Carvedilol-induced antagonism of angiotensin II: A matter of α1-adrenoceptor blockade
Journal of Hypertension , Volume 24 - Issue 7 p. 1355- 1363
OBJECTIVE: To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective β + α1-adrenoceptor blocker carvedilol as compared with the selective β1-adrenoceptor blocker metoprolol. METHODS: Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs. RESULTS: Angiotensin II and the α1-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 β-adrenoceptor antagonist propranolol, nor the α1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. α1-adrenoreceptors and β-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 (AT1) 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: AT1-α1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to α1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its α1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.
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|Journal of Hypertension|
|Organisation||Department of Cardio-Thoracic Surgery|
Batenburg, W.W, van Esch, J.H.M, Garrelds, I.M, Jorde, U, Lamers, J.M.J, Dekkers, D.H, … Danser, A.H.J. (2006). Carvedilol-induced antagonism of angiotensin II: A matter of α1-adrenoceptor blockade. Journal of Hypertension, 24(7), 1355–1363. doi:10.1097/01.hjh.0000234116.17778.63