(model 460, Ohio-Nuclear Inc., Solon, Ohio).'6 Data were collected in a continuous electrocardiographic mode, with 16 frames spanning the cardiac cycle.
The clinical and hemodynamic effects of propranolol, pindolol and verapamil in the treatment of exertional angina pectoris m&dicaments ont souvent repondu A l'un des autres m&dicaments, et les effets secondaires de l'un des m6dicaments n'etaient pas necessairement ressentis avec un autre. En resume, le pindolol et le v4rapamil se sont tous deux reveles comme m6dicaments de relais surs et The efficacy of two d-receptor antagonists, propranolol efficaces dans le traitement de l'angine de poitrine and pindolol, was compared with that of a calcium d'effort chez ces patients. antagonist, verapamil, in the treatment of exertional angina pectoris in 22 men (mean age 51 years). The Propranolol is a nonselective d-receptor antagonist freclinical response and left ventricular function were quently used in the treatment of exertional angina evaluated with treadmill exercise and with radionuclide pectoris.' Occasionally, adverse reactions, lack of theraventriculography performed while the patient was at rest peutic response or the presence of other disease states or exercising supine with a bicycle ergometer. All the (e.g., bronchospasm, diabetes or left ventricular failure) treatments significantly prolonged exercise duration (p < lead a patient's physician to seek alternative agents with 0.001) and reduced the number of patients terminating different mechanisms of action.2 Pindolol and verapamil treadmill exercise because of angina (p < 0.05). The are currently being investigated in North America for resting heart rate was decreased markedly (p < 0.001) by the treatment of exertional angina.3'4 propranolol but only slightly (p < 0.05) by pindolol and Pindolol, because of its intrinsic sympathomimetic verapamil. The left ventricular ejection fraction during activity, is a weak adrenergic-receptor agonist.5 When rest was unchanged by any treatment, but that during the patient is at rest this property allows the drug to exercise was improved (p < 0.05) by all the treatments. exert a mild stimulating effect at the A3-receptor sites, Patients who failed to gain relief from angina with one of whereas during exercise it causes full blockade. Althe drugs often responded to another, and adverse though not yet clearly demonstrated, this property may reactions occurring with one drug did not necessarily favour the use of pindolol in situations in which occur with another. In summary, pindolol and verapamil 1-receptor stimulation is desirable (for example, in the were safe and effective alternatives to propranolol in the presence of bronchospasm, left ventricular dysfunction treatment of the exertional angina pectoris of these or cardiac conduction disorders).`69 patients. During submaximal exercise verapamil decreases the heart rate by reducing sinus node automaticity and L'efficacite de deux inhibiteurs des recepteurs 13, le decreases the blood pressure by causing peripheral propranolol et le pindolol, a ete comparee a celle du vasodilation.'°"' During maximal exercise other variaverapamil, un antagoniste des ions calcium, dans le bles, such as coronary vasodilation and improved left traitement de l'angine de poitrine d'effort chez 22 ventricular diastolic function, both of which would hommes (age moyen de 51 ans). La reponse clinique et la facilitate antegrade and collateral coronary blood flow, fonction ventriculaire gauche ont ete evaluees par l'epreu- may play a role in verapamil's action.'2"3 Verapamil's ve d'effort sur tapis roulant ainsi que par ventriculogra- ability to cause vasodilation and its lack of effect on phie isotopique au repos et a l'effort avec une bicyclette bronchial tone suit it for use in patients with peripheral ergometrique en position couchee. Les trois traitements vascular disease or chronic obstructive pulmonary disont tous prolonge de facon significative la duree de ease. l'epreuve d'effort (p < 0,001) et reduit le nombre de We compared the clinical and hemodynamic effects patients devant interrompre l'exercice sur tapis roulant a of these two new antianginal agents with those of the cause d'une crise d'angine (p < 0,05). La frequence established agent, propranolol. The protocol was apcardiaque au repos a ete nettement diminuee (p < 0,001) proved by the health sciences standing committee on par le propranolol mais de facon beaucoup moins mar- human research of the University of Western Ontario. quee (p < 0,05) par le pindolol et le verapamil. La fraction d'ejection ventriculaire gauche est demeuree Methods inchangee au repos, mais elle a kte amelioree a l'effort (p < 0,05) par tous les traitements. Les patients qui Subjects n'obtenaient pas de soulagement de l'angor avec l'un des All patients presenting to University Hospital's cardiFrom the cardiac investigation unit, University Hospital and the ac investigation unit were interviewed as possible candidates for the trial, and 23 who had previously had department of medicine, University of Western Ontario, London angina during an exercise test were selected from among Reprint requests to: Dr. William J. Kostuk, Cardiac investigation unit, University Hospital, PO Box 5339, Terminal A, London, Ont. the outpatients and those of the inpatients who had N6A 5A5 undergone cardiac catheterization. After giving written DONALD L. JOHNSTON, MD, FRCP[C] DANTE E. MANYARI, MD, FRCP[C] WILLIAM J. KOSTUK, MD, FRCP[C]
CAN MED ASSOC J, VOL. 130, JUNE 1, 1984
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informed consent the 22 men and 1 woman, whose ages ranged from 40 to 68 (mean 51) years, were weaned from their antianginal medication over a period of 3 days. They then entered a 4-day prestudy evaluation to confirm their eligibility and determine their clinical characteristics. Physical examination showed no hypertension, valvular heart disease or other organ disease. All 23 patients had stable exertional angina of functional class 3, as defined by the Canadian Cardiovascular Society,'4 and a positive stress electrocardiogram (one with a horizontal or downward-sloping depression of 1 mm or more in three consecutive ST segments) while exercising upright. They all had to stop the treadmill exercise test because of angina. While exercising supine with a bicycle ergometer 17 of them had a positive stress electrocardiogram. Whether resting or exercising all were in sinus rhythm, with a PR interval of 0.2 seconds or less and a QRS complex lasting 0.12 seconds or less. Although all 23 were entered into the randomized portion of the study, the 1 woman dropped out at an early stage. A second group of 28 healthy, untrained men (mean age 55 years) volunteered to undergo exercise radionuclide ventriculography. None of them had a history of cardiovascular disease, and in all the results of physical examination, chest roentgenography, stress electrocardiography, thallium-201 scintigraphy and technetium 99m ventriculography were normal. They served as a control group for comparison of changes in left ventricular volume. Study design In this unblinded crossover trial the order of the three drug treatments and a single control period was randomized by means of a table of random numbers. The treatment periods lasted 4 to 6 weeks and the control period 1 to 4 weeks (the longer times accommodating the need to reduce the dosage of the 3-blockers gradually). Propranolol and pindolol were administered orally at dosages of 40 mg four times a day and 5 mg twice a day respectively, but the doses were doubled if fl-blockade was not adequate; in this case only the data obtained with the higher dosages were analysed. Betablockade was considered adequate if the maximum heart rate during exercise was lower than 120 beats/min and if there was less angina than there had been during the prestudy evaluation. Verapamil, given orally, was used only at a dosage of 80 mg three times a day in an effort to reduce the likelihood of side effects. At the end of each period the patients underwent, successively, treadmill testing and radionuclide ventriculography in conjunction with bicycle exercise while supine. Their reports of adverse effects were recorded, and their compliance with treatment was checked by pill counts. The five patients who took long-acting nitrates at constant dosages during the trial stopped taking these agents 24 hours before each session of exercise testing and assessment. Clinical and hemodynamic testing Symptom-limited treadmill exercise testing was used with a modified Bruce protocol.'5 The speed and grade 1450
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were changed in increments every 3 minutes. Exercise was performed about 2 hours after the last dose of medication. Heart rate and blood pressure were measured and a 12-lead electrocardiogram was obtained with the patient upright, first at rest, then at the end of each stage of the test and again immediately after the exercise session. Exercise duration was measured to the nearest 5-second interval. ST-segment depression was measured in the lead that showed the greatest change immediately after the exercise. The reason for stopping the exercise was recorded. Equilibrium radionuclide ventriculography was performed with the patient supine, first at rest and then while performing bicycle exercise. The initial workload of 25 W was increased by 25 W every 3 minutes until the patient had to stop the exercise.'6 The heart rate, blood pressure and electrocardiographic changes were also measured during this form of exercise. The patients' erythrocytes were labelled in vivo with 20 mCi of 99mTc pertechnetate, and then cardiac scintigraphy was' performed in the left anterior oblique position that best isolated the left ventricle. Images were collected over 2 minutes with a conventional Anger scintillation camera equipped with a high-sensitivity, parallel-hole collimator and connected to a dedicated medical computer system (model 460, Ohio-Nuclear Inc., Solon, Ohio).'6 Data were collected in a continuous electrocardiographic mode, with 16 frames spanning the cardiac cycle. Analysis was carried out with a mobile medical computer (model 550, Ohio-Nuclear). To calculate the global left ventricular ejection fraction both the background and the left ventricular regions of interest were outlined manually with the aid of an endless-loop cine display.'7 The left ventricular ejection fraction during rest (RV) was shown to be closely correlated (r = 0.92, p < 0.001) with the results of biplane contrast angiography (CV) in the 28 healthy volunteers (CV = 0.9RV + 3.7% [standard error of the estimate, 7.6%]). The percent changes in end-diastolic and end-systolic volumes between rest and exercise and between exercise and the postexercise period were calculated by a method described and validated by Sorensen and colleagues.'8 Statistical analysis We used two-way analysis of variance to determine the significance of circulatory changes and of changes in the left ventricular ejection fraction and volumes. Tukey's multiple comparison test was used to compare means when significance was detected. If the distribution of the measurements appeared to be skewed the Wilcoxon signed-rank test was used. We compared frequency differences with the McNemar test. To analyse changes occurring between rest and maximal exercise, the t test for paired data was used. Probabilities of 5% or less were considered signiflcant. Results The one woman who entered the randomized portion of the study became asymptomatic with the first treatment and refused to participate further. In five and six patients respectively the higher dosages of propranolol and pindolol were needed to achieve adequate 13-blockade.
Adverse effects Three patients reported fatigue as an adverse effect while taking propranolol, three did so while taking pindolol and two did so while taking verapamil. Constipation occurred in four patients while they were receiving verapamil. Two noted leg cramps with propranolol and four did so with pindolol. A generalized maculopapular rash occurred in one patient while taking verapamil. Disturbing dreams and impotence were recorded occasionally with all treatments.
Clinical and hemodynamic findings Exercise duration was significantly increased (p < 0.001) by all three drugs; there were no differences 9
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between the treatments (Fig. 1). During the control period all the patients terminated the treadmill exercise because of angina, but during treatment with propranolol, pindolol and verapamil only 16, 14 and 14 patients respectively did so; this reduction was significant for all the treatments (p < 0.05). The other patients stopped exercising because of fatigue or dyspnea. Of the 16 patients who stopped exercising because of chest pain while taking propranolol, 4 did not have to do so with pindolol, and 3 did not have to with verapamil. Of the 14 who stopped exercising because of chest pain while taking pindolol, 3 did not have to do so with propranolol, and 5 did not have to with verapamil. Of the 14 who had to stop exercising because of chest pain while taking verapamil, 3 did not have to with propranolol and 4 did not have to with pindolol. In all, of the 22 patients who completed the study protocol 10 did not experience angina during treadmill exercise while taking one or another of the study medications. Relative to the control valuds all three drugs lowered the heart rate and the rate-blood pressure product while the patients were upright and resting, but during maximal treadmill exercise only propranolol and pindolol had this effect (Table I). This difference between' the (3-blockers and verapamil was signiflcant (p < 0.001). The systolic blood pressure was not significantly lowered by any of the treatments when the patients were resting, but during exercise both propranolol and pindolol had this effect. During bicycle exercise all three drugs significantly lowered the heart rate and ratepressure product, but only propranolol and pindolol reduced the systolic blood pressure significantly (Table II). There was less ST-segment depression when the patients were receiving medication (Table III), but during treadmill exercise 13, 9 and 12 of the 22 still had a positive stress electrocardiogram while taking propranolol, pindolol and verapamil respectively. During bicycle exercise seven, five and seven patients had positive stress electrocardiograms while taking propranolol, pindolol and verapamil respectively. There were no significant differences between treatments. No alterations in the PR interval were observed.
Fig. 1-Effect of treatment on exercise duration (mean standard error of the mean [SEMI) and on frequency of treadmill-induced angina during control period (C) and during treatment with propranolol (Pr), pindolol (Pi) and verapamil (V) Left ventricular ejection fraction and volume among 22 patients with exertional angina. Differences between control and treatment values significant at p < *0.05 or tO.001. The left ventricular ejection fraction during rest
was
Table I-Effect of propranolol, pindolol and verapamil on heart rate, systolic blood pressure and rate-pressure product in 22 patients during rest or treadmill exercise Mean ± standard deviation (SD)*
Heart rate
(beats/min) Period Control Treatment Propranolol Pindolol Verapamil
Rest
Systolic pressure (mm Hg)
76 i 11
Exercise 136 23
126
65 + 10§ 69 ± llt 71 + 10t
111 16§ 108 i 12§ 134 4 11
119 14 122 ± 13 117± 14
Rest 16
Exercise 162 21
Rate-pressure product ([mm Hg/min]l0-2) Rest Exercise 96 ± 21 220 49
142 21§ 139 ± 17§ 155 21
77 17§ 84 ± 17t 83 1O0t
159 38§ 150 ± 26§ 209 ± 36
*Differences between control and treatment values were significant at p < tO.05, t0.01 or §0.001. CAN MED ASSOC J, VOL. 130, JUNE 1, 1984
1451
not changed by any treatment. During bicycle exercise, however, all three drugs appeared to prevent the significant drop in left ventricular ejection fraction that was observed during the control period, although none of them altered the marked rise that occurred after the exercise (Fig. 2). Assessment of the 28 healthy volunteers showed a slight increase in the mean end-diastolic volume during Table II-Effect of drug treatment on heart rate, systolic blood pressure and rate-pressure product during supine bicycle exercise Mean i SD*
Heart rate (beats/min) 118 i 13
163 + 21
Rate-pressure product ([mm Hg/min10-2) 193 ± 37
98 :i 10§ 97 ± 12§ 110 M 12t
152 i 214 151 i 20* 158 ± 21
150 i 34§ 147 ± 25§ 174 ± 32t
Systolic
Period
Control Treatment Propranolol Pindolol Verapamil
pressure
(mm Hg)
bicycle exercise (Fig. 3). In the patients the end-diastolic volume increased significantly more than this amount during exercise (p < 0.01), whether or not they were receiving one of the drugs. After exercise there were no significant differences in this measure between the volunteers and the patients or between the control and treatment periods. In the healthy volunteers the mean end-systolic volume decreased during bicycle exercise (Fig. 3), whereas among the patients it increased significantly (p < 0.001) Table III-Effect of drug treatment on electrocardiographic changes recorded during exercise
Exercise (and position); ST-segment depression (mm),* mean X SD
Control Treatment Propranolol Pindolol Verapamil
*Differences between control and treatment values were significant at p < tO.05, *0.01 or §0.001.
1.95 i 0.95
Bicycle (supine) 1.50 i 1.00
1.47 i 0.83 1.45 i 0.95 1.45 ± 0.86
1.10 ± 0.72 1.20 ± 0.62 0.90 ± 0.64
Treadmill (upright)
Period
*All the treatment values were significantly lower (p < 0.05) than the control values.
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CAN MED ASSOC J, VOL. 130, JUNE 1, 1984
in the control period. This rise was limited by propranolol and verapamil but not by pindolol. After the exercise the mean end-systolic volume fell to resting levels in the control and treatment periods alike. Coupled with the slight increase in end-diastolic volume, this drop pushed the calculated ejection fraction above the resting values in both the control and the treatment periods.
Discussion A major aim of this study was to compare the effects of propranolol, pindolol and verapamil.on left ventricular function. An open study design was felt to be suitable for this purpose. The more subjective data obtained with treadmill exercise testing were adequate to demonstrate the efficacy of the drugs but must be interpreted within the limitations of an open trial. Angina prophylaxis is better evaluated in double-blind studies. Other considerations important in evaluating the clinical response reported in this study relate to the drug dosages used. A greater therapeutic effect might have been obtained with higher dosages.'92' In establishing the adequacy of A3-receptor blockade, heart rate may not have been a completely satisfactory parameter, for it is possible that higher doses of propranolol could have further reduced the frequency of angina and the amount of ST-segment depression while causing little decrease in the heart rate during exercise.22 Regarding verapamil, early studies showed that a daily dose of 240 mg was effective in controlling angina.23 Pine and associates2'
demonstrated that as the dosage was increased to 480 mg the frequency of adverse effects became unacceptable. Although others have recently confirmed that higher dosages of verapamil are effective24 we elected to use lower doses to avoid side effects.
Effects on left ventricular function
Despite two decades of the drug's use, propranolol's effect on the resting left ventricular ejection fraction remains controversial. A literature review suggests that the route of administration plays an important role in propranolol's effect. Intravenous administration of propranolol is usually associated with a reduction in the left ventricular ejection fraction,2526 which is not often found with sustained oral therapy.26 We have demonstrated that propranolol, pindolol and verapamil given orally do not change the resting left ventricular ejection fraction. Less in dispute is propranolol's effect on the resting cardiac volume. Studies using both intravenous and oral administration of this drug have shown that propranolol causes an increase in the size of the left ventricle.25'2 Whether it does this by increasing diastolic filling time, depressing contractility or both has not been clearly established.28 Pindolol has been shown to cause little change in the left ventricular ejection fraction and volumes whether given intravenously or orally.32930 Pindolol may have a direct stimulating effect on the myocardium, as it has been shown to reduce lactate production and redistribute blood to ischemic regions.3' However, these changes have not -been shown to be clinically significant. Verapamil's effect on left ventricu-
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Fig. 3-Effect of exercise on end-diastolic volume (EDV) and end-systolic volume (ESV) in same 22 patients during control and treatment periods and in 28 normal subjects (N). Values are means i SEM. Exercise-induced increase in EDV was significantly greater (p < 0.01) for patients than for normal subjects in all periods. In patients ESV increased significantly (p < 0.001) with exercise in all periods, but increase was limited (p < 0.05) by propranolol and verapamil; asterisks indicate that postexercise values were significantly different (p < 0.001) from exercise values. CAN MED ASSOC J, VOL. 130. JUNE 1, 1984
1453
lar function is controversial, and this may reflect the different dosages, routes of administration and diagnostic techniques that have been used for investigation.32 Fortunately, when left ventricular function is normal, any depressant effect of verapamil appears to be of little clinical importance because the afterload is reduced through peripheral vasodilation.` In agreement with our findings, several studies have shown that propranolol, pindolol and verapamil can improve left ventricular function during exercise in patients with coronary artery disease.293334 Moreover, these agents may limit the increase in volume that results from ischemia.35'36 In our study propranolol and verapamil (but not pindolol) reduced the increase in the exercise-induced end-systolic volume that was seen in the control period. This increase had resulted in a decrease in the ejection fraction, but following exercise there was a marked rebound in the ejection fraction owing to a sharp decline in the end-systolic volume without a corresponding fall in the end-diastolic volume. The changes seen in our patients differed markedly from the normal response in our healthy subjects, in whom the ejection fraction rose with exercise as the end-systolic volume decreased and then fell slightly after exercise as the end-systolic volume returned to resting values. Rozanski and coworkers36 also observed a marked improvement in postexercise left ventricular function when drugs were given and hypothesized that this was due to an increase in inotropic stimulation from an exercise-induced surge in catecholamine production.36 By causing a relative reduction in the exercise-induced increase in the end-systolic volume all three drugs that we used prevented a significant fall in the ejection fraction. However, none of them prevented the subsequent rise in the postexercise ejection fraction. If the explanation provided by Rozanski and coworkers was correct, it is surprising that fl-receptor blockade did not limit the postexercise increase in our patients. The relief of exercise-induced myocardial ischemia may have helped increase the ejection fraction. Circulatory and electrocardiographic changes In common with others we found that the circulatory changes induced by the two fl-blockers during rest and exercise differed only in that the depression in the resting heart rate was greater with propranolol.3'29 Pindolol's weak adrenergic agonist effect was presumably overwhelmed during exercise by an increase in sympathetic activity, while its fl-blocking action remained intact to restrict the rise in the heart rate and blood pressure. Because verapamil did not alter the ratepressure product during exercise, we believe that its mechanism of action may differ from that of the fl-blocking agents, which reduce myocardial oxygen requirements. Although no comparative electrophysiologic data are available, propranolol and verapamil prolong conduction through the atrioventricular node, while pindolol appears to have a weaker depressant effect.8"l0 In our study none of these agents significantly prolonged the PR interval, which suggests that when this interval is normal a clinically significant depression of conduction does not occur. 1454
CAN MED ASSOC J, VOL. 130, JUNE 1, 1984
Clinical implications All three agents delayed or prevented the onset of angina and improved left ventricular function during exercise. Some patients who failed to gain relief from angina with one agent obtained relief with another. Moreover, adverse effects that occurred with one form of treatment did not necessarily appear with another. Pindolol and verapamil proved to be as safe and effective as propranolol for the treatment of exertional angina pectoris. We thank Kathleen Osagie and Paul Purves for their technical assistance and Allan Donald for his biostatistical help. The verapamil was provided by G.D. Searle and Co. of Canada, Limited. This study was supported in part by the Ontario Heart Foundation and Sandoz (Canada) Limited.
References 1. FOWLER NO (ed): Treatment of coronary artery disease: angina pectoris. In Cardiac Diagnosis and Treatment, 3rd ed, Har-Row, Hagerstown, Md, 1980: 732-747 2. FRISHMAN W, SILVERMAN R, STROM J, ELKAYAM U, SONNENBLICK E: Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 4. Adverse effects. Choosing a ,adrenoreceptor blocker. Am Heart J 1979; 98: 256-262 3. KOSTIS JB, FRISHMAN W, HOSLER MH, THORSEN NL, GONASUN L, WEINSTEIN J: Treatment of angina pectoris with pindolol: the significance of intrinsic sympathomimetic activity of beta blockers. Am Heart J 1982; 104: 496-504 4. WEINER DA, KLEIN MD: Verapamil therapy for stable exertional angina pectoris. Am J Cardiol 1982; 50: 1153-1157 5. AELLIG WH: Clinical pharmacology of pindolol. Am Heart J 1982; 104: 346-356 6. HAMILTON BP, HAMILTON J, KIRKENDALL WM: Pulmonary function in hypertensive patients treated with pindolol: a report of two studies. Ibid: 432-437 7. TAYLOR SH, SILKE B, LEE PS: Intravenous beta-blockade in coronary heart disease. Is cardioselectivity or intrinsic sympathomimetic activity hemodynamically useful? N Engl J Med 1982; 306: 631-635 8. HOMBACH V, BRAUN V, HoPP HW, GIL-SANCHEZ D, BEHRENBECK DW, TAUCHERT M, HILGER HH: Electrophysiological effects of cardioselective and non-cardioselective ,-adrenoceptor blockers with and without ISA at rest and during exercise. Br JClin Pharmacol 1982; 13 (suppl 2): 285S-293S 9. BARRETT AM, NUNN B: Intrinsic sympathomimetic activity in relation to the precipitation of heart failure by beta-adrenoceptive blockade. Arch Int Pharmacodyn 1971; 189: 168-174 10. KAWAI C, KONISHI T, MATSUYAMA E, OKAZAKI H: Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on the sinoatrial and atrioventricular nodes. Experimental and clinical studies. Circulation 1981; 63: 1035-1042 11. SINGH BN, ROCHE AHJ: Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977; 94: 593-599 12. DA Luz PL, MONTEIRO DE BARROS LF, LEITE JJ, PILEGGI F, DECOURT LV: Effect of verapamil on regional coronary and myocardial perfusion during acute coronary occlusion. Am J Cardiol 1980; 45: 269-275 13. BONOw RO, LEON MB, ROSING DR, KENT KM, LIPSON LC, BACHARACH SL, GREEN MV, EPSTEIN SE: Effects of verapamil and propranolol on left ventricular systolic function and diastolic filling in patients with coronary artery disease. Radionuclide angiographic studies at rest and during exercise. Circulation 1982; 65: 1337-1350
14. CAMPEAU L: Grading of angina pectoris [C]. Circulation 1976; 54: 522-523 15. ROBERTSON D, KOSTUK WJ, AHUJA SP: The localization of coronary artery stenoses by 12 lead ECG response to graded exercise test: support for intercoronary steal. Am Heart J 1976; 91: 437-444 16. MANYARI DE, NOLEWAJKA AJ, PURVES P, DONNER A, KOSTUK WJ: Comparative value of the cold-pressor test and supine bicycle exercise to detect subjects with coronary artery disease using radionuclide ventriculography. Circulation 1982; 65: 571-579 17. JOHNSTON DL, GEBHARDT V, BOUGHNER DR, PATEL A, PURVES P, KOSTUK WJ: Mitral stenosis: right and left ventricular volume assessed by radionuclide ventriculography [abstr]. J Nucl Med 1983; 24: P27 18. SORENSEN SG, RITCHIE JL, CALDWELL JH, HAMILTON GW, KENNEDY JW: Serial exercise radionuclide angiography. Validation of count-derived changes in cardiac output and quantitation of maximal exercise ventricular volume change after nitroglycerin and propranolol in normal men. Circulation 1980; 61: 600-609 19. ALDERMAN EL, DAVIES RO, CROWLEY JJ, LOPEZ MG, BROOKER JZ, FRIEDMAN JP, GRAHAM AF, MATLOF HJ, HARRISON DC: Dose-response effectiveness of propranolol for the treatment of
angina pectoris. Circulation 1975; 51: 964-975 20. FRISHMAN W, KOSTIS J, STROM J, HOSSLER M, ELKAYAM U, GOLDNER S, SILVERMAN R, DAVIS R, WEINSTING J, SONNENBLICK E: Clinical pharmacology of the new beta-adrenergic blocking agents. Part 6. A comparison of pindolol and propranolol in treatment of patients with angina pectoris. The role of intrinsic sympathomimetic activity. Am Heart J 1979; 98: 526-535 21. PINE MG, CITRON PD, BAILLY DJ, BUTMAN S, PLASENCIA GO, LANDA DW, WONG RK: Verapamil versus placebo in relieving stable angina pectoris. Circulation 1982; 65: 17-22
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The effects of moderate and high dose propranolol on ventricular function in patients with coronary artery disease [abstr]. Am J Cardiol 1981; 47: 430 23. PHEAR DN: Verapamil in angina: a double-blind trial. Br Med J 1968; 2: 740-741 24. SUBRAMANIAN B, BOWLES M, LAHIRI A, DAVIES AB, RAFTERRY ED: Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing. Am J Cardiol 1981; 48: 529-535 25. COLTART J, ALDERMAN EL, ROBISON SC, HARRISON DC: Effect of propranolol on left ventricular function, segmental wall motion, and diastolic pressure-volume relation in man. Br Heart J 1975; 37: 357-364
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