How intrinsic sympathomimetic activity modulates the haemodynamic responses to beta-adrenoceptor antagonists. A clue to the nature of their antihypertensive mechanism.

Abstract

Abstract 1 A survey has been made of the literature on acute and long-term haemodynamic effects of ten different β-adrenoceptor antagonists. The β-adrenoceptor blockers are: pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol. The total numbers of patients included in this review are 396 patients in 41 acute studies and 410 patients in 36 long-term studies. 2 The effects of β-adrenoceptor blockers on the concentrations of plasma noradrenaline have also been reviewed. Ten studies including 110 patients on non-ISA-β-adrenoceptor blockers and eight studies including 116 patients on pindolol are presented. 3 In the acute studies (i.e. 15-90 min) arterial pressure was lowered by 1-7% and in the long-term studies (i.e. 3 days-5 years) by 6-17%. 4 The degree of cardio-depression induced by the various β-adrenoceptor blockers was inversely correlated with their pharmacologically defined quantity of intrinsic sympathomimetic activity (ISA) both in acute and in long-term studies. 5 In the acute studies the increments in peripheral vascular resistance were directly correlated with the degree of cardio-depression. This suggests that a fall in arterial pressure immediately after administration of a β-adrenoceptor blocker is prevented by increased vasoconstrictor nerve activity mediated through the arterial baroreflex. 6 The compensatory response of vascular resistance to cardio-depression was similar for β1-selective and non-selective blockers, thereby indicating that extra-junctional vascular β-receptors are relatively unimportant for maintaining basal vascular tone. 7 In the long-term studies the correlation between changes in cardiac output and changes in vascular resistance was shifted to a lower level of vascular resistance. This means that the onset of blood pressure reduction during β-adrenoceptor blockade was associated with a fall in vascular resistance at any level of cardiac output. Thus vascular resistance was higher during treatment with a non-ISA-β-adrenoceptor blocker than during treatment with an ISA-β-adrenoceptor blocker. 8 The level of vascular resistance ultimately attained during treatment with the various β-adrenoceptor blockers appears to be inversely related to their effects on plasma renin activity. 9 The concentration of noradrenaline in plasma rose by approximately 30% during treatment with non-ISA-β-adrenoceptor blockers and fell by more than 30% after pindolol. 10 There is evidence that under propranolol, which reduces cardiac output and hepatic blood flow, the plasma noradrenaline clearance is diminished. Since noradrenaline is mainly cleared from the circulation by the lungs and by the liver, and since pindolol has no effect on cardiac output and hepatic blood flow, one may expect the plasma noradrenaline clearance not to be diminished by pindolol. 11 The reported effects of β-adrenoceptor blockers on plasma noradrenaline may indicate that the release of neurotransmitter is diminished, but in the case of non-ISA-β-adrenoceptor blockers this effect is not reflected by a decreased concentration of noradrenaline in plasma, because its clearance is also reduced. 12 The hypotensive effect of β-adrenoceptor blockers appears to be independent of blockade of postjunctional cardiac-β-receptors, juxtaglomerular-β-receptors and extrajunctional vascular β-receptors. This indicates that blockade of β-receptors at other sites (i.e. centrally and/or prejunctionally) is more important.