Direct Vasodilating Effects of the New Dopaminergic Agonist Z1046 in Human Arteries

Abstract

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.

Peripheral chemoreceptor control of cardiovascular function at rest and during exercise in heart failure patients

“…Dopamine has been used to improve renal function in HF (9,18,24,69); however, cardiovascular improvements are not always noted (31,42). Dopamine is thought to work via direct stimulation of dopamine-1 receptors in the peripheral and renal vasculature (26,64), yet dopamine is also known to suppress the peripheral chemoreceptor in HF patients (68). Suppression of peripheral chemoreceptor activity would reduce sympathetic output and, therefore, increase renal blood flow and cardiac function.…”

Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum

“…Dopamine receptor proteins have been localized to the adventitia and media of systemic arteries ( Amenta et al ., 2000 ; Zeng et al ., 2004 ). In mesenteric, aortic coronary, renal, lumbar, mammary, hinquarters, and forearm vascular beds or arterial preparations from various mammals, dopamine receptor agonists or apomorphine have been shown to produce vasorelaxant effects ( Anwar & Mason, 1981 ; Ventura et al ., 1984 ; Gyorgy & Doda, 1985 ; Hughes et al ., 1986 ; 1987 ; Kopia & Valocik, 1989 ; van der Niepen et al ., 1991 ; Han et al ., 1999 ; Teisman et al ., 2000 ; Zeng et al ., 2004 ). Responses to dopamine receptor activation appear to vary depending on which arterial preparation that is studied, and some investigators have found vasoconstrictive actions of dopamine receptor agonists in postglomerular arteries, and in tail arteries from rats ( Rashed & Songu‐Mize, 1995 ; Muhlbauer et al ., 2000 ).…”