Acute and long-term effects of captopril on exercise cardiac performance and exercise capacity in congestive heart failure

Acute and long-term effects of captopril on exercise cardiac performance and exercise capacity in congestive heart failure Although many studies have shown that captopril (CPT) provides acute hemodynamic improvement in patients with severe congestive heart tatlure (CHF) at rest, little information is available concerning exercise hemodynamic responses to CPT or the effect of this drug on exercise tolerance in CHF. Therefore, we evaluated the hemodynamic effects of CPT at rest and during upright bicycle exercise in 15 patients with stable CHF. CPT (25 to 50 mg) reduced both resting heart rate and mean arterial pressure (84 + 11 to 78 + 7 bpm, p < 0.025 and 85 _+ 9 to 64 + 8 mm Hg, p < 0.001). Concomitantly, left ventricular filling pressure dropped dramatically (26 + 9 to 15 4 7 mm Hg, p < O.OOl), while cardiac and stroke indices rose (2.0 + 0.5 to 2.5 + 0.6 L/min/m2, p < 0.001, and 25 f 8 to 33 & 7 ml/m2, p < 0.001). Similar directional changes occurred during exercise, with heart rate, mean arterial pressure, and left ventricular filling pressure at maximum exercise being less (123 rt 15 to 115 + 16 bpm, p < 0.01; 93 _+ 17 to 86 f 14 mm Hg, p < 0.05; and 35 + 10 to 30 + 11 mm Hg, p < 0.001, respectively) after CPT ingestion. Peak exercise cardiac index rose slightly (3.6 + 0.7 to 3.9 + 0.6 L/min/ma) but not significantly. Six patients followed long term on CPT underwent elective recatheterixation after 3 months. In these, the beneficial hemodynamic changes seen acutely persisted or further improvement was noted, both at rest and during exercise. Most impressively, peak exercise cardiac index rose from 3.6 + 0.7 to 4.6 + 1.0 L/min/mz (p < 0.05), and this was associated with an increase in exercise duration (8.0 * 2.2 to 11.5 + 1.4 minutes, p < 0.05) and exercise work load (332 f 32 to 468 f 52 kp-m/min, p < 0.05). These findings indicate that in patients with severe CHF, oral CPT provides markedly beneficial augmentation of cardiac function during activity as well as at rest; moreover, chronic CPT therapy substantially increases exercise capacity in this setting. (AM HEART J 104:1172; 1982.)

Nina Topic, R.N., Barry Kramer,

M.D., and Barry Massie, M.D. Sun Francisco, Calif.

The efficacy of oral vasodilators in the treatment of chronic congestive heart failure (CHF) has become generally recognized. In this regard, the directacting vascular smooth muscle dilators such as hydralazine, minoxidil, and various nitrate preparations and the alpha-adrenergic antagonists such as prazosin and trimazosin have been used alone and in combination to achieve improved cardiac performance.l-14 Recently, several studies have demonstrated that captopril (CPT), an angiotensinconverting enzyme (ACE) inhibitor, produces sub-

From Center

the Cardiology Service of the and the Department of Medicine

Presented Cardiology, Supported Veterans Dr. Massie Reprint Veterans

1172

in part Atlanta,

Veterans Administration Medical of the University of California.

at the annual meeting Ga., April 26-29, 1982.

in part by NHLBI Administration and

of the

Grant HL 28146 the Squibb Institute

is a Clinical

Investigator

requests: Barry Administration

Massie, Medical

of the Veterans

American

College

of

and by grants from the for Medical Research. Administration.

M.D., Department of Medicine (lllc), Center, San Francisco, CA 94121.

stantial acute hemodynamic improvement in patients with chronic CHF.15-22 In a few patients, follow-up clinical and hemodynamic measurements have shown that the beneficial acute effect of this drug is usually maintained during chronic therapy.15-22 It is noteworthy that most of this information has been collected at rest in severely symptomatic patients with advanced left ventricular dysfunction, while few studies are presently available in ambulatory patients with CHF describing predominantly activity-related symptomatology. Therefore, we carefully evaluated the acute and chronic hemodynamic effects of extended CPT therapy on both rest and exercise ventricular function in a group of relatively stable outpatients with congestive cardiomyopathy. In addition, we sought to examine the relationship between the hemodynamic findings and measurements of exercise capacity during 3 months of uninterrupted therapy of heart failure with this oral ACE inhibitor.

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CPT effects on exercise performance

IOO-

90-

go-

1173

SVR

MAP I----p<.W’r- p<.OOll 1 oo-

in CHF

soy3000&300:

2 %

m s

w-

w-

6

Moo-

P E

70-

70-

$

1500-

0” 6050I PI9

I 90 min

%O-

1ooo-

50-

500-

I Peak

90 min

Peak

P:e

Peak

Fig. 1. Acute effect of CPT on HR, MAP, and SVR in 15 patients during rest. Pre = before CPT; 90 min = 90 minutes after CPT; Peak = peak CPT effect. METHODS Patient

Fifteen male outpatients with chronic CHF were entered into the study after giving informed consent. Their mean age was60 years (range 48 to 72 years). Symptoms of CHF had been present for a mean of 37 months (range 3 months to 8 years). Three patients were New York Heart Association (NYHA) class II, 10 were class III, and two had occasionalsymptoms during sedentary activity and were therefore consideredto be classIV at the time of the study. The etiology of CHF wascoronary artery diseasein 10 patients, coronary artery diseasewith hypertension in two, idiopathic cardiomyopathy in two, and rheumatic heart diseasefollowing mitral valve replacement in one. One patient had minimal aortic regurgitation, and eight had ausculatory evidence of secondary mitral regurgitation. All subjects were on stable dosesof digoxin and diuretics at least 2 weeksprior to entry into the study. Vasodilators were withdrawn at least4 weeksprior to entry in the three patients who were previously taking them. To qualify for inclusion, patients had to be able to exerciseon an upright bicycle for at least 3 minutes at a work load of 200 kp-m/min. Further, to ensure an exercise endpoint consistentwith heart failure (dyspnea or fatigue), patients with exercise-limiting angina, claudication, or pulmonary disease(asjudged by FEV, or FEVJFVC 70% lessthan of predicted) were excluded. Study protocol. Patients were hospitalized at least 24 hours prior to the baseline studies to ensure drug and dietary compliance.Digoxin and diuretics were continued and given every evening after completion of all measurements. On the first day, patients practiced on the upright bicycle ergometer to familiarize themselveswith the procedure and to estimate their exercisetolerance. The work load was initially set at 200 kp-m/min and was then increased by 100 kp-m/min every 3 minutes. Patients exercised until they developed limiting dyspnea and/or fatigue. population.

On the second day, patients were transfered to the coronary care unit, where a balloon-tipped thermodilution catheter was placed in the pulmonary artery percutaneously via the right subclavian vein, and a radial artery was cannulated. To achieve hemodynamic stability, patients were then allowed to rest for a minimum of 1 hour after instrumentation prior to baselinesupinemeasurementsof heart rate (HR), arterial pressure(AP), pulmonary artery pressureP (PA), right atrial pressure (RA), and pulmonary capillary pressurewedge(PCWP). The end-expiratory PCWP wasused as a measureof left ventricular filling pressure (LVFP) except in patients whose PA diastolic pressurewas substituted for a technically inadequate or unobtainable PCWP tracing. Cardiac output (CO) was determined in triplicate by thermodilution. Exercise was then performed according to the previously described protocol. HR, AP, and PAP were measuredcontinuously, while RAP and PCWP were measuredevery minute. CO wasdetermined in triplicate during the final 2 minutes of the highest work load achieved. Arterial and pulmonary artery blood gaseswere drawn at rest and at maximal exercise to calculate oxygen consumption. There was no significant difference in duration or work load between the practice and baselineexercises. On the following morning, therapy was begun with 25 mg of CPT given orally every 8 hours. Hemodynamic measurementswere taken prior to administration and 0.5, 1, 1.5, 2, 3,4,6, and 8 hours after CPT administration. On the fourth day of the study, the CPT dosagewasincreased to 50 mg, except in three patients who received 25 mg because of asymptomatic hypotension. Ninety minutes following CPT administration, supine resting hemodynamic measurementswere recorded. Upright exercisewas then performed as described above. Of the 15 patients studied acutely, sevenwere eventually discharged on CPT. The CPT dosagewas gradually increasedto 100 mg three times a day or as closeto this target dose aspermitted by the blood pressureresponse.

1174

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Kramer,

and Massie

American

LVFP

Cl

r----p<.ooi---l

November. 1982 Heart Journal

SI

r---p<.oo+--l

-p<.oo1-

40,

30 I” E 20 E 10,

0

l-

P:e

Peak

10-l Pie

Peak

2. Acute hemodynamic effect of CPT on LVFP, CI, and SI in 15 patients during rest. Pre = before CPT; 90 min = 90 minutes after CPT; Peak = peak CPT effect. Fig.

All other medications were maintained at constant dosages. After 3 months, six of these seven patients agreed to undergo elective recatheterization. On the morning of admission, CPT and diuretics were withheld. After a l-hour stabilization period following catheter placement, resting hemodynamic measurements were recorded. Patients were then given CPT, and hemodynamic measurementswere performed after 90 minutes of resting and exercise. CO and blood gaseswere measuredboth at the pretreatment maximum work load and when the patient was able to exerciselonger at peak exercise. Hemodynamic calculations. The following measurements were derived from the measured hemodynamic variables: co Cardiac index (CI) in L/min/m* = Body surface area Stroke index (SI) in ml/m2 = cI HR Systemic vascular resistance(SVR) in MAP - RAP dynes . set . cme5= co x 80 0, content (ml/dl) = 0, saturation x Hemoglobin concentration x 1.34 0, consumption (ml/min) = (Arterial 0, content-venous 0, content) X CO The arterial and mixed venous (pulmonary artery) oxygen saturations were derived from the PO, measurements using a standard nomogram. Statistical analysis. The significanceof the acute vasodilator effect of CPT on hemodynamic measurementsand on maximal oxygen consumption wasassessed by paired t tests. The relationship of acute and chronic effects of CPT on these measurementsand on exercise tolerance was analyzed using two-way analyses of variance and Neu-

mann-Keuls multiple range tests. All data are presented as the mean ? 1 SD. RESULTS

The effects of CPT in the 15 in Figs. 1 and 2. Both the go-minute measurements taken immediately prior to exercise and the peak resting response to CPT are shown. Peak drug effect, which was determined by the maximum reduction in blood pressure and SVR, occurred anywhere from 0.5 to 6 hours after CPT administration. At rest, CPT produced a modest but significant decrease in HR from 84 + 11 to 78 +- 11 bpm at 90 minutes (p < 0.01) and to 78 + 7 bpm at peak effect Cp < 0.025). MAP fell dramatically with CPT, from 85 +- 9 to 72 + 13 mm Hg at 90 minutes 0, < 0.001) and to 64 f 8 mm Hg (p < 0.001) at peak response. Systolic blood pressure dropped into the 60s in two patients, but both remained asymptomatic and required no treatment. Similarly, SVR was reduced from a pre-CPT level of 1600 + 500 to 1430 + 480 dynes . set - cme5 with this agent (p < 0.05) and further declined to 990 + 250 dynes . set . cme5 at peak drug effect (p < 0.001). LVFP decreased with CPT from 26 -t 9 to 18 rt 9 mm Hg at 90 minutes and further declined to 15 + 7 mm Hg at peak drug effect (both p < O.OOl), a mean peak reduction of 42%. Following CPT, CI rose by 25% at peak effect from 2.0 + 0.5 to 2.5 + 0.6 L/min/m2 (p < 0.001). However, because of the variable individual time courses of the CPT effect, there was no appreciable change for the group as a whole Acute

response

to CPT at rest.

resting hemodynamic measurements patients studied acutely are illustrated

at 90 minutes. SI changed in a similar manner, rising

Volume Number

104 5, Part 2

CPT effects on exercise performance HR -w.o1-

-

150-

MAP K.05 7

130-

in CHF

1175

SVR 7P<.O17 1400-

130In

-

f p llO-

1

Post

Pre

b;e

P;e

Fig. 3. Acute hemodynamic effects of CPT on HR, MAP, and SVR in 15 patients during exercise. Pre = before CPT; Post = after CPT.

LVFP

Cl

SI

-p<.Ol---y 60

-Pas-

6

1

60.

20. PkP

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-x---T

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Fig. 4. Acute hemodynamic effects of CPT on LVFP, CI, and SI in 15 patients during exercise. Pre = before CPT; Post = titer CPT.

by 32% at peak effect from 25 & 8 to 33 f 7 ml/m” (p < O.OOl), and showing no significant change at 90 minutes. Acute response to CPT during exercise. The acute hemodynamic effects of CPT during exercise were directionally similar to those at rest (Figs. 3 and 4). During upright exercise, CPT produced significant hemodynamic improvement at the same level of exercise achieved prior to treatment. Thus, exercise, maximum HR decreased from 123 ? 15 to 115 & 16 bpm (p < O.Ol), and MAP fell from a pre-CPT level of 93 t- 17 to 86 + 14 mm Hg (p < 0.05). It is particularly noteworthy that although exercise markedly lowered SVR to 900 & 174 from a resting value of 1660 + 500 dynes . set . cm+, there was a further reduction during exercise to 780 + 207 dynes . set . cmT5 03 < 0.01). LVFP at the same level of exercise was reduced from 35 f 10 before

CPT to 30 f 11 mm Hg (p < 0.001) after CPT ingestion. Simultaneously, the maximum CI rose slightly from 3.6 + 0.7 to 3.9 +- 0.6 L/min/m*), but this change was not significant b > 0.05). There was, however, a modest but significant increase in SI from 30 +- 5 to 34 + 8 ml/m” (p < 0.05). Resting hemodynamic apy. The six patients

response

to chronic

CPT ther-

maintained on CPT therapy who were restudied at 3 months were comparable to the larger group in terms of their age, etiology of heart failure, duration of heart failure, NYHA functional class, and pretreatment hemodynamic measurements. Table I shows the change in resting hemodynamic measurements after 3 months of CPT therapy. In this smaller group, the slight decrease in HR seen both acutely and chronically was not significant. The CPT-effected acute decline in MAP from 83 f

1176

Topic, Kramer,

and Massie

American

Heart Rate

1

Pre

November, 1982 Heart Journal

Mean Arterial Pressure

3 Mos

---x--l

Pre

3 Mos

Fig. 5. Acute and chronic (3 months) hemodynamic effects of CPT on HR and MAP in six patients during exercise. Pre = before CPT; Post = after acute CPT therapy; 3 mos= after 3 months of CPT therapy.

1. Chronic hemodynamic effect of CPT in six patients at rest Table

Post-CPT Pre-CPT HR MAP LVFP CI SI SVR

77 83 25 2.1 28 1480

+A + + 2 f

Acute 8 9 10 5 9 260

71 67 16 2.6 36 970

‘- 10 I 6* + 8* k 4* z!z 6* * 210*

3 months 69 80 16 2.4 34 1290

+ + k -t + *

8 12 7* 0.5t 7t 220t

* = p < 0.01. t = p < 0.05.

9 to 67 + 9 mm Hg 0, < 0.01) was greatly attenuated at 3 months to 80 f 12 mm Hg (p > 0.05). On the other hand, the acute beneficial effect of the CPT on LVFP, a reduction from 25 f 10 to 16 + 8 mm Hg (p < O.Ol), was maintained during chronic therapy (16 + 7 mm Hg, p < 0.01). Similarly, the increase in CI from 2.1 + 0.5 to 2.6 rt 0.4 L/min/m2 (p < 0.01) seen acutely with CPT persisted at 3 months (2.4 * 0.5 L/min/m2, p < 0.05). The acute decrease in SVR with CPT from 1480 + 260 to 970 + 210 dynes . set . cmm5 (p < 0.01) was somewhat attenuated, but the 3-month SVR value (1290 f 220 dynes . set - cms5, p < 0.05) was still below the control value. Chronic

exercise

hemodynamic

response

to CPT.

The chronic response to CPT during exercise in the patients restudied is shown in Figs. 5 and 6. HR, which decreased slightly from 122 -+: 12 to 111 f 15 bpm with acute therapy, was not significantly different ‘(114 + 23 bpm, p < 0.05) at 3

months. MAP during exercise, which had demonstrated a tendency to decline acutely, returned to the pretreatment level (p > 0.05) during chronic treatment. Exercise LVFP showed an even greater decrease at 3 months of CPT administration than acutely, declining from 40 rt 11 to 26 -+ 11 mm Hg, 03 < 0.05). The small acute increase in maximum CI from 3.6 f 0.7 to 4.0 f 0.6 L/min/m2 0, > 0.05) achieved significance during chronic CPT therapy when it rose to 4.6 f 1.0 L/min/m” (p < 0.05). Exercise SI also improved further at 3 months of CPT therapy to 42 +- 6 ml/m2 (p < 0.01) from the acute treatment value of 36 ? 9 ml/m2. Acute and chronic effects of CPT on exercise tolerance. Despite the acute hemodynamic improvement

at rest and during exercise, there was no immediate change in exercise duration, work load, or oxygen consumption; in contrast, after 3 months of CPT therapy each of these indices of exercise capacity had improved in every patient (Fig. 7). Mean exercise duration increased by 31% from 8.0 it 2.2 to 11.5 + 1.4 minutes 3 months (p < 0.05) after CPT, with individual increases ranging from 2 to 7.5 minutes. Mean maximum work load increased during CPT treatment from 332 & 32 to 469 + 52 kpm/min at 3 months (p < 0.05), an improvement of 41% . Maximum oxygen consumption rose by 25 % from 11.8 f 2.6 to 15.6 +- 2.7 ml/min/kg at 3 months (p < 0.05), with the individual increments ranging from 0.9 to 7.9 ml/min/kg. The two patients who exhibited the greatest improvement in work load and oxygen consumption also had the largest increase in CI and SI. Clinical response during chronic CPT therapy. The

Volume Number

104 5, Part 2

CPT effects on exercise performance LVFP -6.05

in CHF

i 177

SI -

1P<.O5--7

-P‘-ly

6.

60

Fig. 6. Acute and chronic (3 months) hemodynamic actions of CPT on LVFP, CI, and SI in six patients during exercise. Pre = before CPT; Post = after acute CPT therapy; 3 mos = after 3 months of CPT therapy.

Duration

Workload

--p<.Ol-

P[re

0,

--P-11

3 Mos

Consumption

l---!5.05-

i!i-iLzs

Pie

3 Mos

Fig. 7. Acute and chronic (3 months) effects of CPT on duration of bicycle exercise, work load, and oxygen consumption in six patients. Pre = before CPT; Post = after acute CPT therapy; 3 mos= after 3 months of CPT therapy.

clinical response to chronic CPT treatment in the six patients who were electively recatheterized was variable. Although all six patients showed improvement in exercise duration, work load, and oxygen consumption, only two improved by a full NYHA functional class, from classes III and IV to II and III, respectively. These two patients also exhibited the greatest increases in exercise work load, oxygen consumption, CI, and SI. Three patients improved subjectively and increased their exercise tolerance, although the improvements were not sufficient to warrant a change in NYHA classification. The remaining patient showed no subjective or objective response. The one patient who did not agree to elective recatheterization showed modest improvement. Chronic CPT therapy was well tolerated, with

only one patient experiencing a mild taste alteration and transient skin rash, both of which were felt to be drug related. DISCUSSION

CPT is unique among the currently available oral vasodilating agents in that it specifically inhibits the converting enzyme responsible for production of angiotensin II.23 This action interferes with compensatory reflex mechanisms that are responsible for elevating SVR and increasing sodium and volume retention in patients with chronic CHF. Thus, the inhibition of angiotensin II generation with CPT would be anticipated to result in a fall in SVR and left ventricular afterload with a consequent improvement in CO. Indeed, these findings have

1178

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Kramer,

and Massie

been previously documented following the administration of the oral ACE inhibitor at rest.15-22Further, we and other investigators have demonstrated that CPT has a considerably beneficial effect on LVFP that is not adequately explained by its effect on In addition to being angiotensin II levels. 14-20,22,24 indirectly related to the beneficial effects of impedance reduction associated with this agent, this salutary preload-lowering effect of CPT may be caused by concomitant supplementary vasodilator action of bradykinin or prostaglandins25v 26or by an increase in venous capacitance caused by a reflex withdrawal of sympathetic tone posttreatment.23v27 Moreover, an improvement in renal function secondary to increased CO, an increase in renal blood flow as the vasoconstrictor effects of angiotensin II dissipate, and the decreased stimulus for sodium and fluid retention as aldosterone levels fall may help to promote a diuresis that also reduces preload. Acute effects of CPT on resting and exertional hemodynamic actions. The acute effects of CPT on resting

hemodynamic measurements in our group of 15 patients were similar to those reported in previous studies. At peak drug effect, SVR decreased a mean of 38% (Fig. l), CI and SI rose by 25 % and 32 % , respectively (Fig. 2), and there was a mean reduction of 42% in LVFP (Fig. 2). These beneficial changes were important in documenting a response to therapy typical for patients with CHF, but they occurred when our patients were inactive and thus asymptomatic. In contrast to most previous studies, all of our patients were ambulatory outpatients who were clinically stable, with symptoms present predominantly during exertion. Since our patients were able to exercise, we sought to determine whether CPT exerted beneficial hemodynamic effects during symptomatic activity and whether there was an association between these drug effects and subsequent changes in exercise capacity. Our results establish that acute administration of CPT exerts a beneficial effect during upright exercise, with hemodynamic changes similar to those occurring at rest. Since the exercise hemodynamic measurements were made 90 minutes after drug administration rather than at peak effect, there was only a modest increase in CI (Fig. 4). However, following CPT therapy this CI was achieved at a lower maximum heart rate (Fig. 3) and higher SI compared to the baseline performance (Fig. 4). Importantly, the rise in LVFP with exercise was blunted by CPT (Figs. 2 and 4), and SVR decreased an additional 13% during exercise after CPT treatment (Fig. 3). Interestingly, this acute hemodynamic improvement produced by ACE inhibition with

American

November, 1982 Heart Journal

CPT was not matched by an immediate improvement in exercise capacity (Fig. 7). Exercise duration, maximum work load, and maximum oxygen consumption were unchanged with acute CPT administration. Hemodynamic rest and exercise.

effect

of extended

CPT therapy

on

This dichotomy disappeared in the six patients continued on long-term CPT therapy. At 3 months, not only were the hemodynamic benefits of CPT at rest and during exercise sustained in these patients, but all three measurements of exercise capacity were not improved (Table I, Figs. 5 to 7). At rest, CPT continued to cause a significant increase in CI and a reduction in LVFP (Table I), while MAP had returned toward baseline levels and SVR remained lower as a result of the sustained increase in CI. The hemodynamic benefit of chronic CPT therapy was even more apparent during exercise. CI, which rose modestly and insignificantly after acute CPT administration, further increased 18% on sustained treatment and overall improved 28% from baseline (Fig. 6). Similarly, exercise SI rose an additional 17%) and the abnormal increment in LVFP during exercise before CPT therapy showed further attenuation, rising only to a mean of 26 mm Hg after 3 months of treatment (Fig. 6). Most important, the sustained improvement in rest and exercise hemodynamic left ventricular function provided by CPT was transformed clinically in our patients into a considerable increase in exercise capacity (Fig. 7). Each of the six patients was able to increase his exercise duration a minimum of 2 minutes, exercising at least one work load stage higher and achieving a higher oxygen consumption. Conclusions. We have shown that CPT produces beneficial hemodynamic changes at rest and during upright exercise in ambulatory patients with typical, chronic CHF. These changes, while important, are not associated with an immediate improvement in the functional capacity of the patient; however, in a small group of patients maintained on CPT for 3 months, the acute hemodynamic benefit is not only sustained but appears to further increase, especially during exercise. During chronic therapy, the hemodynamic improvement is accompanied by an increase in exercise capacity. These results substantiate the effectiveness of maintenance CPT therapy in the treatment of CHF. REFERENCES

1. Fitchett DH, Oakley CM, Goodwin JF: Hydralazine in the management of left ventricular failure. Am J Cardiol44:303, 1979. 2. Chatterjee K, Ports TA, Brundage BH, Massie B, Holly AN,

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Parmley WW: Oral hydralazine in chronic heart failure: Sustained beneficial hemodynamic effects. Ann Intern Med 92:600, 1980. Massie B, Kramer B, Houghom F: Acute and long-term effects of vasodilator therapy on resting and exercise hemodynamics and exercise tolerance. Circulation 64:1218, 1981. Feldman R, Ball R, Winchester M, Harrison D: Beneficial hemodynamic response to chronic prazosin therapy in congestive heart failure. AM HEART J 101534, 1981. Awan NA, Needham KE, Evenson MK, Amsterdam EA, Mason DT: Therapeutic application of prazosin in chronic refractory congestive heart failure: Tolerance and “tachyphylaxis” in perspective. Am J Med 71:153, 1981. Franciosa JA, Cohn JN: Sustained hemodynamic effects without tolerance during long-term isosorbide dinitrate treatment of chronic left ventricular failure. Am J Cardiol45:648, 1980. Franciosa JA, Mikulic E, Cohn JN, Jose E, Fabie A: Hemodynamic effects of orally administered isosorbide dinitrate in patients with congestive heart failure. Circulation 50:1020, 1974. Taylor WR, Forrester JS, Magnusson P, Takano T, Chatterjee K, Swan HJC: Hemodynamic effects of nitroglycerin ointment in congestive heart failure. Am J Cardiol 54:879, 1976. Chatterjee K, Parmley WW, Massie B, Greenberg B, Werner J. Klausner S, Norman A: Oral hydralazine therapy for chronic refractory heart failure. Circulation 54:879, 1976. Franciosa JA. Pierpont G. Cohn JN: Hemodvnamic imorove_ ment after oral hydralazine in left ventricular failure. Ann Intern Med 86:388, 1977. Massie B, Chatterjee K, Werner J, Greenberg B, Hart R, Parmlev WW: Hemodvnamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol 40:794, 1977. Miller RR, Awan NA, Maxwell KS, Mason DT: Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator prazosin. N Engl J Med 297:303, 1977. Franciosa JA, Cohn JN: Hemodynamic effects of trimazosin in patients with left ventricular failure. Clin Pharmacol Med 23jl1, 1978. Franciosa JA, Cohn JN: Effects of minoxidil on hemodynamits in patients with congestive heart failure. Circulation 63:652, 1981. Ader R, Chatterjee K, Ports T, Brundage B, Hiramatsu.B, Parmley W: Immediate and sustained hemodynamic and

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17.

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23. 24.

25.

26.

27.

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clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation 81:931, 1980. Davis R, Ribner HS, Keung E, Sonnenblick E, LeJemtel T: Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme. N Engl J Med 301:117, 1979. Tarazi R, Fouad R, Ceimo JK, Bravo EL: Renin, aldosterone, and cardiac decompensation: Studies with an oral convertingenzyme inhibitor in heart failure. Am J Cardiol 44:1013, 1979. Levine TB, Franciosa JA, Cohn JN: Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circulation 62:35, 1980. Dzau VJ, Colucci WS, Williams GH, Cureman G, Meggs L, Hollenberg NK: Sustained effectiveness of convertingenzyme inhibition in patients with severe congestive heart failure. N Engl J Med 302:1373, 1980. Awan NA, Evenson MK, Needham KE, Win A, Mason DT: Efficacy of oral angiotensin-converting enzyme inhibition with captopril therapy in severe chronic heart failure. AM HEART J 101:22, 1981. Faxon DP, Halperin JL, Schick EC: Angiotensin inhibition in severe heart failure: Acute central and limb hemodynamic effects of captopril with observations on sustained oral therapy. AM HEART J 101:548, 1981. Awan NA, Amsterdam EA, Hermanovich J, Bommer WJ, Needham KE, Mason DT: Long-term hemodynamic and clinical efficacy of captopril therapy in ambulatory management of severe chronic congestive heart failure. AM HEART d 103:474, 1982. Peach MJ: Renin-angiotensin system: Biochemistry and mechanisms of action. Physiol Rev 57:313, 1977. Rose JC, Kot PA, Cohn JN, Freis ED, Eckert GE: Comparison of effects of angiotensin and norepinephrine on pulmonary circulation, systemic arteries, and veins and systemic vascular capacity in the dog. Circulation 25:247, 1962. Engel SL, Schaeffer TR, Gold BI, Rubin B: Inhibition of pressor effects of angiotensin I and augmentation of depressor effects of bradykinin bv svnthetic neotides. Proc Sot EXD Biol Med 1403246, 1972. - . . Dorer. . FE, JW, Stewart JM: Hydrolysis of bradykinin . Ryan . and its homologues by angiotensin converting enzyme. Biothem J 141:915, 1974. Zimmerman BG, Gomer SK, Liao JC: Action of angiotensin on vascular adrenergic nerve endings: Facilitation of norepinephrine release. Fed Proc 31:1344, 1972.