Comparative cardiovascular effects of propranolol and practolol in puppies.

The present results indicate that in 3-4-weeks-old puppies propranolol induces a significant depression of cardiovascular function expressed by a decrease in heart rate, myocardial contractility, and cardiac output, and an increase in systemic vascular resistance, in doses beyond beta-blocking levels. In contrast, practolol, in the same dose range, did not induce further cardio-circulatory depression, as shown by levels of heart rate, myocardial contractility, and cardiac output similar to the values obtained with beta-blocking doses of this agent. The cardio-depressant activity observed in puppies with doses of propranolol beyond blocking levels is thought to be due to direct negative inotropic and chronotropic effects of this agent, not related to influences on beta receptor sites. Such effect not observed with practolol at doses well beyond beta-blocking levels suggests that this drug exerts a more selective influence on cardiac sympathetic beta receptors.     

Effect of propranolol on glycerol induced acute renal failure in rats

The effect produced by propranolol, administered for a prolonged period of time and in large doses, on renal function in rats has been studied, as well as the modifications induced by this treatment in an experimental model of acute renal failure, and the effects of a single dose of propranolol given 1 hour before provoking failure. Propranolol, administered chronically, causes sodium and water retention and increases creatinine clearance. Acute renal failure induced by glycerol in rats treated for 7 days with propranolol is less severe than the one produced in untreated animals. In this ARF model, a single dose of propranolol does not seem to have a protective effect.     

High dose propranolol in the treatment of angina pectoris: relationship of dose to blood levels and hemodynamic consequences

Propranolol blood levels and the effect of these levels on hemodynamic parameters were evaluated in 25 patients with coronary artery disease undergoing cardiac catheterization and coronary angiography. Fifteen patients were receiving high doses of propranolol (320--1920 mg/day) while ten patients were receiving conventional doses (80--240 mg/day). The high dose propranolol group had significantly higher plasma propranolol levels than the conventional dose group (788 +/- 134 SD vs. 43 +/- 7.2 ng/ml SD), and there was a direct linear relationship between propranolol dose and plasma drug levels (r = 0.85, P < 0.001). There were no significant differences between high and conventional dose propranolol groups in terms of all hemodynamic parameters measured, namely ejection fraction, ventricular volume, cardiac index, or peripheral vascular resistance. Despite high drug dosage and blood levels, only mild side effects were seen.     

Use of beta-adrenolytics in treatment of hyperthyroidism in pregnant women]

Use of propranolol in the treatment of hyperthyreosis in pregnant women is discussed. It was noted, that propranolol given for 24-28 days in low doses, starting from the 34th-35th week of pregnancy, and in higher doses during 5 or 2 days preceding labour diminishes clinical symptoms of hyperthyreosis. It influences thyreotropic hormone levels. No side effects were seen in neonates of mothers treated with propranolol; thyreotrophic hormone levels were within normal values.     

D-propranolol and DL-propranolol both decrease conversion of L-thyroxine to L-triiodothyronine.

The effects of propranolol (DL-propranolol) and D-propranolol on thyroid hormone metabolism were studied in six euthyroid volunteers receiving L-thyroxine (T4) and six hypothyroid patients receiving T4 replacement. D-propranolol as well as propranolol decreased L-triiodothyronine (T3) concentrations and the ratio of T3 to T4 in the euthyroid subjects, and D-propranolol decreased these variables in the subjects with hypothyroidism (propranolol was not given to this group). It is concluded from this study and from parallel invitro investigations that the effect of propranolol on the conversion of T4 to T3 is unrelated to its beta-adrenergic blocking activity, and that at low therapeutic doses propranolol may exert appreciable "membrane-stabilising" effects in vivo.     

Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol.

Twenty-four patients with moderate to severe hypertension were treated for four weeks with captopril, an oral inhibitor of angiotensin-converting enzyme. The fall in blood pressure with captopril alone correlated with pretreatment plasma renin activity. The effect of adding either hydrochlorothiazide or propranolol to the captopril treatment was then studied. The addition of hydrochlorothiazide to captopril produced a dose-dependent fall in blood pressure. At the higher dose of the diuretic this fall in blood pressure correlated with weight loss, suggesting that when the diuretic-induced compensatory rise in angiotensin II is prevented by captopril the fall in blood pressure becomes dependent on loss of sodium and water. In contrast, the addition of propranolol to captopril produced no further fall in blood pressure, suggesting that inhibition of angiotensin-converting enzyme prevents the blood pressure lowering effect of propranolol. This may have implications for the mechanism whereby beta-blockers alone lower blood pressure. These contrasting effects of hydrochlorothiazide and propranolol in the presence of captopril indicate that in patients whose hypertension is not controlled by captopril alone the addition of increasing doses of diuretic is likely to control the blood pressure. The addition of a beta-blocker, however, is less likely to be effective.     

Acute coronary syndromes following abrupt cessation of oral propranolol therapy.

Abrupt cessation of oral propranolol therapy was followed by 15 acute coronary events in 14 patients with severe angina who had been receiving propranolol in daily doses of 80 to 400 mg for periods of 7 days to 6 years. Propranolol had been stopped 1 to 14 days before each acute event because of angiographic study (seven patients), increasing symptoms (three), acute coronary insufficiency (one), asymptomatic bradycardia (one), elective surgery (one) and unknown reasons (two). Before abrupt cessation of propranolol treatment anginal symptoms had been stable in six instances but had increased in the other nine. Cessation was followed by rapid progression of symptoms prior to 11 of the 15 acute events. There were six acute transmural myocardial infarctions with three deaths, three intramural myocardial infarctions, one with ventricular fibrillation, and six episodes of acute coronary insufficiency, Unstable angina followed nine of the events and responded to propranolol therapy (160 to 320 mg/d) in eight instances. Three other patients underwent aortocoronary bypass surgery; perioperative acute myocardial infarction occurred in two. These data suggest that in a minority of patients abrupt cessation of propranolol may be hazardous, particularly in severe or unstable disease. Cessation or propranolol therapy in such patients should be gradual and closely observed. Recurrent symptoms respond to reinstitution of propranolol therapy.     

Effect of propranolol on electrophysiologic features of the heart in patients with hyperthyroidism]

The effect of increasing doses of intravenously administered propranolol on electrophysiological features of heart was studied in 17 patients with untreated hyperthyroidism by using the transesophageal stimulation method. A positive and dose-dependent effect of propranolol on the studied parameters was found with the normalization of the majority of disturbances taking place after the administration of 6 mg of propranolol. This dose was safe and well tolerated by the patients. The sensitivity of the auriculo-ventricular junction to propranolol was less pronounced during the stimulated rhythm than during the sinus rhythm.     

Increased resting metabolic rate and lipid oxidation in exercise-trained individuals: evidence for a role of beta-adrenergic stimulation.

This study investigated the contribution of beta-adrenergic stimulation to the increase in resting metabolic rate (RMR) and lipid oxidation observed in exercise-trained individuals. Nine trained and eight sedentary men were subjected to two testing sessions, during which these variables were measured before and for 3 h after the oral administration of propranolol or placebo. As expected, RMR and lipid oxidation were significantly higher in the trained subjects before the administration of propranolol and throughout the placebo test in comparison with sedentary controls. A significant decrease in RMR and lipid oxidation was induced by propranolol in the trained subjects, whereas no change was observed in the untrained group, and this effect of propranolol was sufficient to abolish the difference between the two groups at baseline and under the placebo condition. Propranolol also induced a significant reduction in heart rate and systolic blood pressure, but the response was comparable in the two groups. In conclusion, the results of this study show that beta-adrenergic stimulation is involved in the increase in RMR and lipid oxidation observed in highly trained individuals. Moreover, the absence of a training-propranolol interaction effect on heart rate and systolic blood pressure suggests the existence of some dissociation between the metabolic and cardiovascular effects of prolonged exercise training.     

Effect of Antihypertensive Drugs on the “Intrinsic” Heart Rate

“Intrinsic” heart rate in man was measured by giving simultaneous atropine and propranolol and used to study the direct effect of antihypertensive drugs on the heart. Though the intrinsic and control heart rates decreased significantly following the administration of reserpine, there was no significant difference between high and low doses. No similar effects were observed with debrisoquine sulphate and methyldopa, though in high doses the latter produced a decrease which was of some statistical significance.     

Effect of propranolol on ECG of Myna, Acridotheres tristis, and Goh, Varanus bengalensis

Effect of propranolol (1 and 3 mg/kg body wt), a sympathetic blocking agent, on ECG patterns was studied in Varanus and Acridotheres. ECG was recorded before and after 5 min (immediate), 15 min and in some cases 25 min of drug infusion. All animals responded to propranolol with bradycardia. The effectiveness is dose dependent and it is also associated with the high heart rate both in Acridotheres and in Varanus. The P-R or P-S interval increased in all cases of Varanus after infusion. In Acridotheres height and duration of P-wave were increased slightly with the lower dose and decreased with the higher dose. The Q-S shortened with the lower dose and widened late with the higher dose in Varanus whereas in Acridotheres it is widened with lower and higher doses of propranolol. The Q-T interval has been increased in both groups of animals. An increased amplitude of T-wave height was observed in Varanus after 5 and 15 min of drug infusion. But it was noted with decrease in amplitude under high dose after 15 min of drug infusion. In Acridotheres it was on increase with lower dose and decrease with higher dose. The delta-wave disappeared after the administration of propranolol in Acridotheres.(ABSTRACT TRUNCATED AT 250 WORDS)     

Propranolol in hypertension: a dose-response study.

The effect of propranolol was studied in a double-blind crossover trial in 24 carefully selected hypertensive outpatients. Each patient received propranolol 60 mg/day, 120 mg/day, 240 mg/day, and placebo for four weeks each according to a randomised sequence. Propranolol 60 mg/day was no better than placebo in reducing blood pressure. The effects of propranolol 120 mg/day and 240 mg/day were not significantly different. Both doses reduced lying blood pressure by about 20/10 mm Hg from an initial level of 173/104 mm Hg. No difference was detected between the effects of the different doses of propranolol and placebo on weight or on the occurrence of adverse reactions.     

Characteristics of emodin on modulating the contractility of jejunal smooth muscle

Emodin is traditionally used as a laxative and is found to increase or decrease the contractility of intestinal smooth muscle in low doses and high doses, respectively. In this study, we propose that bidirectional regulation (BR) on the contractility of jejunal smooth muscle (CJSM) is inducible by emodin in the absence of control by the central nervous system. The results indicated that emodin-induced BR had the following characteristics. A stimulatory effect on CJSM was induced by emodin at 7 low contractile states, and an inhibitory effect was induced on CJSM at 7 high contractile states. Emodin-induced BR on myosin phosphorylation was also observed. BR was not observed in the presence of tetrodotoxin, suggesting that enteric nervous system is required for producing BR. The stimulatory effect of emodin on CJSM was abolished by atropine and diphenhydramine, respectively, suggesting that BR was correlated with cholinergic and histamine system while jejunal smooth muscle was at low contractile state. The inhibitory effect of emodin on CJSM was abolished by phentolamine, propranolol, and L-NG-nitroarginine (L-NNA), respectively, suggesting that BR was related to adrenergic hyperactivity and with a nitric oxide relaxing mechanism while jejunal smooth muscle was in a high contractile state. The exact mechanism, however, needs further investigation.     

Mutagenic evaluation of propranolol in somatic and germ cells of mice

The mutagenic effect of an antihypertensive drug, propranolol, was studied on somatic and germ cells of Swiss albino mice. The induction of a significant increase in the frequency of micronuclei in erythrocytes was observed at higher dose levels, whereas, in germ cells, propranolol failed to induce significant chromosomal aberrations at any dose tested.     

Reduced respiratory responses to carbon dioxide after propranolol: a central action.

In a double-blind study in six subjects propranolol significantly reduced the respiratory sensitivity to carbon dioxide rebreathing. This effect seems to have been due to beta-adrenergic blockade, since it was not seen with D-propranolol. In two subjects increasing doses of propranolol caused progressive reductions in respiratory sensitivity to values below normal and similar to those of patients with ventilatory failure. These changes are probably due to a central action of propranolol.     

Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions

Findings from animal studies have suggested that bone remodeling is under beta-adrenergic control. However, the level of adrenergic inhibition required to achieve the most favorable effects on the skeleton remains unknown. To address this question, we compared the effects of low (0.1 mg/Kg/day), medium (5 mg/Kg/day) or high (20 mg/Kg/day) doses of propranolol given 5 days per week for 10 weeks in ovariectomized (OVX) rats. Characteristics of bone microarchitecture, biomechanical properties and bone turnover were investigated, whilst heart functions were assessed by echocardiography and catheterization of the left ventricle. We first confirmed the expression of Adrbeta2R and the absence of Adrbeta1R on osteoblasts by PCR and confocal microscopy. We then showed that low dose propranolol prevented OVX induced bone loss by increasing bone formation (+30% of MAR vs. placebo, P = 0.01) and decreasing bone resorption (-52% of osteoclast surface on bone surface vs. placebo, P = 0.01). Consequently, rats receiving 0.1 mg/kg/day propranolol displayed higher stress (+27%), intrinsic energy (+28.7%) and Young's Modulus in compression versus placebo (all, P < 0.05). No significant effects on heart hemodynamic parameters were found in rats receiving this dose. In contrast, medium and high doses of propranolol had a negative effect on heart functions but no significant protective effects on bone mass in ovariectomized rats. These results, consistent with the dominant nature of the high bone mass phenotype and normal heart function of Adrbeta2R-deficient mice, suggest that low doses of beta-blockers may have a therapeutic utility in the treatment of osteoporosis with high selectivity for bone tissues.     

Effects of propranolol on the gastroduodenal myoelectrical activity]

The effects of propranolol on the myoelectrical activity of the stomach, pylorus and duodenum were investigated in chronic experiments on rabbits. During the first phase of propranolol action a positive gastro-chronotropic effect was accompanied by a negative cardio-chronotropic effect. The gastro-chronotropic effect was 3 times higher than cardio-chronotropic one. The second phase of the propranolol effect manifested with periodical fluctuation of the gastroduodenal myoelectrical activity during stable bradycardia. Marked reactivity of the gastro-duodenum and periodical fluctuation of its activity are evidence of vital importance of the autoregulation mechanisms for gastroduodenal myoelectric activity.     

Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg(-1)·day(-1)), sorafenib (1 mg·kg(-1)·day(-1)), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant (P < 0.001) and similar reduction in PP (-19 and -15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (-35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (-30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (-39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (-25 and -33%, respectively), splanchnic vascularization (-37 and -41%, respectively), liver fibrosis (38%), and hepatic neovascularization (-42 and -51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.     

Responses of the rat cardiovascular system to substance P,neurotensin and bombesin

The carotid arterial blood pressure and heart rate responses to intravenous injections of substance P, neurotensin and bombesin were compared in anaesthetized rats. In rats anaesthetized with urethane neurotensin produced only a fall in blood pressure but in rats anaesthetized with sodium thiobutabarbitone, the fall was preceded by a transient rise in blood pressure. The reason for the different responses to neurotensin with the two anaesthetics was not investigated. The hypotensive effect of neurotensin observed with both anaesthetics was abolished by mepyramine and therefore appeared to be mediated by action on H₁ receptors either of neurotensin directly or of histamine released. On the other hand, catecholamines might be implicated in the pressor response to neurotensin observed in rats anaesthetized with sodium thiobutabarbitone since it was reduced by phentolamine and hexamethonium. Low doses of substance P produced a depressor response which was not inhibited by the antagonists tested. At higher doses marked tachycardia occurred and the depressor response was less and was often followed by a pressor response. The tachycardia was abolished by propranolol but not by cervical cord section or by hexamethonium. Bombesin produced a pressor response which was unaffected by hexamethonium but was reversed to depressor by phentolamine. This depressor response to bombesin was abolished by propranolol. It was concluded that substance P produced a depressor response by action on its own specific receptors and tachycardia by catecholamine release whereas neurotensin and bombesin produced cardiovascular actions which were mediated entirely by amine release.     

The effect of cyclic nucleotides on the sensitivity of early mouse embryos to biogenic monoamine antagonists]

The effect of lipophilic cAMP analogs on the sensitivity of preimplantation mouse embryos of two strains to cytotoxic serotonin and adrenalin antagonists was studied. Dioctanoyl-cAMP significantly decreased the sensitivity of embryos to inmecarb and cyproheptadine: experimental embryos developed to the stage of morula or blastocyst, in contrast to control embryos incubated without this protector. A somewhat weaker effect was observed in experiments with propranolol: embryos incubated in the propranolol-containing medium after the addition of dioctanoyl-cAMP were capable of one to two cleavage divisions. 8-bromomonobutyryl-cAMP partially suppressed the inhibitory effect of cyproheptadine and did not affect the sensitivity of embryos to propranolol. These data suggest cAMP involvement in the regulatory activity of neurotransmitters in the early mouse embryos.