alpha 1-Adrenoceptor stimulation inhibits the isoproterenol-induced effects on myocardial contractility and protein phosphorylation.
In the present study the influence of alpha 1-adrenoceptor stimulation on the beta-adrenoceptor agonist-induced increases in contractile parameters and protein phosphorylation was determined in isolated perfused hearts and isolated cardiac myocytes, respectively. Methoxamine inhibited the isoproterenol-induced increases in left ventricular pressure and heart rate dose dependently up to 90% and 75%, respectively; the EC50 of this antiadrenergic effect was 4.4 microM. The alpha 1-adrenoceptor antagonist, prazosin (1 microM), greatly diminished methoxamine's inhibitory action, confirming the alpha 1-adrenoceptor-mediated mechanism. The inotropic effect of glucagon was inhibited by methoxamine in a similar manner. Radioligand binding assays with [3H]dihydroalprenolol demonstrated that the antiadrenergic action of methoxamine is not due to an unspecific beta-adrenoceptor blocking property. In an additional experimental series the effects of methoxamine and isoproterenol on the protein phosphorylation pattern of isolated cardiac myocytes were investigated. Isoproterenol increased the phosphorylation state of five proteins (6-kDa, phospholamban; 15-kDa; 28-kDa, troponin I; 97-kDa; 140-kDa) while in the experiments with methoxamine the 15-kDa protein was the only phosphorylated substrate. In the presence of methoxamine the isoproterenol-induced phosphorylation of phospholamban, troponin I and the 97-kDa and 140-kDa protein was markedly inhibited while the phosphorylation state of the 15-kDa protein remained unaltered. The present study clearly demonstrated that alpha 1-adrenoceptor stimulation potently inhibits the beta-adrenoceptor-mediated changes in contractile force and phosphorylation of key regulatory proteins, most likely through modulation of cAMP metabolism.
Hartmann
M
M
Department of Anesthesiology, Heinrich Heine University Düsseldorf, Germany.
Stumpe
T
T
Schrader
J
J
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D007545:Isoproterenol / Q000037:antagonists & inhibitors*; D008729:Methoxamine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017725:Ventricular Pressure / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D008729:Methoxamine; D007545:Isoproterenol; D011224:Prazosin