Govier, Mosal, Whittington & Broom (1966) reported that 5 /AM of adrenaline increases atrial refractory period. As in the presence of the a-receptor antagonist phenoxybenzamine adrenaline reduced atrial refractory period, the authors concluded that the increase in atrial refractory period is an action on a-receptors. Shortening of atrial refractory period by adrenaline was assumed to be an effect on fl-receptors, as the fl-receptor antagonist pronethalol inhibited it.As we had found that a-receptor antagonists such as phenoxybenzamine and phentolamine can potentiate the effect of noradrenaline on atrial contractility (Benfey & Greeff, 1961), we wondered whether the effect of phenoxybenzamine observed by Govier et a1. (1966) was due to a potentiation of adrenaline effects, as large concentrations of adrenaline shorten refractory period. Therefore we decided to study a wide range of concentrations of various sympathomimetic drugs.We found that isoprenaline shortens refractory period in all concentrations used and that phenylephrine prolongs it. Adrenaline had a biphasic action: it prolonged refractory period in small and shortened it in large concentrations. Noradrenaline was similar to adrenaline but less potent in prolonging the refractory period. A small concentration of phentolamine inhibited prolongation of refractory period by adrenaline, noradrenaline and phenlyephrine without increasing the effect of these drugs on contractility. In contrast, cocaine potentiated effects of noradrenaline and adrenaline on atrial contractility without inhibiting prolongation of refractory period by adrenaline. It thus appears that the prolongation of atrial refractory period by phenylephrine and small concentrations of adrenaline and noradrenaline is an effect on a-receptors.It was observed incidentally that concentrations of the fl-receptor antagonist propranolol, which were quite effective against isoprenaline, had little or no effect on the actions of adrenaline, noradrenaline and phenylephrine on atrial contractility, although these concentrations of propranolol had effects on the f8-receptors responsible for shortening of the refractory period.x
Summary1. In the driven rabbit left atrium a-adrenoceptors mediate the inotropic effect of phenylephrine and the prolongation of functional refractory period by sympathomimetic amines. 2. These receptors are highly sensitive to blockade by phentolamine and phenoxybenzamine. 3. Prolongation of functional refractory period is greater with the secondary amines, phenylephrine, adrenaline and epinine, than with the primary amines. norphenylephrine, noradrenaline and dopamine.
Summary1. Sympathomimetic amines which increase the contractility of the isolated heart were tested for effects on cyclic AMP concentrations in rabbit heart slices and on adenyl cyclase activity in rabbit heart homogenate. 2. Noradrenaline, as expected, stimulated adenyl cyclase activity and increased cyclic AMP concentrations, but dopamine and phenylephrine were ineffective. 3. This result does not support the concept that cyclic AMP plays an essential role in the inotropic effect of sympathomimetic amines.
The intravenous administration of the antiadrenaline drug phenoxybenzamine (Dibenzyline) markedly raised the arterial adrenaline and noradrenaline concentration in dogs lightly anaesthetized with thiopentone. Graded haemorrhage led to a further rise in the amounts of amine. In adrenalectomized dogs, phenoxybenzamine moderately increased the plasma noradrenaline concentration. During haemorrhagic hypotension, previous treatment of adrenalectomized animals with phenoxybenzamine led to a significantly greater rise in plasma noradrenaline compared with that of adrenalectomized animals subjected to haemorrhage without treatment with phenoxybenzamine. Thus, phenoxybenzamine (1) raised plasma amine concentration largely due to adrenal medullary stimulation, and (2) led to increased plasma noradrenaline concentrations during sympathetic stimulation in adrenalectomized animals. The previous administration of phenoxybenzamine reduced the amount of blood which could be withdrawn before final circulatory collapse in both normal and adrenalectomized dogs.
In the isolated guinea-pig atrium, phenoxybenzamine and other antagonists of sympathomimetic drugs and the adrenergic nerve blocking agent guanethidine inhibited the action of butyrylcholine and tyramine and potentiated the action of noradrenaline. Also in the isolated guinea-pig atrium, phenoxybenzamine and cocaine abolished the parasympathetic, and potentiated the sympathetic, effects of vagus stimulation.
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