Evaluation of practolol in hypertension. Effects on sympathetic nervous system and renin responsiveness.

Abstract

The ,B-adrenergic blocker, practolol, proved to be an effective antihypertensive agent in a single-blind crossover trial, involving I7 patients with essential hypertension of mild to moderate severity. After a 2-month placebo period, dosage was begun at IOO mg twice a day, and titrated against blood pressure response up to a maximum dose of 400 mg twice a day, leading to an average reduction in blood pressure of 20/18 mmHg, and satisfactory control in I4 of I6 patients (one defaulter). The clinical and physiological data were analysedfor prediction of response to practolol. The urinary noradrenaline response to head-up tilt, an index of the responsiveness of the sympathetic nervous system, correlated significantly with subsequent blood pressure reduction with practolol IOO mg twice a day (r=0-62, P< O.OI). In 8 patients, responsiveness to tilt was retested after control of blood pressure: changes in diastolic blood pressure and pulse rate while on practolol were both significantly less than pretreatment responses. The urinary noradrenaline response was also reduced (+o -o 5,tg/hr vs. pretreatment mean of + i *64,tg/hr; P< o oI), a finding not explicable in terms of known receptor-blocking properties of the drug. It is suggested that the antihypertensive action of /3-adrenergic blockers may be related to a reduction in the reflex activity of the sympathetic nervous system. Plasma renin activity, which was normal in the recumbent state, rose with tilting. The response with tilt was significantly reduced with practolol, though plasma renin activity during recumbency was only marginally lowered by the drug.Although fl-adrenergic blocking drugs are finding increasing application in the treatment of hypertension, the mechanism by which they lower blood pressure remains uncertain. The antihypertensive effect has been attributed to a reduction in cardiac output (Frohlich et al., I968) but a satisfactory reduction in blood pressure with oral medication has been stated to occur after a latent period of several weeks (Prichard and Gillam, I969), whereas the effect on cardiac output is rapid. An unexplained phenomenon is the extreme range of sensitivity to the blood pressure-lowering effects of ,B-blockers shown by essential hypertensives, dose requirements of propranolol varying between perhaps o-i and 3 g daily (Zacharias, I97I; Prichard, 1970).Essential hypertensives exhibit a broad range of sympathetic nervous system responsiveness when subjected to postural stresses, extending from underactivity in patients responding to tilting with pos-

A study of the effects of atenolol and propranolol on renal function in patients with essential hypertension.

“…We have confirmed this slight effect on PRA in the recumbent position, but in our patients ambulant PRA was suppressed more strikingly by atenolol than by propranolol, although the difference between the two did not reach significance. A similar effect on recumbent and headup tilt renin levels to that of atenolol in our patients was observed with the #I -adrenoceptor blocking drug practolol by Esler & Nestel (1973). It seems, therefore, that renin release is likely to be controlled at least in part by #,-adrenoceptors.…”

Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.

“…Evidence exists that reflex noradrenergic responses, to baroreceptor stimulation in rabbits (Komer et al, 1980), and to upright posture in humans (Esler & Nestel, 1973;Foumier et al, 1976-De Champlain, 1977, are reduced by 18-adrenergic receptor blockade. It is possible, but unproven, that inhibition of sympathetic cardiovascular reflexes is one component of the antihypertensive action of f8-adrenoceptor blockers.…”

“…The hope has been expressed that indices of sympathetic nervous system activity might be used clinically to predict the response of patients with essential hypertension to antiadrenergic drugs (Esler & Nestel, 1973;Fourner et al, 1976;De Champlain, 1977). The magnitude of the antihypertensive effect of /8-adrenergic receptor blockers in individual patients, particularly at low doses, does appear to be related to biochemical measures of sympathetic nervous function, such as the plasma noradrenaline concentration at rest De Champlain, 1977), and the noradrenaline responses to upright posture (Esler & Nestel, 1973;Foumer et al, 1976) and exercise (Distler et al, 1978).…”

“…The magnitude of the antihypertensive effect of /8-adrenergic receptor blockers in individual patients, particularly at low doses, does appear to be related to biochemical measures of sympathetic nervous function, such as the plasma noradrenaline concentration at rest De Champlain, 1977), and the noradrenaline responses to upright posture (Esler & Nestel, 1973;Foumer et al, 1976) and exercise (Distler et al, 1978). At full doses of /3-adrenergic blockers, however, these indices of sympathetic function either entirely fail to predict the therapeutic outcome, as we found here and have noted in other studies (Esler& Nestel, 1973;Esler, Zweifler, Randall & De Quattro, 1977), or, much as for plasma renin activity, have predictive power rather too low to be clinically useful.…”

“…Early reports of inhibition of sympathetic nervous system cardiovascular reflexes during f3-adrenergic blockade, both in animals (Dunlop & Shanks, 1969) and patients with essential hypertension (Esler & Nestel, 1973), suggested that suppression of the sympathetic nervous system, perhaps at a site within the central nervous system (Kelliher & Buckley, 1970), might be an antihypertensive mechanism. This viewpoint was subsequently strengthened when it was found that administration of propranolol to rabbits reduced sympathetic nerve firing rates (Lewis & Haeusler, 1975).…”