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

Wendy W. Batenburg, Joep H.M. Van Esch, Ingrid M. Garrelds, Ulrich Jorde, Jos M.J. Lamers, Dick H.W. Dekkers, Thomas Walther, Elaine Kellett, Graeme Milligan, Jorge P. Van Kats, A. H.Jan Danser

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1355-1363
Number of pages9
JournalJournal of Hypertension
Volume24
Issue number7
DOIs
StatePublished - Jun 2006
Externally publishedYes

Keywords

  • Adrenergic receptors
  • Angiotensin
  • Heart failure
  • Signal transduction

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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