Carteolol, a non-conventional partial agonist of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through antagonism at alpha(1)-adrenoceptors

Eur J Pharmacol. 2008 Aug 20;590(1-3):269-75. doi: 10.1016/j.ejphar.2008.05.023. Epub 2008 May 24.

Abstract

This in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of beta(1)-adrenoceptors or antagonist effect at alpha(1)-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD(2)=3.65+/-0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (100 microM) or cyclo-oxygenase inhibitor indomethacin (10 microM). The effect of carteolol was unaffected by the non-selective beta-adrenoceptor antagonist propranolol (1 microM), or the beta(2)-adrenoceptor selective antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 microM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration-response curves for phenylephrine-induced contraction, exhibiting a pK(B) of 4.28+/-0.07. Carteolol affinity for alpha(1)-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant alpha(1D)-adrenoceptor, the alpha(1)-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [(3)H]prazosin, exhibiting a pK(i) value (3.39+/-0.31) similar to its pD(2) and not very far from its pK(B). In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its alpha(1)-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of beta-adrenoceptors, particularly of the low-affinity state of beta(1)-adrenoceptors, by the drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Adrenergic beta-1 Receptor Agonists*
  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Aorta / drug effects*
  • Aorta / physiology
  • Carteolol / pharmacology*
  • Dinoprost / pharmacology
  • Dose-Response Relationship, Drug
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Male
  • Phenylephrine / pharmacology*
  • Prazosin / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Vasodilation / drug effects*

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-Agonists
  • Imidazoles
  • Receptors, Adrenergic, alpha-1
  • Phenylephrine
  • Carteolol
  • Dinoprost
  • CGP 20712A
  • Prazosin