Endothelium-Derived Dopamine and 6-Nitrodopamine in the Cardiovascular System

Abstract

The review deals with the release of endothelium-derived dopamine and 6-nitrodopamine (6-ND) and its effects on isolated vascular tissues and isolated heart. Human isolated umbilical cord vessels, human popliteal vessels, non-human primate vessels, and reptilia aortae, present basal release of both dopamine and 6-ND. The 6-ND basal release was significantly reduced when the tissues were treated with L-NAME and virtually abolished when the endothelium was mechanically removed. 6-Nitrodopamine is a potent vasodilator, and the mechanism of action responsible for this effect is the antagonism on dopamine D2-like receptor. As a vasodilator, 6-ND constitutes a novel mechanism by which NO modulates vascular tone. The basal release of 6-ND was substantially decreased in eNOS-/- mice and not altered in nNOS-/- mice, indicating a non-neurogenic source for 6-ND in the heart. Indeed, in rat isolated right atrium, the release of 6-ND was not affected when the atria were treated with tetrodotoxin. In the rat isolated right atrium, 6-ND is the most potent endogenous positive chronotropic agent, and in Langendorff's heart preparation, it is the most potent endogenous positive inotropic agent. The positive chronotropic and inotropic effects of 6-ND are antagonized by β1-adrenoceptor antagonists at concentrations that do not affect the effects induced by noradrenaline, adrenaline, and dopamine, indicating that blockade of 6-ND receptor is the major modulator of heart chronotropism and inotropism. The review proposes that endothelium-derived catecholamines may constitute a major mechanism for control of vascular tone and heart functions, in contrast to the overrated role attributed to the autonomic nervous system.

3-Nitroatenolol: First Synthesis, Chiral Resolution and Enantiomers’ Absolute Configuration

“…It is 100 times more potent than noradrenaline and adrenaline [6]. Owing to the critical significance of endothelium-derived 6-ND, a great deal of research has been conducted to characterize its effects on the cardiovascular system and ascertain the amounts released from cardiac tissues [7].…”

Basal Release of 6-cyanodopamine From Rat Isolated Vas Deferens and Its Role on the Vas Deferens Contractility

“…6-Nitrodopamine is also released from vascular endothelium and presents major cardiovascular actions (14). 6-Cyanodopamine (6-CYD) is a new endogenous catecholamine that is released from rabbit isolated atria and ventricles (15) and found in plasma of chronic kidney disease patients (16).…”

GKT137831 and hydrogen peroxide increase the release of 6-nitrodopamine from the human umbilical artery, rat-isolated right atrium, and rat-isolated vas deferens

“…(Britto-Júnior et al, 2023a) and in non-vascular tissues, such as rat-isolated atria (Britto-Júnior et al, 2022b) and rat- (Britto-Júnior et al, 2021b) and human-isolated vas deferens (Britto-Júnior et al, 2022c). In the cardiovascular system, 6-ND acts as a potent vasodilator and presents both positive chronotropic and inotropic effects (Zatz and De Nucci, 2023). In all the tissues mentioned above, pre-incubation of the tissues with the NO synthase (NOS) inhibitor N ω -nitro-L-arginine methyl ester (L-NAME) caused a significant reduction in the synthesis/ release of 6-ND, indicating a major role of nitric oxide synthases in the biosynthesis of 6-ND.…”

“…Indeed, DPI produces only a transient pressor response following systemic administration to animals, and the dose-dependent increases in the mean arterial pressure induced by L-NAME in conscious rats were shifted to the right by pre-treatment with DPI (Wang et al, 1995). Since 6-ND is a potent vasodilator (Zatz and De Nucci, 2023), it is possible that an increase in the basal release of 6-ND induced by DPI counteracts the vasoconstriction induced by the lack of NO in vivo.…”