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 language | English (US) |
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Pages (from-to) | 1355-1363 |
Number of pages | 9 |
Journal | Journal of Hypertension |
Volume | 24 |
Issue number | 7 |
DOIs | |
State | Published - Jun 2006 |
Externally published | Yes |
Keywords
- Adrenergic receptors
- Angiotensin
- Heart failure
- Signal transduction
ASJC Scopus subject areas
- Internal Medicine
- Physiology
- Cardiology and Cardiovascular Medicine