title: Carvedilol-induced antagonism of angiotensin II: a matter of alpha1-adrenoceptor blockade.
abstract: OBJECTIVE
  To investigate whether renin-angiotensin system blockade might underlie the favorable metabolic effects of the nonselective beta + alpha1-adrenoceptor blocker carvedilol as compared with the selective beta1-adrenoceptor blocker metoprolol.
  
  
  METHODS
  Human coronary microarteries (HCMAs), obtained from 32 heart valve donors, were mounted in myographs.
  
  
  RESULTS
  Angiotensin II and the alpha1-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 alpha1-adrenoceptor antagonist prazosin affected the constrictor response to angiotensin II. alpha1-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 (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-alpha1-receptor crosstalk, involving inositol phosphates, sensitizes HCMAs to alpha1-adrenoceptor agonists. Our results suggest that, in the presence of an increased sympathetic tone, carvedilol provides AT1 receptor blockade via its alpha1-adrenoceptor blocking effects. This could explain the favorable effects of carvedilol versus metoprolol.
authors.affiliation: Department of Pharmacology, The Netherlands.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Batenburg
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jorde
authors.forename: Jos M J
authors.initials: JM
authors.lastname: Lamers
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Elaine
authors.initials: E
authors.lastname: Kellett
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Jorge P
authors.initials: JP
authors.lastname: van Kats
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000293:Adolescent; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D003331:Coronary Vessels / Q000502:physiology; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D000077405:Irbesartan; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008875:Middle Aged; D009213:Myography / Q000379:methods; D011412:Propanolamines / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D018674:Adrenergic Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D002227:Carbazoles; D007295:Inositol Phosphates; D011412:Propanolamines; D013777:Tetrazoles; D000077261:Carvedilol; D000804:Angiotensin II; D008156:Luciferases; D008790:Metoprolol; D000077405:Irbesartan