Carvedilol-induced antagonism of angiotensin II:: a matter of α1-adrenoceptor blockade

Objective To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha(1)-adrenoceptor blocker carvedilol as compared with the selective beta(1)-adrenoceptor blocker metoprolol. Methods Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. Results Angiotensin II and the a(1)-adrenoceptor agonist phenylephrine constricted HCMAs to maximally 63 +/- 10 and 46 +/- 15% of the contraction to 100 mmol/l K+. Neither carvedilol, metoprolol, the nonselective beta-adrenoceptor antagonist propranolol, nor the alpha(1)-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha(1)-adrenoreceptors and beta-adrenoceptors are thus not involved in the direct constrictor effects of angiotensin II. When added to the organ bath at a subthreshold concentration, angiotensin II greatly amplified the response to phenylephrine. Both carvedilol and the angiotensin II type 1 (AT(1)) receptor antagonist irbesartan inhibited this angiotensin II-induced potentiation. Furthermore, carvedilol blocked the angiotensin II-induced amplification of phenylephrine-induced inositol phosphate accumulation in cardiomyocytes. Conclusions AT(1)-alpha(1)-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha(1)-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT(1) receptor blockade via its alpha(1)-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.