Non-selective Beta-adrenoceptor Blocker Research Articles

Effect of β-Adrenoceptor Blockade on Exercise-Induced Plasma Catecholamine Concentration-Heart Rate Response Relationship

We examined the chronotropic and sympathoadrenal responses to a strenuous exercise in eight normal subjects receiving placebo and carteolol, a nonselective beta-adrenoceptor blocker. Plasma catecholamines were measured with high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Mean plasma norepinephrine (NE) and epinephrine (E) concentrations attained at 0.5 and 2 min after exercise were significantly (p less than 0.001-0.05) greater in the carteolol trial than in the placebo trial and approached concentrations fairly similar to preexercise baseline values by 15 min after cessation of exercise in the two trials. The postexercise plasma NE and E concentration-chronotropic response relationships were shifted to the right in the carteolol as compared with the placebo phase. The maximal postexercise NE concentrations measured during the placebo trial correlated significantly with beta-adrenoceptor blockade (p less than 0.05, r = 0.74), whereas the relationship between E concentrations and beta-adrenoceptor blockade did not reach significant level in this small group of study subjects. The results suggest that beta-adrenoceptor blockade increases plasma concentrations of both NE and E during an earlier postexercise period and may cause a greater reflex sympathetic activation as compared with the adrenal response. However, the mechanism(s) remains unclear. Whether the exercise-induced NE rather than E would participate more predominantly in the chronotropic response to beta-adrenoceptor blockade requires further studies.

Effect of Combined Blockade of β-Adrenoceptors and Acetylcholinesterase in the Treatment of Postoperative Ileus after Cholecystectomy

The effect of treatment with a non-selective beta-adrenoceptor blocker (propranolol) and an acetylcholinesterase blocker (neostigmine) on the duration of postoperative ileus after cholecystectomy was investigated in a double-blind, randomized study comprising 51 patients. Propranolol (P), 10 mg intravenously twice daily was, together with neostigmine (N), 0.5 mg subcutaneously twice daily, administered to 16 patients. Eighteen patients were treated with neostigmine, 0.5 mg subcutaneously twice daily only, and 17 patients were placebo-treated controls (C). The medical treatment started in the evening of the day of operation. The time to first passage of stool after operation was determined and used as a measure of duration of the postoperative ileus. The mean time was 68 +/- 6 h in the P + N-treated group, 82 +/- 6 h in the N group, and 90 +/- 7 h in the C group. The difference between the P + N group and controls was significant (p less than 0.01). P + N was effective in patients older than 60 years (p less than 0.01), whereas no effect was seen in patients younger than 60 years. In conclusion, treatment with a combination of propranolol and neostigmine shortened the duration of postoperative paralytic ileus after cholecystectomy. This effect was not seen after treatment with neostigmine only. The effect of P + N was most marked in patients older than 60 years.

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.

Pharmacodynamic effects of prenalterol in healthy subjects.

1. Prenalterol induces a dose-dependent effect on different variables reflecting myocardial contractility and heart rate. A clearcut effect can be demonstrated after an oral dose of 2.5 mg. The duration of the effect increases considerably when prenalterol is administered as a controlled release preparation partly due to an increased bioavailability. 2. Prenalterol induces a lipolytic effect manifested as a rise in free fatty acids and glycerol. Also a slight increase of plasma insulin is recorded while plasma potassium decreases somewhat. 3. When prenalterol is administered together with therapeutic doses of a selective or non-selective beta-adrenoceptor blocker it induces the same haemodynamic effects as before the beta-blocker but the dose has to be increased ten-fold. These results suggest that prenalterol might be a useful drug to counteract unwanted haemodynamic effects of a beta-blocker. 4. In animal studies it has been shown that prenalterol has affinity for both beta 1- and beta 2-adrenoceptors. However, it has a stimulating effect mainly on beta 1-adrenoceptors. Therefore, theoretically it might act as a beta 2-adrenoceptor antagonist. Preliminary results from studies in patients with chronic asthma indicate that prenalterol only has an insignificant beta 2-blocking effect when the drug is administered in doses which induce a significant beta 1-adrenoceptor stimulating effect.

Influence of non-selective and selective beta adrenoceptor blockade on isoxsuprine-dependent hemodynamic and rheologic changes.

The infusion of isoxsuprine was followed by an increase of heart rate and calf blood flow and by a decrease of arterial diastolic pressure and blood viscosity both in normal controls and patients with peripheral obstructive arterial disease. The pre-treatment with a non-selective beta adrenoceptor blocker (propranolol) canceled all the isoxsuprine-dependent changes, while the pre-treatment with a selective beta adrenoceptor blocker (metoprolol) abolished only tachycardia and did not influence the increase of calf blood flow and the decrease of blood viscosity. These findings indicate the different role of vascular beta receptors in the regulation of muscular blood flow and suggest the pharmacologic possibility to unmask the beta2-dependent vasodilation.

Antihypertensive effect of a non‐selective (propranolol) and a cardioselective (metoprolol) beta‐adrenoceptor blocking agent at rest and during exercise.

1 The antihypertensive effects at rest and during physical exercise of the non-selective beta-adrenoceptor blocker propranolol and the cardioselective beta-adrenoceptor blocker metoprolol were compared in a double-blind cross-over study. 2 Eighteen patients with mild hypertension entered the trial. One patient was withdrawn from the study due to side effects on both drugs. 3 The two beta-adrenoceptor blockers were compared using doses earlier shown to have the same beta-adrenoceptor blocking potency, as measured by their effect on exercise tachycardia in healthy men. 4 Arterial blood pressure was reduced to the same extent by propranolol and metoprolol at rest as well as during submaximal work. 5 It is concluded that the antihypertensive effect of beta-adrenoceptor blockers is mainly mediated through blockade of the beta 1-adrenoceptors.

The selective action of beta-adrenoceptor blocking drugs and the nature of beta1 and beta2 adrenoceptors.

1 Purified membranes retaining a catecholamine responsive adenylate cyclase have prepared from rabbit heart, lung and (pseudo-pregnant) uterus. 2 These preparations have the characteristics of plasma membranes and both heart and lung respond to beta-adrenoceptor agonists in the order: (+/-)-isoprenaline greater than (-)-noradrenaline greater than (-)-adrenaline greater than (+)-isoprenaline greater than salbutamol. The sensitivity of the adenylate cyclase to beta-adrenoceptor stimulation is improved by pre-treatment of the animals with reserpine and syrosingopine. 3 Dose-ratios for several concentrations of propranolol (non-selective beta-adrenoceptor blocker), practolol and atenolol (cardio-selective beta-adrenoceptor blockers) have been measured on all three membrane preparations. Schild plots of log (dose ratio -1) vs. log dose were virtually coincident for heart and lung with a dissociation constant (Kb) for propranolol very close to the pharmacological value. The ratio of Kb values was 0.65 for practolol and 1.23 for atenolol compared with pharmacological cardio-selectivity ratios (measured on isolated atria and tracheal chain) of 67.6 and 110 respectively. The uterus/heart Kb ratio was 51.5 for atenolol. Inhibition of the uterus by practolol gave a Schild plot with slope significantly less than 1, indicating a different mechanism of action from the heart. 4 Kb values obtained by measuring adenylate cyclase stimulation in chopped tissue (including preparations of bronchial tree and alveolar tissue as well as whole lung) resembled the membrane values rather than those found in whole organs. 5 The results show that the pharmacological selectivity of practolol and atenolol is maintained at the receptor-adenylate cyclase level, at least as far as heart and uterus are concerned, though the smaller selectivity ratios in the biochemical system suggest that receptor differences is not the only factor and that phase distribution of the drug may also be important. Membranes prepared from whole lung show that phase distribution of the drug may also be important. Membranes prepared from whole lung show an overall beta1 response which may simply reflect the predominance of beta1 cell types containing beta1-adrenoceptors over bronchial smooth muscle.