Vascular smooth muscle relaxation by alpha 1-adrenoceptor blocking action of denopamine in isolated rabbit aorta

We investigated the mechanism of vascular relaxation by denopamine (Deno), an oral positive inotropic agent that has selective beta 1-adrenergic action. Deno relaxed, dose-dependently (0.1-30 microM), ring segments of rabbit aorta, which were partially precontracted with 1 microM phenylephrine (Phe) or norepinephrine (NE), but did not relax those precontracted with 5 microM prostaglandin F2 alpha or 40 mM K+. The relaxation was not significantly inhibited by pretreatment with 10 microM propranolol or metoprolol. Deno produced parallel shifts in concentration-response curves to Phe, but this was not true for clonidine. The Schild plot analysis resulted in a linear regression of a slope of 1.075 +/- 0.063, which was not significantly different from unity, and the pA2 value of Deno against Phe was 5.57 +/- 0.02. The specific binding of [3H]prazosin to a rabbit aorta membrane preparation was displaced in a concentration-dependent manner by the simultaneous addition of Deno. The slope of a Hill plot was not significantly different from unity (1.102 +/- 0.147). The pK1 value for Deno calculated from the displacement curve was 5.29 +/- 0.17, which was not significantly different from the pA2 value of Deno. In conclusion, vascular smooth muscle relaxation by Deno was mediated by the blocking effect of alpha 1-adrenoceptors. Thus, these findings suggest that Deno may be effective in the treatment of congestive heart failure because it elicits a positive inotropic effect by beta 1-adrenergic action and vasodilation by alpha 1-adrenergic blocking action.