Adaptational Responses to Prolonged Β‐adrenoceptor Blockade in Adult Rabbits

Abstract

A method for measuring propranolol concentrations in plasma has been modified to permit estimations to be made on small volumes. The method has been used to correlate blockade of heart rate increases in response to intravenous isoprenaline, in both young and adult rabbits, with plasma concentrations of propranolol after subcutaneous injections of 2 or 4 mg/kg. It has been found that the relation between β‐adrenoceptor blockade and plasma concentrations is the same in rabbits as that determined by previous workers in man. Adult Dutch dwarf rabbits were treated for 9 weeks twice daily subcutaneously with 2 mg/kg propranolol, or 10 mg/kg practolol, or with saline. The treatment caused no change in heart weight in relation to body weight or in the water content of the hearts, in contrast to effects previously observed in young rabbits. As in the young rabbits, treatment did cause a prolongation of action potential duration, as measured with intracellular electrodes in hearts of animals killed 24 h after the last dose of drug. In another series of experiments, with a similar regime of treatment for 6 weeks, a significant reduction of diastolic blood pressure was observed in the propranolol group. During the course of treatment and at the end, there was no change in the heart‐rate increases observed in response to intravenous isoprenaline administered not less than 15 h after the previous dose of β‐blockers. Thus no functional alteration in sensitivity to β‐adrenoceptor stimulation was apparent.

Modulation of the QT interval duration in hypertension with antihypertensive treatment

“…100 Controversially, some experimental studies in the past demonstrated QT prolongation following the administrations of BBs. 101,102 The ability of BBs to shorten the duration of the QT interval, which has made possible their use in the treatment of long QT syndrome, 103 strengthens the case that BBs reduce the duration of the QT interval. The QT-modulating actions of BB may be an additional benefit that complements their antihypertensive effects.…”

Effects of selective alpha 1‐, alpha 2‐, beta 1‐and beta 2‐adrenoceptor stimulation on potentials and contractions in the rabbit heart.

“…A slow rise of catecholamine level following the onset of exercise, and a slow fall afterwards, cannot therefore be the cause of the slow changes of Q-T interval.' It is not, of course, permissible to extrapolate directly from rabbits to 542 SELECTIVE ADRENOCEPTOR ACTIONS ON RABBIT HEART man, but if human cardiac tissues are similar to those of rabbits in their responses to adrenergic stimulation, as seems probable from previous work (Raine & Vaughan Williams, 1980, 1981, f-adrenoceptor activation could well be responsible for a shortening of the Q-T interval independently of any change in heart rate.…”

Hypoxic cardiac hypertrophy is not inhibited by cardioselective or non‐selective beta‐adrenoceptor antagonists.

“…Since the aim was to employ doses of fl-blockers which would be approximately equivalent to those used clinically, 5 mg kg-' twice daily s.c. was chosen as the appropriate dosage for propranolol, since previous work in rabbits had indicated that this would ensure a substantial degree off6-adrenoceptor blockade for about 9 hr after each dose (Raine & Vaughan Williams, 1980). The mean initial weights of group P were 780-75 + 22-9 g (treated) and 814 + 20-9 g (controls).…”

“…Prolonged ,f-blockade in children with hypertrophic obstructive cardiomyopathy causes regression of the hypertrophy (Shand, Sell & Oates, 1971). Electrophysiological changes, including a prolongation ofintracellularly recorded action potential duration, reflected as a lengthening of Q-T P. DENNIS AND E. M. V. WILLIAMS interval of the electrocardiogram, are induced by prolonged f-blockade in adult rabbits (Raine & Vaughan Williams, 1980) and in adult humans (Vaughan Williams, Hassan, Floras, Sleight & Jones, 1980). Adult rats administered low doses of propranolol or atenolol for five months had significantly reduced heart weights in relation to body weight (Manning, Coltart & Hearse, 1981), and Ostman-Smith (1976) concluded, from the suppression by guanethidine ofcardiac hypertrophy in swimming rats: 'the hypertrophy produced by chronic exercise is not caused by a direct effect of the increased work load, but is instead mediated by release of a trophic factor from cardiac sympathetic nerves, probably noradrenaline itself, but possibly a secretary protein'.…”

“…Thus, although it is clear that adrenergic stimulation can induce cardiac hypertrophy, and that such stimuli can be blocked, it seemed worthwhile to attempt to determine whether adrenergic activation is a necessary stimulus. We also wished to study the effects of fl-blockade on cardiac hypertrophy in rabbits, since much previous work has shown that in this species the duration and intensity of blockade is similar to that observed in man at comparable plasma concentrations (Raine & Vaughan Williams, 1980).…”