Effects of 10 different beta-adrenoceptor antagonists on hemodynamics, plasma renin activity, and plasma norepinephrine in hypertension: the key role of vascular resistance changes in relation to partial agonist activity.

Abstract

Summary The literature was surveyed for the acute and long-term hemodynamic effects of 10 different β-adrenoceptor antagonists and their long-term effects on plasma renin activity and plasma norepinephrine concentrations. The β-blockers are pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol, and timolol. Forty-four acute and 41 long-term hemodynamic studies in 430 and 482 patients, respectively, 54 renin studies in 784 patients, and 17 norepinephrine studies in 217 patients were analyzed. In the acute studies, blood pressure was hardly lowered. In spite of many pharmacological and physicochemical differences, the drugs appeared to possess a hypotensive potency of approximately equal magnitude in long-term studies. The degree of cardiodepression and the suppression of renin as exerted by the different β-blockers were inversely correlated with their pharmacologically defined quantity of partial agonist activity (PAA) or intrinsic sympathomimetic activity. In the acute studies, the increments in vascular resistance were proportional to the degree of cardiodepression, suggesting that increased vasoconstrictor nerve activity mediated through the baro-reflex had prevented an acute fall in arterial pressure in response to a given fall in cardiac output. The resistance response to cardiodepression was similar for β1- and non-selective blockers, indicating that vascular β2- adrenoceptors are relatively unimportant for maintaining basal vascular tone. After long-term therapy the inverse correlation between changes in cardiac output and changes in vascular resistance was shifted to a lower level of vascular resistance. Thus, the onset of blood pressure reduction during long-term therapy with β-blockers is always associated with a fall in vascular resistance at any given value of cardiac output. Therefore, the level of vascular resistance appears to be determined mainly by the degree of PAA, irrespective of the quality of cardioselectivity. Plasma renin activity and vascular resistance are inversely correlated during long-term β-blocker therapy. Consequently, the fall in vascular resistance that appears to underlie the fall in blood pressure reduction cannot be explained by the suppression of plasma renin activity. The accessibility of the central nervous system to the different β-blockers neither determines the time of onset of blood pressure reduction nor the magnitude of this effect. The nonessentiality of cardiodepression, renin suppression, and blockade of central β-receptors suggests that blockade of presynaptic β-receptors underlies the vasodilatory and antihypertensive effects of these drugs. Changes in the concentrations of norepinephrine in plasma are compatible with this supposition, provided that changes in clearance of norepinephrine from plasma are taken into account.