Activation of peripheral dopamine presynaptic receptors lowers blood pressure and heart rate in dogs.

Abstract

Several N,N-dialkyl substituted analogs of dopamine lower blood pressure and cause renal and femoral vasodilation by activation of noradrenergic neuronal dopaminergic receptors that inhibit further release of norepinephrine (presynaptic DA2) or of vasodilatory dopaminergic receptors located in vascular beds (postsynaptic DA1). Unlike dopamine itself, these analogs demonstrate minimal .beta.1-adrenergic receptor activation and .alpha.1-vasoconstrictor effect. The relative hemodynamic, renal and emetic properties of 4 of these dopamine analogs were compared in anesthetized and/or conscious dogs. The purposes of the studies were: determination of the relative contribution of central vs. peripheral nervous system sites of action of these analogs to their effects on cardiovascular function, assessment of the relative importance of activation of DA1 vs. DA2 receptors for the observed hemodynamic effects and investigation of the relative efficacy of dopamine antagonists for DA2 vs. DA1 receptors. The reduction in blood pressure, increase in renal blood flow and decrease in renal vascular resistance produced by propylbutyl-(PBDA), ethylbutyl-(EBDA) or propylpentyl-(PPDA) dopamine was similar to that reported previously for dipropyldopamine (DPDA). All analogs except PPDA also lowered heart rate. Doses of either the peripheral dopamine receptor antagonist, domperidone, or the peripheral and central dopamine receptor antagonist, metoclopramide, which attenuated PBDA-induced reductions in mean arterial pressure and heart rate did not antagonize the increase in renal blood flow produced by this analog. Following electrical stimulation of the cardioaccelerator nerve, all 4 dopamine analogs reduced the heart rate of spinally transected, vagotomized, anesthetized dogs. Sulpiride but not phentolamine antagonized the reduction in both heart rate and coronary sinus norepinephrine secretion produced by PBDA during cardioaccelerator nerve stimulation. In conscious dogs, the emetic potency was: DPDA > PPDA = PBDA > EBDA. The dopamine receptor antagonist, (.sbd.)-sulpiride, completely abolished the emesis induced by PBDA administration. Evidently PBDA and other N,N-dialkyl substituted dopamine derivatives can alter cardiovascular hemodynamics primarily by agonism of peripheral dopamine receptors. PBDA appears to lower blood pressure primarily through agonism of presynaptic DA2 receptors rather than postsynaptic DA1 vascular receptors.