Quantitative differences in the hemodynamic effects of captopril and nitroprusside in severe chronic heart failure

Quantitative Differences in the Hemodynamic Effects of Captopril and Nitroprusside in Severe Chronic Heart Failure MILTON PACKER, MD, JOSE MELLER, MD, NORMA MEDINA, RN, and MADELINE YUSHAK, RN The hemodynamic effects of oral captopril and intravenous nitroprusside were compared in 15 patients with severe chronic congestive heart failure. At doses of both drugs titrated so as to produce similar decreases in systemic vascular resistance in each patient, nitroprusside produced substantially greater increases in cardiac index ( + 0 . 6 7 versus +0.31 liters/min/m 2, p <0.01) but smaller decreases in mean arterial pressure (--18.4 versus -11.0 mm Hg, p <0.01) than did captopril. This finding was due to a significant decrease in heart rate with captopril (--7 beats/min, p <0.01 ) which was not seen with nitroprusside, since changes in stroke volume index with both drugs were similar. Nitroprusside produced a decrease in pulmonary arteriolar resistance quantitatively similar to the decrease in systemic vascular resistance, but the decrease in pulmonary arteriolar resistance with

captopril was not significant. Despite similar decreases in systemic resistance, captopril produced a greater decrease in left ventricular filling pressure (--10.2 versus --6.9 mm Hg, p <0.01) but a smaller decrease in mean right atrial pressure (--3.1 versus --5.3 mm Hg, p <0.01) than did nitroprusside. Thus, captopril has actions independent of its systemic vasodilator effects which account for the quantitative differences observed in its hemodynamic responses compared with those of nitroprusside in patients with severe chronic heart failure. These differences support experimental evidence that angiotensin, in addition to its direct systemic arterial vasoconstrictor actions, exerts positive chronotropic effects and alters ventricular compliance but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature.

All vasodilator drugs used in the management of patients with severe chronic heart failure are thought to exert their beneficial hemodynamic and clinical effects by acting on the peripheral circulation and thereby altering the loadings conditions that modulate cardiac performance. 1 Although these drugs may also directly improve myocardial contractility, coronary blood flow, or ventricular compliance, 2-7 it is difficult to determine to what extent such effects contribute to the hemodynamic changes caused by their use in humans. This is largely because changes in ventricular performance produced by changes in loading conditions are qualitatively similar to those that might be expected to result from an improvement in contractility or compliance. Captopril is an orally effective inhibitor of the angiotensin-converting enzyme s which produces substantial hemodynamic and clinical improvement in patients with severe chronic heart failure. 9-13 It differs from direct-acting vasodilator drugs in that it exerts its effects not by a direct agonist action on the peripheral

vasculature, but by inhibiting the circulatory responses to the endogenous vasoconstrictor angiotensin3, s Because its administration is accompanied by both increases in cardiac output and decreases in ventricular filling pressure, captopril has been thought by many investigators to produce balanced vasodilation of peripheral arteries and veins in a fashion similar to nitroprusside. TMLimb plethysmographic studies, however, have failed to confirm that captopril has important effects on the limb peripheral circulation in patients with heart failure. 15 This suggests that captopril improves cardiac performance by acting on regional circulations other than those in the extremities 15 or through mechanisms that do not involve systemic vasodilation. 2 We sought to investigate this hypothesis by comparing the central hemodynamic effects of captopril with those of nitroprusside in patients with severe heart failure. The differences we observed in the responses to these 2 drugs suggest that captopril exerts some of its effects by mechanisms independent of its vasodilator actions.

From the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York, New York. Dr. Packer is the recipient of Young Investigator's Research Award 1-R23-HL-25055-01 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received December 14, 1981; revised manuscript received August 6, 1982, accepted August 8, 1982. Address for reprints: Milton Packer, MD, Division of Cardiology, Mount Sinai Medical Center, 1 Gustave Levy Place, New York, New York 10029.

Methods Patient population: We evaluated 15 patients with severe chronic heart failure who had persistent dyspnea, fatigue, or

both at rest or on minimal exertion despite optimal conventional therapy with digitalis and diuretic agents. They included 9 men and 6 women aged 29 to 83 years (mean 66). The cause of heart failure was ischemic cardiomyopathy in 6 patients, idiopathic or alcoholic cardiomyopathy in 8 patients, 183

184

CAPTOPRILIN HEART FAILURE

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FIGURE 1. Changes in cardiac index, stroke volume index, and heart rate with captopril (CPT) and nitroprusside (NP), the latter titrated to 2 dose levels: NP1, doses (104 #g/min) which produced captopril-like decreases in systemic vascular resistance, and NP2, doses (180 #g/min) which produced captopril-like decreases in left ventricular filling pressure. All values are expressed as mean 4- standard error of the mean. Asterisks and daggers represent significance of changes with each drug compared to its control values. P values above the bars represent significance of the hemodynamic changes with captopril compared with those produced by nitroprusside. C = control; NS = not significant.

and primary aortic valvular regurgitation with advanced ventricular dysfunction in 1 patient. The duration of heart failure was 11 months to 10 years. Normal sinus rhythm was present in 10 patients, atrial fibrillation in 4, and a ventricular pacemaker rhythm in 1. Hemodynamic measurements: All patients were studied during a period of relative clinical stability. Bed rest was maintained, and all medications were withheld for 12 hours before evaluation. After written informed consent was obtained, right heart catheterization was performed with a triple-lumen flow-directed catheter for measurement of right atrial, pulmonary arterial, and pulmonary capillary wedge pressures. Arterial cannulas were inserted into the radial artery of all patients for measurement of systemic pressures. Measurements were made with zero reference level at the mid-axillary line with the patient in a supine position. Left ventricular filling pressure was measured as the mean pulmonary capillary wedge pressure. Thermodilution cardiac outputs were determined in triplicate by a bedside cardiac

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output computer with the use of iced injectate. Heart rates were derived from a continuously recorded electrocardiogram. Drug administration: A protocol was designed to compare oral captopril with an intravenous infusion of nitroprusside titrated so as to achieve a similar reduction in systemic vascular resistance and left ventricular filling pressure in each patient under similar baseline hemodynamic conditions. Baseline determinations of the following variables were made repeatedly over 1 to 2 hours (with a variation <10%) before any drug intervention to ensure stability of the hemodynamic state: mean arterial pressure, heart rate, left ventricular filling pressure, mean pulmonary artery pressure, mean right atrial pressure, and cardiac output. Each patient received both nitroprusside and captopril. Nine patients received nitroprusside first and captopril thereafter; the order was reversed in the other 6 patients. The administrations of the 2 drugs were separated by at least 24 hours.

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January 1, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 51

30

I( NS >1 l,e~p<:Ol~._T_

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15 I0

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Sodium nitroprusside was administered in a fashion similar to that previously described. 16 Briefly, 50 mg of the drug (Nipride®) was reconstituted in 250 ml of 5% dextrose in water and infused by peripheral vein at controlled rates determined by an IVAC 530 infusion pump apparatus. The infusion rate was initially 16 #g/min and was increased to 33, 67, 107, 213, and 330 #g/min with increments every 30 minutes; all hemodynamic variables were redetermined 20 minutes after each increment in the nitroprusside infusion. After the maximal dose of nitroprusside was infused, the drug was discontinued and hemodynamic variables were permitted to return to control values. Captopril was administered as 25 mg orally. This dose was chosen because of its established effectiveness in previous evaluations of this agent.9,11-13After captopril administration, all hemodynamic variables were redetermined at 30-minute intervals for 3 hours. Data analysis: Mean systemic and pulmonary artery pressures were determined by electronic filtration. Derived hemodynamic variables were calculated as follows: cardiac index (CI) - CO/body surface area (liter/rain/m2); stroke volume index (SVI) = CI/HR (ml/beat/m2); systemic vascular resistance (SVR) = 80 × (MAP - MRAP)/CO (dynes s cm-5); pulmonary arteriolar resistance (PAR) = 80 × (MPAP LVFP)/CO (dynes s cm-5), where CO denotes cardiac output, HR = heart rate, MAP = mean arterial pressure, MRAP = mean right atrial pressure, MPAP = mean pulmonary artery pressure, and LVFP = left ventricular filling pressure. The hemodynamic responses at the time of maximal captopril effect (30 to 120 minutes after drug administration) were noted. The range of infused rates of nitroprusside was then examined retrospectively and 2 doses were selected for COmparative analysis: (1) the dose of nitroprusside which produced a percent reduction in systemic vascular resistance in each patient of magnitude similar to that produced by captopril (NP0, and (2) the dose of nitroprusside which produced a reduction in left ventricular filling pressure in each patient of magnitude similar to that produced by captopril (NP2). The hemodynamic effects of each drug were compared to their respective control values by the t test for paired data. The magnitude of the hemodynamic responses to captopril and to both dose levels of nitroprusside were compared by analysis of variance; Duncan's multiple range test was used to differentiate among mean responses. 17 Group data are expressed as mean 4- standard error of the mean.

5 C CPT

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0

C CPT

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Results T h e control h e m o d y n a m i c variables before the administration of captopril and nitroprusside were similar. W i t h b o t h drugs, cardiac and stroke volume indexes increased in association with decreases in right and left ventricular filling pressures, in mean systemic and p u l m o n a r y arterial pressures, and in systemic vascular resistance (p <0.01 or p <0.001 for all variables). T h e h e m o d y n a m i c responses to the administration of each drug are shown in Figures 1 to 3. C o m p a r a t i v e r e s p o n s e s a t m a t c h e d r e d u c t i o n s in s y s t e m i c r e s i s t a n c e : T h e doses of nitroprusside which p r o d u c e d decreases in systemic vascular resistance similar to those observed with captopril in each patient ranged from 16 to 330 # g / m i n (mean 104 4- 27). At this dose, nitroprusside p r o d u c e d substantial decreases in p u l m o n a r y arteriolar resistance as well (p <0.001) and the magnitude of this effect was similar to that observed in the systemic circulation ( - 3 0 versus -34%, respectively). In contrast, captopril produced no significant decreases in p u l m o n a r y arteriolar resistance (-11%, p >0.10), and the magnitude of the decrease in vascular resistance in the systemic circuit with captopril in each patient always exceeded that observed in the pulmonary circulation. T h e effects of nitroprusside and captopril on p u l m o n a r y arteriolar resistance differed significantly, p <0.01. Despite similar decreases in systemic vascular resistance with both drugs, nitroprusside produced significantly greater increases in cardiac index (+0.69 versus +0.31 liters/min/m 2, p <0.01) and smaller decreases in m e a n arterial pressure ( - 1 1 . 0 versus - 1 8 . 4 m m Hg, p <0.01) t h a n captopril. T h e smaller increase in cardiac index with captopril was associated with a decrease in heart rate ( - 7 beats/min, p <0.01), whereas no significant changes in heart rate were observed with nitroprusside. Changes in stroke volume index with b o t h drugs were similar (+7.9 ml/beat/m 2 with nitroprusside and +6.3 m l / b e a t / m 2 with captopril). Despite similar decreases in systemic vascular resistance with both drugs, captopril produced substantially

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greater decreases in left ventricular filling pressure (-10.2 mm Hg versus -6.9 mm Hg, p <0.01) but significantly smaller decreases in mean right atrial pressure (-3.1 mm Hg versus -5.3 mm Hg, p <0.01) than did nitroprusside. Changes in mean pulmonary artery pressure with both drugs were similar (-9.3 mm Hg with captopril and -8.0 mm Hg with nitroprusside). Comparative responses at m a t c h e d reductions in left h e a r t filling pressures: The doses of nitroprusside which produced decreases in left ventricular filling pressures similar to those observed with captopril in each patient ranged from 67 to 330 t~g/min (mean 180 ± 43), a dose significantly larger than that needed to produce captopril-like decreases in systemic vascular resistance (p <0.01). As a result, these larger doses of nitroprusside produced significantly greater decreases in systemic vascular resistance than did captopril ( - 4 4 versus -34%, p <0.01). Despite this greater decrease in systemic resistance with nitroprusside, mean arterial pressure decreases similarly with both drugs; this reflected the substantially smaller increase in cardiac index with captopril than was seen with nitroprusside (+0.31 versus +0.90 liters/min/m 2, p <0.01). The different effects on cardiac index were the result of both a decrease in heart rate seen with captopril (but not seen with nitroprusside) and a greater increase in stroke volume index with this higher dose of nitroprusside than was seen with captopril (+10.5 versus +6.3 ml/beat/m 2, respectively, p <0.01). Although (with these larger doses of nitroprusside) left ventricular filling pressure decreased similarly with both drugs, nitroprusside produced significantly greater decreases in mean right atrial pressure (-5.9 versus -3.1, p <0.01) and in mean pulmonary artery pressure (-11.6 versus 9.3 mm Hg, p <0.01) than did captopril. Discussion

The hemodynamic responses to captopril in our patients with severe chronic heart failure differed from those observed with nitroprusside with respect to 3 variables: (1) heart rate, (2) pulmonary arteriolar resistance, and (3) right and left ventricular filling pressures. E f f e c t s of c a p t o p r i l on h e a r t rate: Heart rate decreased significantly with captopril in our patients but did not change after the administration of nitroprusside. Hence, when doses of both drugs Were matched so as to produce similar decreases in systemic vascular resistance, cardiac index increased less and mean arterial pressure decreased more with captopril than with nitroprusside. Although decreases in heart rate have been noted by other investigators after captopril administration to patients with heart failure,n, 13 such changes might have been a nonspecific effect of therapy, since heart rate frequently slows after the administration of any vasodilator drug that improves cardiac performance, and thereby leads to a withdrawal of reflex adrenergic activity. 1s,19In the present study, captopril and nitroprusside both produced marked improvements in stroke volume and left ventricular filling pressure, but

a decrease in heart rate was observed only with captopril, and thus, must have been the consequence of a negative chronotropic effect of the drug independent of its peripheral vasodilator actions. Such effects are likely mediated by inhibition of the direct cardioaccelerating effects of angiotensin. 2°,2i When captopril is administered to hypertensive patients, the negative chronotropic effects of the drug are offset by baroreceptor-mediated reflex tachycardia, and thus little change in heart rate is observed. 22 In contrast, in patients with heart failure, autonomic reflexes are attenuated, 23 and thus the negative chronotropic actions of captopril are left unopposed and heart rate slows. A similar explanation has been proposed to account for the responses seen with the peripheral vasodilator drug, prazosin, which directly slows the sinus node. 24 Like captopril, prazosin produces no change in heart rate in hypertensive patients but may decrease heart rate in patients with heart failure; in doing so, prazosin produces relative changes in cardiac index, mean arterial pressure, and systemic vascular resistance similar to those observed in the present study with captoprilJ 6 E f f e c t s of e a p t o p r i l on p u l m o n a r y arteriolar resistance: Captopril exerted minimal effects on pulmonary arteriolar resistance and right heart filling pressures in our patients with severe heart failure. This is consistent with experimental evidence that angiotensin has no direct effects on the pulmonary vasculature or the limb venous circulation, 25-2s and with clinical evidence that angiotensin inhibition produces little change in pulmonary vascular resistance 12,15,29-31 or systemic limb venous capacitance. 15,29 It is likely that both of these factors contribute to the modest decreases in mean right atrial pressure we observed with captopril, since right ventricular filling pressures are determined both by systemic venous return and by the impedance to right ventricular ejection. Accordingly, because of its marked effects on systemic limb venous capacitance and on pulmonary arteriolar resistance, 14 nitroprusside produced greater decreases in mean right atrial pressure than did captoprih The minimal effects of captopril on pulmonary arteriolar resistance may explain why arterial oxygen content does not decrease in patients with heart failure after converting-enzyme inhibition 32 but does decrease significantly with drugs that possess direct pulmonary vasodilating actions (such as nitroprusside).33 E f f e c t s of c a p t o p r i l on v e n t r i c u l a r filling pressures: Despite smaller decreases in right heart filling pressures, captopril produced greater decreases in left ventricular filling pressure than did nitroprusside. This was an unexpected finding. Since captopril exerts minimal effects on systemic venous capacitance and right heart filling pressures, we would have expected a smaller decrease in central blood volume (volume of the circulation from the pulmonary valve to the aortic valve 34) and hence in pulmonary capillary wedge preSsure with captopril than with nitroprusside at doses matched to produce similar decreases in systemic vaScular resistance. Even if we attributed the more modest decreases in mean right atrial pressure with captoprl!

January 1, 1983

entirely to its lesser reduction of right ventricular afterload (thus assuming that decreases in central blood volume with both drugs were similar), we would have anticipated ghat left heart filling pressure would have decreased similarly with captopril and nitroprusside. Our observation, however, that left ventricular filling pressure decreased m o r e with captopril suggests that this drug must act to lower left heart pressure by a mechanism independent of changes in the peripheral arterial or venous circulations, possibly by a direct effect on pulmonary vascular compliance or by changing the pressure-volume relations in the left ventricle. 2 The latter hypothesis is supported by the work of Alderman and Glantz, 5 who noted that angiotensin shifts the pressure-volume relations of the human left ventricle so as to make the ventricle less compliant; antagonism of this shift by captopril could contribute to the marked decrease in left ventricular filling pressure we observed. Limitations of the study: We tried to explain the observed differences between the effects of captopril and nitroprusside in our patients with severe heart failure by attributing to captopril actions opposite of those characteristic of angiotensin. However, since we only measured a limited number of central hemodynamic variables, our hypotheses are based on several assumptions. Although both drugs were titrated to produce similar decreases in systemic vascular resistance, direct measurements of ventricular afterload (wall stress and aortic impedance 35,36) were not performed; if these loading variables were affected differently by nitroprusside and captopril, this might have contributed to some of the differences we observed between them. We attributed observed differences in the effects of the 2 drugs on left heart filling pressure to hypothesized differences in their effects on ventricular compliance; yet, we did not measure ventricular volumes, and we assumed that the effects of nitroprusside were entirely attributable to peripheral vasodilation. However, nitroprusside may also alter ventricular pressure-volume relations, although such effects appear quantitatively less marked than those exerted by angiotensin. 5 Finally, we assumed that observed differences in the effects of the 2 drugs on heart rate were the result of a direct negative chronotropic effect of captopril, but since both drugs affected right and left ventricular filling pressures differently, differences in degree of reflex stimulation of intracardiac mechanoreceptors ~7 might also have accounted for the observed heart rate responses; captopril-induced decreases in heart rate may also be secondary to its effects on the Sympathetic nervous system. 38 Further work needs to be done to confirm by direct measurement the hypotheses suggested by our observations. Clinical implications: The differences we observed !n the circulatory effects of captopril and nitroprusside In our patients with severe heart failure have important clinical implications. Although captopril's negative Chronotropic effects could be clinically beneficial in Patients with underlying coronary artery disease, the eCrease in heart rate could potentiate the profound otension that is occasionally seen with initial doses

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of the drug11,12; indeed, the decreases in mean arterial pressure with captopril in heart failure patients are greater than those observed with most other vasodilator agents. Furthermore, patients with sick sinus syndrome may experience severe symptomatic bradycardias with the use of antihypertensive agents that possess direct negative chronotropic effects, 39 and caution should be exercised in the use of captopril in these patients. Of 54 patients with severe chronic heart failure that we have treated with captopril, 2 manifested asymptomatic but recurrent episodes of severe sinus bradycardia (heart rates <40 beats/rain), which were shown to be directly attributable to treatment with the drug by rechallenge studies. Both patients had a history compatible with sick sinus syndrome before institution of captopril therapy. Our findings that captopril has minimal effects on pulmonary arteriolar resistance also has clinical iraportance. The lack of a significant pulmonary vasodilator action suggests that captopril has limited usefulness in patients with marked impairment of right ventricular function, whereas most other systemic vasodilator drugs used in the management of heart failure possess marked effects on the pulmonary vasculature and can improve right heart performance. 4° As a result, the use of captopril should probably be avoided in patients with severe pulmonary vascular disease, regardless of whether it is structurally fixed or due to active vasoconstriction. In such patients, the fail~re of captopril to reduce transpulmonary resistances is likely to limit any increases in cardiac output that might otherwise be expected to accompany drug-induced systemic vasodilation, and this might result in profound systemic hypotension. This hypothesis requires further study. Conclusion: Our comparative study of the responses to Captopril and nitroprusside in patients with severe heart failure indicates that captopril exerts hemodynamic effects independent of its systemic vasodilator actions. These effects are consistent with the concept that the responses to captopril are mediated by inhibition of angiotensin, which has direct arterial vasoconstrictive and positive chronotropic actions and alters ventricular compliance, but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature. Acknowledgment: We are indebted to the nurses of the Ames and Rose Cardiac Care Units of the Mount Sinai Medical Center for their invaluable help in the completion of this study; to Leonard G. Dennick, MD, of the Squibb Institute for Medical Research, Princeton, New Jersey, who generously provided supplies of captopril; and to Irma Rosenblatt for secretarial assistance. References 1. Packer M, Le Jemtel TH. Physiologic and pharmacologic determinants of vasodilator response: a conceptual framework for rational drug therapy for chronic heart failure. Prog Cardiovasc Dis 1982;24:275-292. 2. Zells R, Flaim SF, Moskowifz RM, Nellis SH. How much can we expect from vasodUator therapy in congestive heart failure? Circulation 1979; 59:1092-1097. 3. Khatri I, Uemura N, Notargiacom A, Freis E. Direct and reflex cardiostimulatory effects on hydralazine. Am J Cardiol 1977;40:38-42. 4. Leier CV, Desch CE, Magorien RD, Triffon DW, Unverferth DV, !Boudoulas I.I, Lewis RP. Positive inotropic effects of hydralazine in human subjects:

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comparison with prazosin in the setting of congestive heart failure. Am J Cardiol 1980;46:1039-1044. 5. Alderman EL, Glantz SA. Acute hemodynamic interventions shift the diastolic pressure-volume curve in man. Circulation 1976;54:662-671. 6. Brodle BR, Grossman W, Mann T, McLaurin LP. Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations. J Clin Invest 1977;59:59-68. 7. Cohn PF, Maddox D, Holman BL, Markis JE, Adams DF, See JR. Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease. Am J Cardiol 1977;39:672678. 8. Ferguson RK, Tumini GA, Brunner HR, Gavras H. A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet 1977;1:775778. 9. Davis R, Ribner HS, Keung E, Sonnenblick EH, Le Jemtel TH. Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme. N Engl J Med 1979;301:117-121, 10. Turnlni GA, Brenner HR, Gribic M, Waeber B, Gavras H. Improvement of chronic congestive heart failure by oral captopril. Lancet 1979;1:12131215. 11. Ader R, Chatterjee K, Ports T, Brundage B, Hiramatsu B, Parmley W. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation 1980;61:931-937. 12. Levlne TB, Franciosa JA, Cohn JN. Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circulation 1980;62:35-41. 13. Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hollenberg N. Sustained effectiveness of converting-enzyme inhibition in patients with severe chronic heart failure. N Engl J Med 1980;302:1373-1379. 14. Miller RR, Mason DT, Zelis R, Amsterdam EA, Mason DT. Clinical use of sodium nitroprusside in chronic ischemic heart disease: effects on peripheral vascular resistance and venous tone and on ventricular volume, pump and mechanical performance. Circulation 1975;57:328-336. 15. Faxon DP, Halperin JL, Creager MA, Gavras H, Schlck EC, Ryan TJ. Angiotensin inhibition in severe heart failure: acute central and limb hemodynamic effects of captopril with observations on sustained therapy. Am Heart J 1981;101:548-556. 16. Packer M, Meller J, Gorlin R, Herman MV. Differences in the hemodynamic effects of nitroprusside and prazosin in severe chronic heart failure. Evidence for a direct negative chronotropic effect of prazosin. Am J Cardiol 1979;44:310-317. 17. Duncan DB. T tests and intervals for comparisons suggested by the data. Biometrics 1975;31:339-359. 18. Cohn JN, Taylor N, Vrobel T, Moskowltz R. Contrasting effect of vasodilators on heart rate and plasma catecholamines in patients with hypertension and heart failure (abstr). Clin Res 1978;26:547A. 19. Packer M, Meller J, Medina N, Yushak M, Gorlln R. Determinants of drug response in severe chronic heart failure. I. Activation of vasoconstrictor forces during vasodilator therapy. Circulation 1981 ;64:506-514. 20. Heyndrickx GR, Boettcher DH, Vatner SF. Effects of angiotensin, vasopressin and methoxamine on cardiac function and blood flow distribution in conscious dogs. Am J Physiol 1976;231:1579-1587. 21. Nishith SD, Davis LD, Youman WB. Cardio-acceleration action of angiotensin. Am J Physiol 1962;202:237-240. 22. Faggard R, Amery A, Reybrouck T, Lijnen P, Billiet L. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting

23. 24. 25.

26. 27. 28. 29.

30. 31. 32. 33.

34. 35. 36. 37. 38. 39. 40.

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