Phosphodiesterases inhibition unmask a positive inotropic effect mediated by beta2-adrenoceptors in rat ventricular myocardium.
The effects of salbutamol on contractility and cAMP levels were investigated in rat right ventricular myocardium. Salbutamol (1-300 microM), produced a concentration-dependent positive inotropic effect which was not affected by ICI 118551 (50 nM), a beta2-adrenoceptor antagonist but was abolished by CGP 20712A (1 microM) a beta1-adrenoceptor antagonist. However, in rats pretreated with pertussis toxin (30 microg/kg intraperitoneal injection) salbutamol increases contractility (Emax = 9.8 +/- 1.8%, - log EC50 = 6.25 +/- 0.07, n = 5). The combination of salbutamol + CGP 20712A, also produces a concentration-dependent enhancement of contractility (Emax = 43.0 +/- 7.5%, - log EC50 = 6.3 +/- 0.04, n = 6), in the presence of 30 microM of the non selective phosphodiesterase (PDE) inhibitor 3-isobutylmethylxantine (IBMX) which was prevented by ICI 118551 (50 nM). Also, salbutamol + CGP 20712A fail to increase cAMP tissue levels but enhance them in the presence of IBMX. This effect was also prevented by ICI 118551. These results indicate that PDEs blunt contractility and cAMP production mediated by beta2-adrenoceptors in rat ventricular myocardium. Gi protein, although less efficiently than PDEs, also limits inotropic effects of salbutamol mediated by beta2-adrenoceptors in this tissue.
Gonzalez-Muñoz
C
C
Department of Pharmacology, Medical School, University of Murcia, Spain.
Fuente
Teodomiro
T
Hernández-Cascales
J
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D037342:Pertussis Toxin; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; C026777:ICI 118551; C049763:CGP 20712A; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000420:Albuterol; D015056:1-Methyl-3-isobutylxanthine