Effects of beta adrenergic blocking agents and calcium antagonists on atherogenic properties of blood serum of patients with ischemic heart disease

The beta-adrenoblockers anapriline and visken and the calcium antagonist corinfar were studied for effects on the atherogenic properties of the sera from patients with coronary heart disease who took the drugs. The study was performed by using cultured atherosclerotically altered human aortic smooth muscle cells. A single dose of anapriline, 80 mg, and that of visken, 20 mg, were found to give rise to or to enhance atherogenic properties of the patients' sera, while that of corinfar, 20 mg, yielded their antiatherosclerotic properties.     

Effects of intrinsic sympathetic activity of beta-blockers on SA and AV nodes in man

The authors compare the effects of beta-blockers without intrinsic sympathetic activity (ISA) (propranolol, 160 mg/day), moderate ISA (acebutolol, 800 mg/day) and high ISA (pindolol, 20 mg/day). The sinus rate decreases more with propranolol than with acebutolol, during the day (P less than 0.01) and during the night (P less than 0.001), whereas pindolol does not change the daylight rate and increases the nighttime rate (P less than 0.001). The ventricular rate during atrial fibrillation (AV nodal transmission) is modified as is sinus rate. There is no significant difference between propranolol and acebutolol, and a highly significant difference between pindolol and propranolol (P less than 0.001) or acebutolol (P less than 0.01). Moreover, the eurythmic effect of beta-blockers, making RR intervals more regular, is maximal with propranolol and minimal with pindolol, as judged on RR interval histograms. The ISA of the beta-blockers is of major importance for the clinical use of these drugs, and in the case of SA or AV node dysfunction ISA can be useful, but it can obscure the beneficial effects of beta-blocking therapy.     

The role of alpha-receptors in bronchoconstriction induced by beta-blockade

We examined 10 patients with an exercise-induced asthma. Physical exercise was carried out under placebo, 40 mg propranolol, 5 mg pindolol and 50 mg metoprolol, respectively, before and after alpha blockade. After exercise, we noted a distinct increase of airway resistance in all cases, the increase of which, however, was lower after a preceding alpha blockade. Under propranolol, the increase of the airway resistance and of norepinephrine, as compared with pindolol, metoprolol, and placebo, was most intensive.     

Beta-blockers: propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol, manifest atherogenicity on in vitro, ex vivo and in vivo models. Elimination of propranolol atherogenic effects by papaverine.

The addition of the beta-blockers propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol to a culture of peritoneal macrophages or smooth muscle cells induced an increase in the intracellular cholesterol content. Blood serum obtained from a rabbit after a peroral administration of beta-blockers also induced cholesterol accumulation. This property of drug or blood serum obtained after peroral administration is conventionally referred to as atherogenic potential or atherogenicity. Regular administration of propranolol during a 21-day period evoked stable atherogenicity of rabbit blood serum. This was accompanied by stimulation of manifestations of atherosclerosis in the aorta deendothelialized with a balloon catheter. Propranolol increased neointimal thickening, lipid accumulation, an increase in cell number and in the collagen content. In vitro, the combination of propranolol with papaverine eliminated the atherogenic effect of propranolol which manifested itself as stimulation of cholesterol accumulation in cultured cells. Simultaneous peroral administration of propranolol and papaverine prevented the appearance of serum atherogenicity. Papaverine eliminated neointimal thickening, an increase in cell number and in the lipid and collagen contents evoked by propranolol. Papaverine itself had no effect on these parameters. Thus, the atherogenicity of propranolol as well as capacity of papaverine to eliminate beta-blocker atherogenicity revealed in cell culture was confirmed in vivo. We hope that these results may be useful in the development of new drugs and optimization of antiatherosclerotic drug therapy.     

The influence of intrinsic sympathomimetic activity on regional left ventricular function; use of regional ejection fraction to demonstrate a beneficial action by pindolol over propranolol on hypokinetic segments

In a previous report from our laboratory, visual assessment of wall motion in patients with coronary artery disease demonstrated no advantage for pindolol, a beta blocking agent with intrinsic sympathomimetic activity (ISA), over propranolol on impaired regional left ventricular (LV) function. In this study, we reanalyzed the radionuclide ventriculograms using a computer-assisted method of deriving regional ejection fraction. Use of normalized values allowed hypokinetic and normokinetic segments to be identified and examined separately. Pindolol (5-10 mg twice a day) was compared to propranolol (40-80 mg 4 times a day) in 23 patients using a randomized, crossover study design. Supine resting heart rate was reduced less (70 +/- 12 beats/min vs 63 +/- 10 beats/min, p less than 0.01) by pindolol; exercise heart rate was reduced equally by both agents. Derivation of normalized regional LV ejection fractions showed that 17 segments were hypokinetic at rest. Function of these segments increased (p less than 0.02) with pindolol. This improvement was not detected by visual assessment of regional wall motion. Thirty-seven segments were found to be hypokinetic during exercise and a significant (p less than 0.05) improvement in function occurred with pindolol and propranolol. In summary, derivation of normalized regional LV ejection fraction values allows the demonstration of significant improvement in resting LV function with pindolol, but not with propranolol in patients with regional dysfunction due to coronary artery disease. This advantage may provide a rationale for further evaluation of this agent in patients with more widespread ventricular dysfunction.     

Comparison of the effects of pindolol and propranolol on exercise performance in patients with angina pectoris

The effects of pindolol (mean dose 17 +/- 8 mg/day), a beta-blocking drug with intrinsic sympathomimetic activity (ISA), and propranolol (130 +/- 40 mg/day) on exercise performance in 11 patients with stable angina pectoris were compared. Doses were titrated to symptoms. The design was a randomized, double-blind, crossover protocol with 8 weeks of treatment with each drug. At the end of each drug period, subjects performed 3 exercise tests: a symptom-limited test on a cycle ergometer with measurement of gas exchange parameters; a steady-state exercise test to measure cardiac output by the CO2 rebreathing method; and a supine exercise test with radionuclide angiography. The ISA effect of pindolol was evident at rest in that the heart rate of 82 +/- 4 beats/min was higher than with propranolol (70 +/- 3). At low levels of exercise heart rate, cardiac output and O2 consumption (VO2) were still higher. However, there was no difference in cardiac output or VO2 at higher levels of exercise and no difference in the VO2 at the anaerobic threshold and peak exercise. Peak VO2 was 1,344 +/- 108 ml/min with propranolol and 1,350 +/- 116 with pindolol therapy. There were also no differences in ejection fraction or cardiac volumes at rest or during exercise. The incidence of side effects was similar with both drugs and there was no significant preference for either medication. In conclusion, patients with angina treated with pindolol had the same peak exercise performance as with an 8:1 equivalent dose of propranolol (clinically equivalent), although at lower levels of exercise, VO2, cardiac output and heart rate were higher from the ISA of pindolol.     

Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation

Beta-adrenergic blocking agents differ considerably in their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might contribute to such differences has not been adequately explored. This study examined the influence of intrinsic sympathomimetic activity on the electrophysiologic effects of three agents with varying degrees of such activity. Intravenous propranolol (0.5 mg/kg), oxprenolol (0.5 mg/kg) and pindolol (0.05 mg/kg) were administered in 16 anesthetized dogs. The effects of the drugs on ventricular vulnerability were studied over a 2 hour period. Propranolol and oxprenolol raised the ventricular fibrillation threshold by 42 and 56%, respectively. In contrast, pindolol resulted in an elevation of only 25%. After depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decrease of the ventricular fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic activity of beta-adrenergic blocking agents substantially alters their ultimate effect on myocardial excitable properties.     

Hemodynamic effects of beta-adrenergic blockade with pindolol, oxprenolol, propranolol and bufetolol hydrochloride in essential hypertension.

Hemodynamic studies (using (131)I-labeled albumin [RISA]) Were performed before and 5 and 42 weeks after the oral administration of pindolol (av. 30 mg/day), oxprenolol (av. 216 mg/day), propranolol (av. 75 mg/day) or bufetolol hydrochloride (av. 30 mg/day) in 40 patients with essential hypertension. Responders to the antihypertensive actions of short-term (5 weeks) pindolol or bufetolol showed a reduction in total peripheral resistance (pindolol, from av. 2622 to 2022 dyne-sec-cm-5-m2; befetolol, from av. 3301 to 2620, p less than 0.05), without significant changes in cardiac index, while hypotensive actions of propranolol or oxprenolol appeared to be due mainly to a decrease in cardiac output (propranolol, from av. 4.03 to 2.99 L/min/m2; oxprenolol, from av. 3.97 to 3.29 L/min/m2), although the decrease in cardiac output was not significant. In long-term (42 weeks) oxprenolol therapy, antihypertensive effects seemed to be related to reduced cardiac output and a readaptation of peripheral resistance to chronic reduction of cardiac output was not always observed. Circulation time was determined in 9 patients with oxprenolol therapy and 8 with pindolol therapy by the measurement of the arrival time in the cerebral hemisphere of the intravenously injected radioisotope. The patients with oxprenolol therapy showed significant prolongation in circulation time (short-term administration, av. 6.6 to 8.4 sec; long-term administration av. 6.6 to 9.2 sec, p less than 0.05), while no prolongation was observed in pindolol therapy. These results suggest that hemodynamic responses to beta-blocking agents are not uniform and that the antihypertensive actions of beta-blockers depend on the effects on both cardiac output and peripheral vascular resistance.     

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 6. A comparison of pindolol and propranolol in treatment of patients with angina pectoris. The role of intrinsic sympathomimetic activity.

Pindolol, a new beta-adrenergic blocking drug with intrinsic sympathomimetic activity, and propranolol were given in increasing equipotent doses (pindolol: 2.5 to 10 mg. every 6 hours; propranolol: 10 to 40 mg. every 6 hours) over 12 weeks in a double-blind randomized trial to 41 patients with angina pectoris. The drugs were then gradually withdrawn over a two week period. With maximum doses, both pindolol and propranolol increased exercise capacity, compared to control, on multistage treadmill testing (pindolol: 8.0 ± 0.4 to 9.7 ± 0.3 mets, p < 0.01; propranolol: 8.0 ± 0.4 to 9.6 ± 0.3 mets, p < 0.05). At each exercise level both pindolol and propranolol decreased the heart rate, systolic blood pressure, and rate-pressure product (HR × BP). At the 9 met exercise level, the HR × BP decreased from 17,420 ± 850 to 13,205 ± 510 mm. Hg min.^?1 with pindolol (p < 0.002); with propranolol; 18,106 ± 440 to 13,205 ± 480 mm. Hg min.^?1 (p < 0.01). At the same level the magnitude of exercise-induced ECG ST depression decreased from 1.3 ± 0.3 to 0.4 ± 0.15 mm. with pindolol (p < 0.05), and from 1.3 ± 0.3 to 0.8 ± 0.2 mm. with propranolol (p < 0.05). Both drugs reduced the number of spontaneous attacks of angina pectoris per week. Pindolol did not appreciably decrease the resting heart rate (66.8 ± 1.9 vs 64.6 ± 1.2) or HR × BP (8,254 ± 418 vs 7,651 ± 210 mm. Hg min.^?1 in contrast to propranolol, which reduced both (heart rate: 70.5 ± 2.2 to 62.2 ± 2.4, p < 0.01; HR × BP: 8,677 ± 423 to 7,338 ± 455 mm. Hg min.^?1, p < 0.005). In addition, pindolol slightly increased the echocardiographically estimated ejection fraction at rest (0.59 ± 0.02 to 0.62 ± 0.02, p < 0.02), while propranolol depressed it (0.57 ± 0.02 to 0.51 ± 0.01, p < 0.04). Both pindolol and propranolol could be safely withdrawn over a gradual two week withdrawal interval.     

Comparison of slow-release pindolol, standard pindolol, and propranolol in angina pectoris

Twenty-two patients with chronic, stable, exercise-induced angina pectoris were assessed during periods of therapy with propranolol, standard-formulation pindolol, and a slow-release preparation of pindolol. Patients maintained diaries of the frequency of angina pectoris and nitroglycerin consumption and underwent treadmill exercise testing at 2 weekly intervals. No significant differences were observed in nitroglycerin consumption or anginal frequency during these 3 treatment programs. Resting heart rates were higher with pindolol than with propranolol, but no differences were noted between periods on standard and slow-release pindolol. Systolic and diastolic blood pressures were similar during therapy with these 3 treatment programs. Treadmill walking time to the development of moderate angina and systolic and diastolic blood pressure was similar during treatment with propranolol, standard-formulation pindolol, and slow-release pindolol. Exercise heart rates were slightly higher during therapy with slow-release pindolol than during standard-formulation pindolol. It is concluded that propranolol, pindolol, and slow-release pindolol are equally effective in the management of patients with chronic, stable, exercise-induced angina.     

Effect of pindolol and propranolol on sinus node recovery time and atrioventricular conduction intervals

In a randomized, observer-blind study, the effect of incremental doses of pindolol 0.001, 0.002, 0.003, and 0.004 mg/kg IV and propranolol 0.01, 0.02, 0.03, and 0.04 mg/kg IV on SA nodal recovery time (SNRT) and atrioventricular conduction interval (AH) was assessed in 20 patients (15 men and 5 women age range thirty to seventy-two, mean age fifty-three). AH and His bundle-to-ventricle (HV) intervals and SNRT were measured at spontaneous heart rate and at incremental atrial pacing rates (80, 100, 120, 140 bpm). Both drugs caused significant beta blockade as estimated by the percentage suppression of heart rate increment induced by 3 mcg isoproterenol administered intravenously (pindolol 67.6 +/- 5.3%, P less than 0.007; propranolol 38.6 +/- 10.6%, P less than 0.001). Propranolol significantly prolonged SNRT (P less than 0.05) and AH interval (P less than 0.05). Pindolol did not significantly affect either SNRT (P = 0.25) or AH intervals (P = 0.78). Significant effects on HV interval were not seen. Thus, in the doses tested that resulted in significant beta blockade, propranolol prolonged SA nodal recovery times and depressed AV nodal conduction while pindolol did not affect these variables.     

Comparison of the subacute hemodynamic effects of atenolol, propranolol, pindolol, and nebivolol

In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant (p = 0.02) and comparable for the four drugs studied and varied between 15% and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEPc) to the left ventricular ejection time (LVETc), an indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. PEPc/LVETc progressively and significantly improved with nebivolol from a control value of 0.37 +/- 0.012 to 0.31 +/- 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEPc and an increase in LVETc, suggestive of a combined effect both on preload and afterload. Postexercise LVETc, an index of the intrinsic positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a beta 1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular compliance.     

Influence of propranolol, metoprolol, and pindolol on mucociliary clearance in patients with coronary heart disease

The effects of the beta-adrenoceptor-blocking drugs propranolol, metoprolol, pindolol, and placebo, on mucociliary clearance were studied in three groups of 6 subjects with coronary heart disease and normal lung function. Clearance rates of inhaled 99mTc-labeled human serum albumin minimicrospheres were determined over the apical right region of the lung with a gamma camera. A 3-day medication of propranolol 40 mg b.i.d., when compared with placebo, led to a significant decrease (p less than or equal to 0.05) in mucociliary clearance. Metoprolol 50 mg b.i.d. or pindolol 5 mg b.i.d. did not show any influence on mucociliary clearance. Implications for the use of different types of beta-adrenoceptor-blocking drugs in the treatment of coronary heart disease are discussed.     

Effects of pindolol and propranolol on blood lipids in hypertensive patients

Summary Since beta-blockers could affect lipid levels at the therapeutic dose range in hypertensive patients, a parallel 6-month randomized trial with pindolol (PDL) (16 pts.) and propranolol (PPL) (23 pts.) was designed (mean age=55+7.1 years and 57+8.0 years; 9 males, 7 females and 15 males, 8 females, respectively). Total cholesterol, LDL and HDL fractions, and triglycerides (TGs) were determined before (washout phase) and during 1, 3, and 6 months of therapy. Patients were instructed to maintain their usual dietary habits. Daily drug doses were adjusted step by step to attain an optimal hypotensive effect (PDL 15–45 mg, PPL 180–240 mg). In the PPL-treated group, total cholesterol and LDL did not change significantly, HDL decreased (from 45.2 to 40.5 mg/dl, p<0.05) and TG increased (from 133 to 169 mg/dl, p<0.05). In the PDL group total cholesterol and LDL did not change either, but HDL increased (35.9 to 44.7 mg/dl, p<0.01) and TGs, were reduced (from 169 to 131 mg/dl, p<0.05). No dose-effect relationship was recorded. It is concluded that pindolol does not negatively influence HDL nor the TG blood lipid profile as does PPL. Accordingly, pindolol might be preferred to propranolol in the treatment of hypertensive patients with an unfavorable lipid profile, but this assumption remains to be proven in larger, prospective, long-term followup trials.     

Hemodynamic effects of hydrochlorothiazide, propranolol and a combination of pindolol and clopamide in patients with essential hypertension

To characterize the haemodynamic effects of diuretics, betablockers and the association of both, 24 hypertensive patients, stages I-II WHO criteria, were studied. Two haemodynamic studies were performed, before under placebo and after two month of active drug therapy. Seven patients received propranolol (PPL) (160-240 mg/day); 7 patients, hydrochlorothiazide (HCT) (150-100 mg/day), and 10 a combined fixed dose of pindolol (PDL) and clopamide (CLP): PDL 10 mg, CLP 5 mg per tablet, each patient receiving one to three tablets according blood pressure response. The haemodynamic study was performed with percutaneous intravenous flow-directed. Swan-Ganz catheter, associated with direct puncture of femoral artery and measuring cardiac output by thermodilution. Arterial pressure was significantly reduced on PPL (p less than 0.05) and PDL-CLP (p less than 0.01) groups, but not in the HCT group. The cardiac index was reduced by PPL (p less than 0.05) but not by HCT and PDL-CLP. The systemic vascular resistance was only reduced in the PDL-CLP group (p less than 0.05). The use of a betablocker with intrinsic sympathetic activity (ISA) (pindolol) in association with a thiazide diuretic (clopamide) seems to induce a favourable change in systemic resistance without a deleterious change in cardiac output as occurred with propranolol.     

Effects of beta-adrenoceptor-related agents on hypoxic pulmonary vasoconstriction and relation with cyclic AMP and prostaglandins]

Effects of a beta-agonist (isoproterenol) and beta-antagonists (propranolol and pindolol) on hypoxic pulmonary vasoconstriction (HPV) and on changes in some chemical mediators were compared between HPV-responsive lobes and non-responsive lobes in which HPV was induced by aspirin DL-lysine (ASA groups). Hypoxic ventilation (4 min) was repeated in 56 of isolated, blood-perfused dog lung lobes. Each drug was administrated in a bolus dose of 0.2 mg in the intermittent period between hypoxia. In HPV-responsive lobes, the first hypoxia increased pulmonary vascular resistance by 33% or more in all groups. Both isoproterenol and pindolol inhibited the elicitation of HPV completely, but propranolol induced almost the same degree of HPV as control. In ASA groups, HPV was completely inhibited by isoproterenol, but was not influenced by propranolol. However, pindolol's inhibitory effect on HPV was less than that in HPV-responsive lobes. Isoproterenol significantly increased cyclic AMP from 17.0 to 76.7 pmol/ml in HPV-responsive lobes (n = 7). Pindolol increased prostaglandin E2 from 87.0 to 1015.4 pg/ml in HPV-responsive lobes (n = 7), and from 93.4 to 361.3 pg/ml when ASA was treated. Propranolol did not show the different results from the control group whether ASA was present or not. The different mechanisms among beta-adrenoceptor-related agents in HPV and pulmonary circulation were investigated.     

Interaction between two calcium antagonists and two beta blockers in conscious rabbits: hemodynamic consequences of differing cardiodepressant properties

The interaction between beta-adrenoreceptor blockers and calcium antagonists may occasionally be dangerous. The effects of the new calcium antagonist PN 200-110 (isradipine) were compared with those of verapamil in 3 groups of conscious rabbits pretreated with either pindolol 0.3 mg/kg, propranolol 1 mg/kg intravenously or placebo. Each animal received PN 200-110 (0.01, 0.03 and 0.1 mg/kg) and 2 or more days later verapamil (0.1, 0.3 and 1 mg/kg). The calcium antagonists were given to lower mean blood pressure to the same extent as in the placebo group. This blood pressure effect remained unchanged after pretreatment with pindolol or propranolol. Both PIN 200-110 and verapamil increased heart rate to the same extent as in the placebo group. Both beta blockers blunted the effect of PN 200-110 on heart rate but converted the verapamil-induced tachycardia to bradycardia. Propranolol blunted the PN 200-110-induced increase in cardiac output and total peripheral conductance, whereas the high verapamil dose decreased cardiac output and caused peripheral vasoconstriction in propranolol-pretreated animals. Thus, both agents lowered blood pressure by peripheral vasodilatation in the placebo group, after beta blockade; however, the mechanism of the verapamil-induced blood pressure decrease changed from pure vasodilation to a decrease in cardiac output, i.e., cardiac depression. Verapamil but not PN 200-110 prolonged the PQ interval, especially in animals who had received beta blockade. Most differences in the interaction were attributable to differences between the 2 calcium antagonists; the differences between the beta blockers were small and in favor of pindolol.     

Effect of intrinsic sympathomimetic activity on the ability of hypertensive patients to derive a cardiorespiratory training effect during chronic beta-blockade

The effect of intrinsic sympathomimetic activity (ISA) on the ability of patients with high blood pressure (BP) to derive a cardiorespiratory training effect during long-term beta-blocker therapy was studied. Fifty sedentary hypertensive subjects were randomly assigned to propranolol (n = 23) or pindolol (n = 27) therapy for a 22 week double-blind parallel study. Over the first 2 weeks, during which subjects remained sedentary, drug doses were titrated to produce equipotent, clinically significant BP reductions. Subjects subsequently continued drug therapy and completed 20 weeks of exercise training. Although pindolol tended to preserve submaximal exercise heart rates to a greater degree than propranolol, the initial 2 weeks of drug therapy resulted in equivalent reductions in maximal oxygen uptake with propranolol (6% reduction) and pindolol (8% reduction). Likewise, 20 weeks of training induced similar, statistically significant (P = .0001) increases in maximal oxygen uptake during propranolol (10% increase) and pindolol (11% increase) treatment. We therefore conclude that ISA does not confer any advantage to patients with high BP who receive chronic beta-blocker therapy and wish to improve their cardiorespiratory fitness by participating in exercise training.     

Clinical, cardio- and hemodynamic effects of long- and short-acting beta-adrenergic blockers in the treatment of patients with stable stenocardia

Sixty-nine coronary heart disease patients with stable angina of effort of Classes II-IV of functional activity were studied for the effect of three nonselective beta-adrenergic blockers on the incidence and intensity of angina attacks, on the tolerance to exercise on the bicycle ergometer, as well as on the heart rate, arterial pressure, cardiac volumes and intracardiac hemodynamics using a complex of clinical and instrumental methods. It was proved that nadolol, pindolol and propranolol hydrochloride possessed similar anti-anginal effects but nadolol exerted the greatest negative chronotropic action while propranolol hydrochloride exerted a negative inotropic action. As regards the degree of the effect on cardiac volumes, corgard (nadolol) occupied an intermediate position between anaprilin (propranolol hydrochloride) and visken (pindolol).     

A study on the cardiodepressant action of a beta-blocking agent carteolol in heart-lung preparation of the dog

Direct cardiodepressant activities of three beta-blockers, carteolol, pindolol and propranolol, were estimated using heart-lung preparation of the dog. Beta-blocking doses of these drugs to inhibit the positive chronotropic effect of isoproterenol by 50% were 2.2 micrograms for carteolol, 4.0 micrograms for pindolol and 21 micrograms for propranolol. Cardiac performance of the preparation was not influenced by up to 1 mg of these three beta-blockers. After 10 mg of these drugs, the cardiac function curves were shifted rightward and downward indicating the heart failure. It was doubtful, however, that this result indicated the cardiodepressant action of beta-blockers, for the preparation showed spontaneous deterioration without beta-blocker treatment. The influences of these beta-blockers on the compromised heart-lung preparations showed essentially similar results. In conclusion, direct cardiodepressant activity of the beta-blocker, if any, was exerted with far more large doses than their beta-blocking doses. The implication of the results in clinical use of beta-blockers, especially in relation to heart failure, was discussed.