drug
142 27.1 136 25.8 1.8 eo.30 5.4 41.2 18.9 22.2
164 26.7" 128 55.4 1.3 20.21 6.7 i1.2* 26.7 24.s
different
Dopamine, 10 pgekg- lamin- 1
l
Control
Drug
134 t9.4 120 k4.9 1.6 kO.51 5.5 20.91 18.9 51.8
(P 5 0.05) change
156 211.6
117 k6.7 1.5 LO.'57 6.5 21.0 24.4 *2.2* from
control
TABLE 3. Cardiovascular alterations on serial inductions of RAL and RALH
HR, beats/min MAP, Torr PVR, pru CO, llmin (dP/dt)/CPIP
NAB
to RAL
+45
k 6.6*
-8.5 -0.22 +0.21 +2.11
4 k + 2
3.2* 0.09* 0.32 1.7
RAL to RALH
-14
t 8.5
+7.4 +0.13 -0.34 -1.06
Values are means k SE; n = 15. * Statistically 5 0.05) change. Abbrevations as in Tables 1 and
k 2.3* 5 0.07 TL 0.27 r~ 1.1
significant
(P
2.
tended to decrease slightly, while cardiac output remained essentially unchanged. The results of drug infusion during pure alkalosis are shown in Table 4. Epinephrine and isoproterenol exhibited effects on all variables similar to those observed within a normal acid-base environment. Heart rate, cardiac output, and myocardial contractile force increased, peripheral vascular resistance decreased, and mean arterial pressure was minimally affected. Less vigorous but similar trends were noted with dopamine. The exception was a moderate decrease in heart rate during dopamine infusion. Respiratory alkalosis with normal pH (RALH) . Upon addition of lactic acid to create a state of hypocarbia and normal pH, values for all variables tended to return toward those recorded under normal acid-base conditions (Table 3). Nevertheless, heart rate remained significantly elevated. During compensated alkalosis only isoproterenol persisted in causing cardiovascular alterations uniformly representative of beta-adrenergic stimulation (Table 5). Epinephrine infusion elicited a substantial increase in mean arterial pressure accompanied by a decrease in heart rate. Both isoproterenol and epinephrine continued to produce significant increases in cardiac output and myocardial contractile
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CATECHOLAMINE TABLE
amines
MAP,
EFFECTS
4. Cardiovascular during respiratory
Torr
PVR, pru CO, llmin (dP/dt)/CPIP
are means
effects of sympathomimetic alkalosis
106
123
109
120
115
i4.3 1.2 20.12 5.6 20.66 21.2
24.5 0.7 +0.06” 9.2 20.88” 34.7
14.9 1.2 LO.14
k7.6 0.9 kO.09”
i8.0 1.4 40.47
kg.8 1.4 kO.49
6.1 kO.55 22.3
7.0 *0.40* 28
5.9 kO.84 24.5
6.1 +0.97 30.2
&4.0*
k3.1
2 SE.
z3.F
L3.1
* Significantly
5. Cardiovascular during respiratory
TABLE
amines
different
Isoproterenol, 0.2 pgekg--I-min-’ Control
HR, beatalmin Torr
PVR,
pm
1.2 *o-o9 5.7 t0.55 21.9 k2.2
CO, llmin (dP/dt)/CPIP Values value.
are means
+ SE.
(P 5 0.05) change
*2.2* from
control
effects of sympathomimetic alkalosis and normal pH
Epinephrine, 2 gg- kg-‘. min. ’
MAP,
583
ALKALOSIS
106
k3.1 Values value.
DURING
1.1 kO.09 7.3 k 0.75* 33.1 54.5” * Statistically
154 + 15.6 129 22.7 1.4 50.12 5.6 kO.64 19.5 21.3 different
Drug 202 +10.3* 123 27.6 0.9 kO.12” 8.2 -+0.62* 32.4 *4.5*
Dopamine, pg-kg-‘*min-l Control
Drug
172 +10.3 131 +6.3 1.6
136 416.1” 132
48.5 1.5
iO.42 5.4 20.72 23.3 e1.3
(P 5 0.05) change
20.32 5.4 kO.65 32.4 53.1” from
control
force. The responses to dopamine were similar to those observed during pure alkalosis, with the exception of a statistically significant bradycardia. DISCUSSION
The data presented indicates that respiratory alkalosis neither-inhibits nor potentiates the beta-adrenergic-stimulating properties of sympathomimetic amines. ks reported by previous investigators (11, 16), the most prominent cardiovascular changes observed during respiratory alkalosis were tachycardia and increased mybcardial contractile force. Nevertheless, even in the presence of pure alkalosis, epinephrine, isoproterenol, and dopamine affected cardiovascular dynamics to the same degree that each respectively exhibited during acid-base balance. These results suggest that the positive inotropic and chronotropic responses to respiratory alkalosis are not mediated by occupation of beta receptors. This proposal agrees with work by Richardson (13) showing that beta-receptor inactivation with proprano101 did not alter circulatory responses to hypocapnia in man However, prior administration of .an antihistamme significantly reduced the characteristic changes associated with hyperventilation. Richardson and his colleagues hypothesized that histamine release might be implicated in the circulatory responses to acute hypocapnia. Histamine exerts positive inotropic and chronotropic effects on the heart, and the systemic vasodilation induced by this amine may evoke a reflex increase in heart rate and cardiac output.
Within all three acid-base environments, isoprotereno1 elicited the strongest, most consistent beta-receptor excitation; dopamine produced the weakest* Thus, the acid-base changes studied do not appear to disturb the normal hierarchy of drug affinities for beta receptors. We could locate only one earlier study concerning the cardiovascular effects of sympathomimetic amines given during hypocapnic states. Greenburg et al. (8) studied the interaction of isoproterenol and acid-base disturbances in open-chested calves. Respiratory alkalosis alone produced an increase in coronary blood flow and heart rate accompanied by a decrease in systemic pressure, cardiac output, and peripheral resistance. Administration of 100 pg isoproterenol markedly potentiated the tachycardia, hypotension, peripheral vasodilatation, and coronary blood flow. However, ca rdiac output did not increase , and calculated cardi ac work was significantly lowered. These findings suggested that respiratory alkalosis enhances the chronotropic, and antagonizes the inotropic effects of isoproterenol. This was not observed in the present study. A possible explanation lies in Greenburg’s use of halothane to anesthetize his study animals. Other investigators (7, 14) have shown that with continued halothane anesthesia, there is a gradual reversal of depressant effects on the myocardium. Although the exact mechanism for this phenomenon is still unclear, Price et al. (12) have been able to inhibit the reaction with a beta-receptorblocking drug. Subsequently, Greenburg’s results may possibly represent a case of isoproterenol’s potentiation by prolonged halothane anesthesia, rather than by hypocapnia* It is difficult to satisfactorily explain the observations recorded during compensated alkalosis. Previous work (17) has shown that the hydrogen ion concentration rather than arterial PcoZ, is primarily responsible for the cardiac effects of hypocapnia. Indeed, in this study, infusion of lactic acid was associated with a general return of all cardiovascular variables towards prealkalosis values. Notably, the chronotropic and inotropic effects of isoproterenol d uring ’ ‘compe nsa .ted” alkalosis were even greater tha .n those record .ed duri ng either pure alkalosis or acid-base balance. We have no explanation for this finding, but the observation does agree with that of Chaffed (5) who found that metabolic acidosis enhanced the stimulative properties of isoproterenol. These data require further confirmation since the results appear contrary to the traditional concept that acidosis inhibits the myocardial response to all catecholamines. As opposed to the situation with isoproterenol, administration of dopamine and epinephrine during compensated alkalosis produced significant bradycardias. This suggests that, despite the arterial CO, level, an increased hydrogen ion concentration may, initially at least, inhibit the chronotropic responses of certain catecholamines. Indeed, Manley and co-workers (10) have reported such a preferential inhibition upon administration of epinephrine during respiratory acidosis. The divergent effects of epinephrine and dopamine in the face of the relatively inflexible beta-adrenergic stimulation provided by isoproterenol, regardless of
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584 acid-base state, might cast doubt upon the assumption that all three drugs were given in equipotent doses. However, some evidence of equipotency is derived from the fact that during acid-base-balance, the intial values and subsequent changes in heart rate and LV dP/dt were approximately the same in all three drug groups. Chloralose anesthesia has been demonstrated to potentiate left ventricular contractile responses to isoproterenol, but this effect dissipates within several minutes after administration (6). None of the cardiovascular measurements in this study were made less than 15 min following additional doses of chloralose. Chloralose has not been shown to interfere with responses of heart rate, arterial pressure, peripheral resistance, or cardiac output to isoproterenol (6).
YAKAITIS,
DODGE,
AND
THOMAS
In conclusion, the data presented indicate that in the intact dog, the beta-adrenergic responses to the administration of epinephrine, isoproterenol, and dopamine are not significantly affected by pure respiratory alkalosis. Infusion of these amines during the mixed acidbase disturbance of compensated alkalosis resulted in significant bradycardias with dopamine and epinephrine, while isoproterenol continued to exhibit pronounced inotropic and, p*articularly, chronotropic effects. This Carolina Received
work Heart
was supported Association.
for publication
by
8 August
a grant-in-aid
from
the
South
1977.
REFERENCES 1. ATKINSON, J. M., AND M. J. RAWD. Reduction of cardiovascular responses to some sympathomimetic amines during hypercapnia. European J. Pharmacok 18: 166-173, 1972. 2. BEIERHOLM, E. A,, R. NATHAN GRANTHAM, D. D. O’KEEFE, M. B. LAVER, AND W, M. DOGGET. Effects of acid-base changes, hypoxia, and catecholamines on ventricular performance. Am. J. Physid. 228: 1555-1561, 1975. 3. BENDIXEN, H. H., M. B. LAVER, AND W. E. FLACKE. Influence of respiratory acidosis on circulatory effect of epinephrine in dogs. Circulation Res. 13: 64-70, 1963. 4. BRAWNWALD, E., J. Ross, JR., J. H. GAULT, D. T. MASON, C. MILLS, I. T. GABE, AND S. E, EPSTEIN. Assessment of cardiac function, Ann. Internal Med. 70: 369-399, 1969. 5. CHAFFEE , C. B. The effect of acidosis and alkalosis on response to vasopressor and vasodilator drugs. J. Trauma 9: 147-148, 1969. 6. COX, R. H. Influence of chloralose anesthesia on cardiovascular function in trained dogs. Am. J. Physiol. 223: 660-667, 1972. 7. EGER, E. I. II, N. T. SMITH, R, K, STOELTING, AND C. WHITCHER. The cardiovascular effects of various alveolar halothane concentrations in man, Anesthesiology 29: 185487, 1968. 8. GREENBURG, A. G., R. B. DREISIN, G. WV, AND C, F. KITTLE. Isoproterenol, hemodynamics and acid-base alterations. Arch. SUFg, 99: 744-749, 1969. 9. KETY, S. S., AND C, F. SCHMIDT. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J. C,h.
10
11.
12.
13.
14.
15.
16.
17.
Invest. 27: 484-492, 1948. MANLEY, E. S., JR., R. A. WOODBURY, AND C. B. NASH. Cardiovascular responses to epinephrine during acute hypercapnia in dogs: effects of autonomic blocking drugs. Circulation Res. 18: 573-584, 1966. MITCHELL, J. H., K. WILDENTHAL, AND R. L. JOHNSON, JR. The effects of acid-base disturbances on cardiovascular and pulmonary function. Kidney Intern. 1: 375-389, 1972. PRICE, H. L., P. SKOVSTED, A. L. PANCA, AND L. H. COOPERMAN. Evidence for P-receptor activation produced by halothane in normal man. Anesthesiology 32: 389-395, 1970. RICHARDSON, D. W., H. A. KONTOS, A. J. RAPER, AND 5. L. PATTERSON, JR. Systemic circulatory responses to hypocapnia in man. Am. J. PhysioZ. 223: 1308-1312, 1972. SMITH, N. T., E. I. EGER, II, R. K. STOELTING, AND C. E. WHITCHER. Cardiovascular effects of halothane in man. J. Am. Med. Assoc. 206: 1495-1499, 1968. STREISAND, R. L., A. GIOURIN, AND J. H. STUCKEY. Respiratory and metabolic alkalosis and myocardial contractility. J. Thorack Cardiovascular Surg. 62: 431-435, 1971. SUNTARINEN, T. Cardiovascular response to changes in arterial carbon dioxide tension. Acta Physiol. Stand Suppl 266: l-76, 1966. WEAD, W., AND R. C. LITTLE. Effect of hypocapnia and respiratory alkalosis on cardiac contractility. PFOC. Sot. ExptZ. BioZ. Med. 126: 606-609, 1967.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.081.226.078) on January 16, 2019.
during
respiratory
RONALD W. YAKAITIS, TERRY L. DODGE, AND JOHN D. THOMAS Department of Anesthesiology, University of Arizona Medical Center, Tucson, and Department of Anesthesiology, Medical University of South Carolina, Charleston, South Carolina 29401
W., TERRY L. DODGE, AND JOHN II, catecholamines during respiratory alkahis in dogs. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(4): 581-584, 1978. -The effects of three catecholamines (epinephrine, 2 pg. kg-l. min-l; isoproterenol, 0.2 pg kg-l. min--l; dopamine, 10 pg kg-l min-l) were compared in dogs during 1) normal acid-base balance, 2) respiratory alkalosis, and 3) respiratory alkalosis with normal pH. Fifteen dogs were divided into three groups according to the drug administered. Each dog was anesthetized with chloralose and urethan, intubated, and mechanically ventilated. Hypocarbia was induced by hyperventilation with air; simultaneous infusion of 0.3 M lactic acid produced a “compensated” alkalosis. Cardiovascular variables measured were heart rate, mean arterial blood pressure, left ventricular dP/dt, right atria1 pressure, and cardiac output (thermodilution technique); peripheral vascular resistance was calculated. Measurements in each acid-base state were made immediately before drug administration and at the point of greatest change during drug infusion. Among the three agents, the respective magnitudes of beta-receptor stimulation were essentially equal during normal acid-base and purely alkalotic conditions* This suggests that respiratory alkalosis does not appreciably affect beta receptors. Respiratory alkalosis with normal pH accentuated isoproterenol’s beta-receptor activity; conversely, epinephrine and dopamine exhibited significant negative chronotropic effects. YAKATTXS, RONALD THOMAS. Effects of
l
acid-base
l
balance;
epinephrine;
l
dopamine;
isoproterenol
VASCULAR EFFECTS of respiratory alkalos$ are relatively distinct within the cerebral circulation (9). Outside the brain, the variability of cardiovascular responsesto this acid-base abnormality derives primarily from differences in investigative methodology. The more consistent effects of respiratory alkalosis, in both animals and man, appear to be tachycardia, increased myocardial contractility, and decreased peripheral vascular resistance (11, 15, 16). Generally, respiratory alkalosis produced alterations resembling those following beta-adrenergic receptor stimulation. Although a number of investigators (1-3, 10) have found hypercarbia to significantly inhibit the chronotropic, inotropic, and pressor responses to epinephrine, little is known about the influence of respiratory alkalosis on the cardiovascular effects of sympathomimetic amines. After inducing sympathetic and parasympathetic blockade in intact dogs, Bendixen et al. (3) demonstrated OOZl-8987/78/0000-0000$01.25
Copyright
0 1978
the American
Physiological
Arizona
85724;
that the degree of positive myocardial contractile response to epinephrine was inversely related to arterial partial pressure of carbon dioxide (Pa,,,). Greenburg (8) found that isoproterenol significantly potentiated the chronotropic and hypotensive prdperties of pure respiratory alkalosis. The present study was undertaken to expand the observations of previous investigators and evaluate, in the dog, the cardiovascular effects of several sympathomimetic amines infused during states of 1) acid-base balance, 2) respiratory alkalosis, and 3) hypocapnia with normal pH. METHODS
Mongrel dogs weighing 15-20 kg were anesthetized with choloralose, 50 mg/kg, and urethan, 750 mg/kg. The dogs were intubated, connected to a Harvard pump respirator, and ventilated with air at an initial tidal volume of 25 ml/kg. The respiratory rate was adjusted to maintain PacOzat 35-45 Torr. One femoral artery was cannulated to obtain samples for blood gas determinations, and to measure arterial blood pressure through a Statham P23DB pressure transducer. A Statham SF1 catheter-tip transducer was inserted through the opposite femoral artery into the left ventricle. The signal from this catheter was split and sent through both a Statham P23DB pressure transducer and a passive R-C differentiator. This divided signal provided continual measurement of, respectively, left ventricular pressure and the first derivative of intraventricular pressure rise (LV dP/&). A femoral vein was cannulated for the purpose of fluid and drug administration. Through the right jugular vein a Swan-Ganz 7F thermodilution catheter was advanced into the pulmonary artery. One lumen was connected to a Statham P23DB transducer to permit measurement of right atria1 pressure. The catheter was also attached to an Eds Lab 9510 cardiac output computer to determine cardiac output using the thermodilution technique. Lead II of the electrocardiogram (ECG) was continuously monitored. All pressures, LV dP/dt, and the ECG were displayed and recorded on an Electronics for Medicine DR8 Research Recorder. Acid-base balance was defined as a pH of 7.35-7.45 and a PacOz of 35-45 Torr; it was established by adjustment of ventilation and sodium bicarbonate infusion, if necessary. Arterial PO, was maintained at 80-110 Torr throughout the study. The following cardioSociety
581
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.081.226.078) on January 16, 2019.
582
YAKAITIS,
vascular variables were directly recorded: heart rate (HR), mean arterial pressure (MAP), right atria1 pressure (RAP), cardiac output (CO), maximum left ventricular dP/dt (max LV dP/dt), and left intraventricular pressure (LVP), Peripheral vascular resistance (PVR), denoted in peripheral resistance units, was calculated by subtracting right atria1 pressure from mean arterial pressure and dividing by cardiac output. As a quantitative assessment of myocardial contractility, left ventricular dP/dt was divided by an isovolumetric ventricular pressure ((dP/dt)/CPIP) common to contractions in both the control state and following pharmacologic intervention, This measurement has been described previously (4) and is relatively unaffected by moderate changes in preload and afterload. No less than 1 h after initial anesthetization, control measurements were recorded. The animals were divided into three groups of five dogs each. Group A received epinephrine intravenously at an infusion rate of 2 pg kg-’ min-l; group B was given isoproterenol at a rate of 0.2 pgm kg-l . min-I; and dogs in group C were infused with dopamine at a rate of 10 pg kg-l min? Infusion rates were chosen to elicit predominately betaadrenergic receptor stimulation by these amines+ Arterial blood gas values and all the aforementioned cardiovascular variables were remeasured after stabilization of maximal changes in blood pressure and heart rate. Drug infusion was then discontinued, and a 30-min interim wad allowed before proceeding to the next phase. Respiratory alkalosis was induced by hyperventilation to a PaCO, of lo-15 Torr. After stabilization, base-line cardiovascular functions were measured, and infusion of the appropriate drug restarted. Variables were measured during drug administration as previously described. After another 30-min hiatus, a 0.3 M lactic acid infusion was started to return the pH to 7.357.45; hyperventilation was continued to maintain Pco2 at lo-15 Torr. Once again, cardiovascular measurements were recorded before and during administration of the prescribed drug. Intraand intergroup drug response differences during the three acid-base states were analyzed with the Student paired and unpaired ttests. l
l
l
Table 1 shows the mean Pcoz and pH values induced within each drug group during each acid-base state. Values were comparable between the groups studied. Acid-base balance (NAB) (Table 2). Under normocarbic conditions, all three amines produced effects characteristic of beta-adrenergic receptor stimulation: increased heart rate, cardiac output, and estimated myocardial contractile force; decreased peripheral vascular resistance; and relatively undisturbed mean arterial pressure* Statistically, these alterations were least significant with dopamine. Respiratory alkalosis (RAL). In all three drug groups, the induction of respiratory alkalosis produced significant increases in heart rate, and generally enhanced myocardial contractile force (Table 3). Mean arterial pressure and peripheral vascular resistance
AND
THOMAS
1, Mean PacO,,and pH values induced during drug infusion
TABLE
Group
h-,, PH NAB alkalosis
A, Epinephrine
Group
B, Isoproterenol
Group
C, Dopamine
NAB
RAL
RALH
NAB
RAL
RALH
NAB
RAL
RALH
40 7.36
13 7.59
14 7.43
41 7.36
13 7.59
13 7.42
39 7.37
12 7.62
12 7.42
balance;
RAL
= normal acid-base with normal pH.
= respiratory
alkalosis;
RALH
= respiratory
TABLE 2. Cardiovascular effects of sympathomimetic amines during acid-base balance Epinephrine, 2 pgkg “.rnin-’ ~~ Control Drug HR, beatslmin MAP,
Torr
PVR, pru CO, llmin (dPldt)/CPIP
l
RESULTS
DODGE,
Values value.
142 k 10.3 119 k4.0 1.2 kO.11 6.2 20.51 23.8 24.0
Isoproterenol, 0.2 pg-kg-‘emin
164 210.3 117 25.8 0.8 20.04 8.8 ~0.64' 35.6 +5.4*
* Significantly are means 2 SE. pru = peripheral resistance units.
Control
Drug
142 27.1 136 25.8 1.8 eo.30 5.4 41.2 18.9 22.2
164 26.7" 128 55.4 1.3 20.21 6.7 i1.2* 26.7 24.s
different
Dopamine, 10 pgekg- lamin- 1
l
Control
Drug
134 t9.4 120 k4.9 1.6 kO.51 5.5 20.91 18.9 51.8
(P 5 0.05) change
156 211.6
117 k6.7 1.5 LO.'57 6.5 21.0 24.4 *2.2* from
control
TABLE 3. Cardiovascular alterations on serial inductions of RAL and RALH
HR, beats/min MAP, Torr PVR, pru CO, llmin (dP/dt)/CPIP
NAB
to RAL
+45
k 6.6*
-8.5 -0.22 +0.21 +2.11
4 k + 2
3.2* 0.09* 0.32 1.7
RAL to RALH
-14
t 8.5
+7.4 +0.13 -0.34 -1.06
Values are means k SE; n = 15. * Statistically 5 0.05) change. Abbrevations as in Tables 1 and
k 2.3* 5 0.07 TL 0.27 r~ 1.1
significant
(P
2.
tended to decrease slightly, while cardiac output remained essentially unchanged. The results of drug infusion during pure alkalosis are shown in Table 4. Epinephrine and isoproterenol exhibited effects on all variables similar to those observed within a normal acid-base environment. Heart rate, cardiac output, and myocardial contractile force increased, peripheral vascular resistance decreased, and mean arterial pressure was minimally affected. Less vigorous but similar trends were noted with dopamine. The exception was a moderate decrease in heart rate during dopamine infusion. Respiratory alkalosis with normal pH (RALH) . Upon addition of lactic acid to create a state of hypocarbia and normal pH, values for all variables tended to return toward those recorded under normal acid-base conditions (Table 3). Nevertheless, heart rate remained significantly elevated. During compensated alkalosis only isoproterenol persisted in causing cardiovascular alterations uniformly representative of beta-adrenergic stimulation (Table 5). Epinephrine infusion elicited a substantial increase in mean arterial pressure accompanied by a decrease in heart rate. Both isoproterenol and epinephrine continued to produce significant increases in cardiac output and myocardial contractile
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CATECHOLAMINE TABLE
amines
MAP,
EFFECTS
4. Cardiovascular during respiratory
Torr
PVR, pru CO, llmin (dP/dt)/CPIP
are means
effects of sympathomimetic alkalosis
106
123
109
120
115
i4.3 1.2 20.12 5.6 20.66 21.2
24.5 0.7 +0.06” 9.2 20.88” 34.7
14.9 1.2 LO.14
k7.6 0.9 kO.09”
i8.0 1.4 40.47
kg.8 1.4 kO.49
6.1 kO.55 22.3
7.0 *0.40* 28
5.9 kO.84 24.5
6.1 +0.97 30.2
&4.0*
k3.1
2 SE.
z3.F
L3.1
* Significantly
5. Cardiovascular during respiratory
TABLE
amines
different
Isoproterenol, 0.2 pgekg--I-min-’ Control
HR, beatalmin Torr
PVR,
pm
1.2 *o-o9 5.7 t0.55 21.9 k2.2
CO, llmin (dP/dt)/CPIP Values value.
are means
+ SE.
(P 5 0.05) change
*2.2* from
control
effects of sympathomimetic alkalosis and normal pH
Epinephrine, 2 gg- kg-‘. min. ’
MAP,
583
ALKALOSIS
106
k3.1 Values value.
DURING
1.1 kO.09 7.3 k 0.75* 33.1 54.5” * Statistically
154 + 15.6 129 22.7 1.4 50.12 5.6 kO.64 19.5 21.3 different
Drug 202 +10.3* 123 27.6 0.9 kO.12” 8.2 -+0.62* 32.4 *4.5*
Dopamine, pg-kg-‘*min-l Control
Drug
172 +10.3 131 +6.3 1.6
136 416.1” 132
48.5 1.5
iO.42 5.4 20.72 23.3 e1.3
(P 5 0.05) change
20.32 5.4 kO.65 32.4 53.1” from
control
force. The responses to dopamine were similar to those observed during pure alkalosis, with the exception of a statistically significant bradycardia. DISCUSSION
The data presented indicates that respiratory alkalosis neither-inhibits nor potentiates the beta-adrenergic-stimulating properties of sympathomimetic amines. ks reported by previous investigators (11, 16), the most prominent cardiovascular changes observed during respiratory alkalosis were tachycardia and increased mybcardial contractile force. Nevertheless, even in the presence of pure alkalosis, epinephrine, isoproterenol, and dopamine affected cardiovascular dynamics to the same degree that each respectively exhibited during acid-base balance. These results suggest that the positive inotropic and chronotropic responses to respiratory alkalosis are not mediated by occupation of beta receptors. This proposal agrees with work by Richardson (13) showing that beta-receptor inactivation with proprano101 did not alter circulatory responses to hypocapnia in man However, prior administration of .an antihistamme significantly reduced the characteristic changes associated with hyperventilation. Richardson and his colleagues hypothesized that histamine release might be implicated in the circulatory responses to acute hypocapnia. Histamine exerts positive inotropic and chronotropic effects on the heart, and the systemic vasodilation induced by this amine may evoke a reflex increase in heart rate and cardiac output.
Within all three acid-base environments, isoprotereno1 elicited the strongest, most consistent beta-receptor excitation; dopamine produced the weakest* Thus, the acid-base changes studied do not appear to disturb the normal hierarchy of drug affinities for beta receptors. We could locate only one earlier study concerning the cardiovascular effects of sympathomimetic amines given during hypocapnic states. Greenburg et al. (8) studied the interaction of isoproterenol and acid-base disturbances in open-chested calves. Respiratory alkalosis alone produced an increase in coronary blood flow and heart rate accompanied by a decrease in systemic pressure, cardiac output, and peripheral resistance. Administration of 100 pg isoproterenol markedly potentiated the tachycardia, hypotension, peripheral vasodilatation, and coronary blood flow. However, ca rdiac output did not increase , and calculated cardi ac work was significantly lowered. These findings suggested that respiratory alkalosis enhances the chronotropic, and antagonizes the inotropic effects of isoproterenol. This was not observed in the present study. A possible explanation lies in Greenburg’s use of halothane to anesthetize his study animals. Other investigators (7, 14) have shown that with continued halothane anesthesia, there is a gradual reversal of depressant effects on the myocardium. Although the exact mechanism for this phenomenon is still unclear, Price et al. (12) have been able to inhibit the reaction with a beta-receptorblocking drug. Subsequently, Greenburg’s results may possibly represent a case of isoproterenol’s potentiation by prolonged halothane anesthesia, rather than by hypocapnia* It is difficult to satisfactorily explain the observations recorded during compensated alkalosis. Previous work (17) has shown that the hydrogen ion concentration rather than arterial PcoZ, is primarily responsible for the cardiac effects of hypocapnia. Indeed, in this study, infusion of lactic acid was associated with a general return of all cardiovascular variables towards prealkalosis values. Notably, the chronotropic and inotropic effects of isoproterenol d uring ’ ‘compe nsa .ted” alkalosis were even greater tha .n those record .ed duri ng either pure alkalosis or acid-base balance. We have no explanation for this finding, but the observation does agree with that of Chaffed (5) who found that metabolic acidosis enhanced the stimulative properties of isoproterenol. These data require further confirmation since the results appear contrary to the traditional concept that acidosis inhibits the myocardial response to all catecholamines. As opposed to the situation with isoproterenol, administration of dopamine and epinephrine during compensated alkalosis produced significant bradycardias. This suggests that, despite the arterial CO, level, an increased hydrogen ion concentration may, initially at least, inhibit the chronotropic responses of certain catecholamines. Indeed, Manley and co-workers (10) have reported such a preferential inhibition upon administration of epinephrine during respiratory acidosis. The divergent effects of epinephrine and dopamine in the face of the relatively inflexible beta-adrenergic stimulation provided by isoproterenol, regardless of
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584 acid-base state, might cast doubt upon the assumption that all three drugs were given in equipotent doses. However, some evidence of equipotency is derived from the fact that during acid-base-balance, the intial values and subsequent changes in heart rate and LV dP/dt were approximately the same in all three drug groups. Chloralose anesthesia has been demonstrated to potentiate left ventricular contractile responses to isoproterenol, but this effect dissipates within several minutes after administration (6). None of the cardiovascular measurements in this study were made less than 15 min following additional doses of chloralose. Chloralose has not been shown to interfere with responses of heart rate, arterial pressure, peripheral resistance, or cardiac output to isoproterenol (6).
YAKAITIS,
DODGE,
AND
THOMAS
In conclusion, the data presented indicate that in the intact dog, the beta-adrenergic responses to the administration of epinephrine, isoproterenol, and dopamine are not significantly affected by pure respiratory alkalosis. Infusion of these amines during the mixed acidbase disturbance of compensated alkalosis resulted in significant bradycardias with dopamine and epinephrine, while isoproterenol continued to exhibit pronounced inotropic and, p*articularly, chronotropic effects. This Carolina Received
work Heart
was supported Association.
for publication
by
8 August
a grant-in-aid
from
the
South
1977.
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