Z-1046

Dopaminergic agonists remain of interest in the treatment of heart failure; however, concomitant stimulation of alpha- and beta-receptors should be avoided. This study evaluates the dopaminergic and adrenergic (vasodilating) properties of Z1046, epinine (the active metabolite of ibopamine), and dopamine. Isotonic contraction experiments were performed on human internal mammary artery rings in vitro. alpha1-Antagonistic effects of Z1046 were demonstrated by performing cumulative dose-response curves with the selective alpha1-agonist phenylephrine in the presence of Z1046. Furthermore, both alpha1- and dopamine-mediated receptor effects of Z1046, epinine, and dopamine were studied by performing cumulative dose-response relations both at baseline and in precontracted artery rings both with and without the D1-like antagonist SCH23390. In contrast to both epinine and dopamine, Z1046 is devoid of alpha1-receptor-mediated contraction. Furthermore, Z1046, epinine, and dopamine induced direct dopamine receptor-mediated vasodilation when interfering alpha1 effects were blocked. In contrast to epinine and dopamine, Z1046 is devoid of vasoconstricting properties at higher dosages. Because of its D1-like agonistic and alpha1-antagonistic properties, Z1046 is an effective vasodilator in the whole dosage range. Because of its total receptor profile, Z1046 appears to be more favorable for treatment of heart failure than is ibopamine.

In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3≥ D4> D2> D5> D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 μg ⋅ kg−1⋅ min−1( n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by itself decreased urine flow and sodium excretion without affecting RBF and blocked the diuretic, natriuretic, and renal vasodilatory effect of Z-1046. We conclude that the renal vasodilatory effect of Z-1046 is D1-like receptor dependent, whereas the diuretic and natriuretic effects are both D1- and D2-like receptor dependent.