Selective and Non-Selective Beta-Blockade in Renin Release

Abstract The effects of two beta-adrenergic receptor blocking drugs, the non-selective propranolol and the beta₁selective metoprolol, were studied on hemodynamics and plasma renin activity (PRA) of healthy volunteers in an ergometric exercise test. Oral doses of 160 mg of propranolol and 200 mg of metoprolol were tested against placebo. The drug plasma concentrations were determined. Heart rate and systolic blood pressure were equal and significantly lower during treatment with both active drugs when compared to placebo. The effect of drugs on exercise heart rate was correlated with the logarithm of drug plasma concentration with both propranolol and metoprolol. Propranolol, but not metoprolol, decreased the basal level of PRA. The ergometric exercise induced a significant rise in PRA after placebo but this increase was partially inhibited by the both active drugs. On the basis of these findings it is suggested that in man the basal level of PRA could be decreased mainly by blocking the beta₂-adrenoceptors. Instead the exercise induced increase of PRA could be inhibited by blocking the beta₁-adrenergic receptors.     

Alpha- and beta-adrenoceptor blocking properties of labetalol in renin release.

The effect of labetalol, an alpha- and beta-adrenergic receptor blocking antihypertensive, on plasma renin activity (PRA) and the hemodynamics of healthy volunteers at rest and during an ergometric exercise test was studied. Oral doses of 200 and 400 mg labetalol were tested against a placebo in a crossover manner. The labetalol plasma concentrations were determined. Systolic and diastolic blood pressures in the supine position decreased after 400 mg labetalol as did the response of the heart rate to exercise. The lower dose decreased the resting heart rate, but had no effect on the heart rate during exercise. The ergometric exercise induced an increase in PRA which was partly inhibited after 200 mg labetalol in a manner similar to that induced by beta-blockers in our earlier studies. After 400 mg labetalol PRA was already increased at one hour at sitting rest and this higher basal level was maintained for four hours. After this higher dose of labetalol the reaction of PRA to exercise was not significantly inhibited. In renin release the vasodilating alpha-blockade thus dominated the beta-blocking property of labetalol at the dose which decreased the blood pressure.     

Comparison of beta-adrenoceptor selectivity of acebutolol and its metabolite diacetolol with metoprolol and propranolol in normal man

Summary 1. The beta-adrenergic selectivity of diacetolol, the major metabolite of acebutolol, has been compared with that of acebutolol, metoprolol and propranolol in 11 normal subjects.2. Bronchial and cardiac beta-adrenoceptor blockade were assessed on separate occasions after diacetolol 600 mg, acebutolol 400 mg, metoprolol 200 mg, propranolol 80 mg and placebo.3. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose response curve to inhaled isoprenaline after each beta blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the 5th minute of exercise at 70% of the subject's maximum work rate.4. There was a significant reduction in exercise heart rate with all 4 beta-blocking drugs when compared with placebo, 22% for diacetolol, 24% for acebutolol, 25% for propranolol and 28% for metoprolol. The reduction with metoprolol was significantly greater than the reduction with the other three beta-adrenoceptor antagonists.5. Mean dose ratios for the airway isoprenaline dose response curves after each of the 4 beta-blocking drugs were 2.4 for diacetolol, 2.7 for metoprolol, 8 for acebutolol and 72 for propranolol. The difference between diacetolol and metoprolol was not significant.6. Thus diacetolol appears to be more cardioselective than acebutolol and both are more cardioselective than propranolol in man. Metoprolol is probably more cardioselective than diacetolol though interpretation of the differences in exercise heart rate is complicated by the fact that diacetolol has some intrinsic sympathomimetic activity.     

Comparative beta-adrenoceptor blocking effects and pharmacokinetics of penbutolol and propranolol in man.

1 The beta-adrenoceptor blocking effects of penbutolol were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 7 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and plasma levels of penbutolol and propranolol were determined. 3 Penbutolol proved to be a non-cardioselective beta-adrenoceptor blocking drug, antagonizing exercise-induced tachycardia, reducing exercise-induced increase in PEFR and decreasing PRA. The beta-adrenolytic potency of penbutolol was shown to be four-fold that of propranolol but the duration of its effect was similar. 4 The peak plasma level of penbutolol was reached 1 h after administration and its half-life was 4.5 h. 5 Comparison of plasma levels and biological activity of penbutolol revealed that after oral administration this drug is transformed into an active metabolite in man.     

Comparative β-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man

Summary The -adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective -adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its T_max and T_1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac -adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.     

The effects of acute or chronic ingestion of propranolol or metoprolol on the metabolic and hormonal responses to prolonged, submaximal exercise in hypertensive men.

We have studied the effects of single oral doses of, and of 28 days treatment with, placebo, propranolol or metoprolol, on the metabolic and hormonal responses to prolonged exercise in hypertensive men. Blood glucose levels fell during exercise on all occasions. No additional effects of the beta-adrenoceptor antagonists, compared to placebo, were observed. The exercise-induced increase in plasma potassium was enhanced after a single dose of propranolol or metoprolol, and also after chronic treatment with propranolol. Chronic treatment with either drug led to an increase in plasma potassium levels at rest. The growth hormone response to exercise was potentiated by a single dose of metoprolol or propranolol, and after chronic treatment with the drugs. A single dose of propranolol (but not metoprolol) was associated with a marked increase in plasma cortisol and adrenaline levels during exercise. After chronic treatment no such increase occurred. In both the acute and chronic phases of the study, blood lactate levels were higher during exercise in the presence of either propranolol or metoprolol compared to placebo, whereas non-esterified fatty acid levels were lower. A single dose of metoprolol produced a significantly greater reduction in blood glycerol levels during exercise than a single dose of propranolol. After chronic treatment, both propranolol and metoprolol produced similar reductions in blood glycerol levels during exercise. After a single dose, both drugs significantly augmented the increase in plasma noradrenaline levels during exercise. A similar effect was seen after chronic treatment.     

Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?

The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.     

Effect of the Arg389Gly β(1) -adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment

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Assessment of beta-adrenoceptor selectivity of a new beta-adrenoceptor antagonist, bisoprolol, in man

Bisoprolol is a new beta-adrenoceptor antagonist which has shown beta-adrenoceptor selectivity in studies in isolated tissues. Bronchial and cardiac beta-adrenoceptor blockade were assessed in eight normal subjects before and after oral ingestion of placebo, bisoprolol 20 and 40 mg, metoprolol 200 mg and propranolol 80 mg in random order. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose-response curve to inhaled isoprenaline after each beta-adrenoceptor blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the fifth minute of exercise at 70% of the subject's maximum work rate. Bisoprolol 20 and 40 mg caused a 24 and 25% reduction in exercise heart rate respectively, compared to 26% with metoprolol 200 mg and 20% with propranolol 80 mg. The dose ratios for the airway dose-response curves for the four beta-adrenoceptor blocking drugs were 1.04 and 3.4 for bisoprolol 20 and 40 mg, 1.4 for metoprolol 200 mg and 30 for propranolol 80 mg. Both doses of bisoprolol produced considerably less bronchial beta-adrenoceptor blockade than propranolol 80 mg despite causing a greater reduction in exercise heart rate. Bisoprolol 20 mg caused a similar amount of bronchial beta-adrenoceptor blockade and a similar reduction in exercise heart rate as metoprolol 200 mg, confirming that it is cardio-selective in man.     

Can the biochemical responses to a beta 2-adrenoceptor stimulant be used to assess the selectivity of beta-adrenoceptor blockers?

The extent to which beta-adrenoceptor blocking drugs counteract the biochemical responses to an infusion of terbutaline, a beta 2-adrenoceptor agonist, has been investigated. In this study the beta 1-selectivity of metoprolol was compared with the non-selective beta-adrenoceptor blocker propranolol. The hypokalaemia produced by an infusion of terbutaline was reduced by low dose (50 mg) and high dose (200 mg) metoprolol and by low dose (40 mg) and high dose (160 mg) propranolol. The effects of propranolol on terbutaline induced hypokalaemia were more marked than those of metoprolol at both low dose (P = 0.01) and high dose (P = 0.05). Furthermore low dose metoprolol had less effect than high dose metoprolol (P = 0.05). The serum potassium appeared to rise slightly after propranolol. Low and high doses of both beta-adrenoceptor blockers markedly reduced the terbutaline-induced hyperglycaemia, but the differences between the two drugs were not statistically significant.     

Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of metoprolol and propranolol on furosemide-stimulated renin release in healthy subjects

Summary The effects of single doses of the beta₁-receptor antagonist metoprolol (40 mg orally), propranolol (40 mg orally) and placebo were compared on furosemide-stimulated plasma renin activity (PRA) in seven healthy subjects. In the placebo studies, PRA increased by 0.59±0.18 ng×ml^–1×h^–1 60 minutes after intravenous administration of 30–60 mg furosemide. After propranolol and metoprolol, the corresponding increases in PRA were significantly less pronounced amounting to 0.16±0.06 and 0.24±0.08 ng×ml^–1×h^–1, respectively. The resting heart rate was reduced to the same extent after the two beta-blockers, which means that the two drugs had been given in equipotent beta₁-receptor blocking doses. It is suggested that the release of renin from the kidney may partly be mediated via an adrenergic beta₁-receptor.Metoprolol (piNN)=H 93/26=CGP 2175     

Effect of Captopril and Propranolol,Alone and in Combination,on the Responses to Isometric and Dynamic Exercise in Normotensive and Hypertensive Men

This study evaluated the effects of single doses of the angiotensin converting enzyme inhibitor captopril and the beta-adrenergic blocking agent propranolol, alone or in combination, on the blood pressure, heart rate and humoral responses to both isometric (handgrip) and dynamic (ergometric) exercise in normotensive and hypertensive men. Single oral doses of either placebo, captopril 50 mg, propranolol 80 mg, or the latter two in combination were administered to age-matched groups (n = 5) of normotensive and hypertensive men in a random, double-blind manner. Captopril alone was indistinguishable from placebo after both isometric and ergometric exercise. Propranolol suppressed heart rate after both types of exercise and tended to decrease systolic blood pressure only in the hypertensive group; combination with captopril did not alter these responses. These data suggest that in sodium-replete subjects undergoing short-term vigorous exercise, the renin-angiotensin system, as measured by captopril inhibition, is less important than the sympathoadrenal system, as measured by propranolol inhibition, in the reflex cardiovascular adjustments accompanying acute isometric and dynamic exercise in both normotensive and hypertensive men.     

Effect of the beta-adrenergic blocking agent bupranolol on the plasma renin activity in normotensive rats]

The effects of the beta-adrenergic blocking agent 3-tert.-butyl-amino-1-(6'-chloro-3'-methylphenoxy)-propan-2-ol hydrochloride (bupranolol; KL 255; Betadrenol) on the plasma renin activity (PRA) of normotensive rats were studied in comparison to propranolol. Bupranolol (10--100 microgram/kg) reduced basal PRA and inhibited the isoproterenol as well as dihydralazine induced increase of PRA in a dose dependent fashion. Bupranolol exhibited an effect 2--4 times stronger than that of propranolol. The PRA inhibiting effects of bupranolol seem to be linked to its beta-receptor blocking properties.     

Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects.

1. The effect of 1 week of treatment with propranolol LA (160 mg), atenolol (100 mg) and metoprolol CR (100 mg) on awareness of and the physiological responses to moderate hypoglycaemia were compared with placebo using a randomised, cross-over design in 12 healthy volunteers. 2. All three beta-adrenoceptor antagonists reduced resting heart rate, systolic blood pressure and heart rate responses to submaximal exercise compared with placebo. 3. Under hyperinsulinaemic (60 mu m-2 min-1) clamp conditions, at a blood glucose of 2.5 mmol l-1, atenolol prevented the rise in systolic and atenolol and metoprolol CR prevented the fall in diastolic blood pressure usually associated with hypoglycaemia. At this level of hypoglycaemia, the expected increase in heart rate was inhibited by atenolol but not metoprolol CR. Pre-treatment with propranolol LA resulted in a significant pressor response and a bradycardia during hypoglycaemia. In addition the normal increase in finger tremor was abolished by propranolol LA. 4. During hypoglycaemia all three beta-adrenoceptor blockers augmented sweating compared with placebo but hypoglycaemic symptoms, awareness and slowing of reaction time were the same with drugs and placebo. 5. The rise in plasma adrenaline and other counter-regulatory hormones during hypoglycaemia was enhanced by beta-adrenoceptor blockade. 6. We conclude that beta-adrenoceptor antagonists modify the physiological and hormonal responses to, but do not adversely affect awareness of, moderate hypoglycaemia in healthy volunteers.     

Beta-adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.

1 The pharmacological effects and the pharmacokinetics of betaxolol (SL 75212), a new beta-adrenoceptor blocking agent, were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), myocardial contractile force (MCF), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 25 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and blood levels of betaxolol and propranolol were determined. 3. Betaxolol proved to be a potent and long-lasting beta-adrenoceptor blocking drug, devoid of intrinsic beta-sympathomimetic activity. Its beta-adrenoceptor blocking action was shown to four-fold that of propranolol at the cardiac and renal levels and to last at least 25 h after drug intake. 4 The peak blood level of betaxolol was reached 2 to 4 hr after its administration, the first-pass loss is likely to be low and the half-life is 12.3 h. These pharmacokinetic data are perfectly consistent with the long duration of the pharmacological effects of betaxolol in man.     

Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

1. The antagonist activity of atenolol, metoprolol and propranolol in the CNS was estimated by determining the extent to which the drugs occupy animal beta 1- and beta 2-receptors in CSF ex vivo at the time of lumbar puncture. 2. Five CSF and plasma samples were obtained 4 h after drug intake from subjects treated for hypertension with atenolol, 100 mg once daily and five from subjects treated with metoprolol, 50 mg three times daily. Twenty-four samples were obtained 1, 2, 4 or 12 h after drug intake from subjects receiving a single 40 mg dose of propranolol. 3. The receptor occupancy in the samples was determined by adding beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes into the samples and labeling the receptors with a nonselective beta-adrenoceptor antagonist, (-)-[3H]-CGP-12177. 4. Atenolol and metoprolol occupied, as expected, larger fractions of beta 1- than beta 2-receptors in CSF and plasma samples. The receptor fraction occupied by atenolol in CSF was significantly (P < 0.05) lower than that occupied by metoprolol. The differences in occupancy between the drugs in plasma, however, were not statistically significant. 5. Propranolol occupied larger fractions of beta 2- than beta 1-receptors in the samples. Although propranolol concentrations in CSF were only 1/20-1/40 of those in plasma, the receptor occupancy of propranolol in CSF was similar to that in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of different beta-blocking drugs on the peripheral circulation in Raynaud's phenomenon and in hypertension.

In a double-blind, randomized, placebo-controlled study, the authors investigated the effects of different beta-adrenoceptor blocking drugs on the peripheral circulation. A single intravenous injection of the nonselective beta-blocker propranolol (0.20 mg/kg), the beta 1-selective adrenoceptor blocker metoprolol (0.25 mg/kg), and the nonselective beta-blocker with partial agonistic activity (PAA) pindolol (0.04 mg/kg) and of placebo (saline) was given to eight patients with a primary Raynaud's phenomenon and to nine untreated patients with primary hypertension. The authors measured finger skin temperature (FST), and laser Doppler estimated finger skin blood flux (LDF) before, during, and after a standardized finger cooling test, performed 25 minutes after the administration of the drugs. In both patients groups propranolol, metoprolol, and pindolol had no significant effect on FST and LDF in the first 25 minutes after administration both in comparison to baseline value and to placebo. Also, no significant differences were found in the recoveries of FST and LDF after cold challenge between all drugs and placebo in both groups. The authors conclude that no adverse effect of any type of beta-adrenoceptor blocker in comparison to placebo could be detected after a single administration on both the baseline finger skin perfusion and the recovery after cold-induced vasoconstriction. In addition, the authors could not demonstrate a favorable effect of beta 1-selectivity or PAA in comparison to a nonselective beta-adrenoceptor blocker without PAA, in any group.     

Long acting beta-blockers in the twenty fourth hour

Fifteen mild to moderate hypertensives were submitted to exercise testing using a bicycle ergometer with a fixed load. Heart rate, blood pressure and ECG were recorded throughout 5 min exercise and 10 min recovery. Oxygen uptake was measured during the final minute of exercise and blood glucose estimation and serum drug levels assessed 5 min after recovery. The above measurements were made after exactly 24 h following seven days administration of 160 mg of long acting (L.A.) propranolol, 200 mg of sustained action (S.A.) metoprolol and two matched placebos. Propranolol L.A. was superior to Metoprolol S.A. in the reduction of exercise induced tachycardia and both drugs were significantly superior to placebos. Both drugs were effective agents for the lowering of resting blood pressure after 24 h but propranolol L.A. was more effective in the lowering of systolic peaks observed during exercise. There was no significant effect upon oxygen uptake and blood glucose. The incidence of side effects was low and showed no significant difference from placebo.     

β-Adrenoceptor blocking effects and plasma levels of bornaprolol and propranolol in man

Summary The -adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new -adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2, 24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63–86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting -adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.