6-Nitrodopamine Is the Most Potent Endogenous Positive Inotropic Agent in the Isolated Rat Heart

Abstract

Background: 6-nitrodopamine released from rat isolated atria exerts positive chronotropic action, being more potent than noradrenaline, adrenaline, and dopamine. Here, we determined whether 6-nitrodopamine is released from rat isolated ventricles (RIV) and modulates heart inotropism. Methods: Catecholamines released from RIV were quantified by LC-MS/MS and their effects on heart inotropism were evaluated by measuring left ventricular developed pressure (LVDP) in Langendorff’s preparation. Results: 6-nitrodopamine was the major released catecholamine from RIV. Incubation with L-NAME (100 µM), but not with tetrodotoxin (1 µM), caused a significant reduction in 6-nitrodopamine basal release. 6-nitrodopamine release was significantly reduced in ventricles obtained from L-NAME chronically treated animals. 6-nitrodopamine (0.01 pmol) caused significant increases in LVDP and dP/dtmax, whereas dopamine and noradrenaline required 10 pmol, and adrenaline required 100 pmol, to induce similar increases in LVDP and dP/dtmax. The infusion of atenolol (10 nM) reduced basal LVDP and blocked the increases in LVDP induced by 6-ND (0.01 pmol), without affecting the increases in LVDP induced by 10 nmol of dopamine and noradrenaline and that induced by adrenaline (100 nmol). Conclusions: 6-nitrodopamine is the major catecholamine released from rat isolated ventricles. It is 1000 times more potent than dopamine and noradrenaline and is selectively blocked by atenolol, indicating that 6-ND is a main regulator of heart inotropism.

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

“…Interestingly, the positive inotropic effect of 6-ND was inhibited by the supposed β 1 -adrenoceptor antagonist atenolol at a concentration (10 nM) that did not affect the positive inotropic effect induced by dopamine, noradrenaline, and adrenaline. At this concentration, atenolol caused a significant reduction of the basal left ventricular developed pressure, indicating that it may be acting as a selective 6-ND receptor antagonist, rather than a β 1 -adrenoceptor antagonist ( 72 ).…”

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

“…Although there are known factors that can precipitate acute heart failure, such as myocardial ischemia, cardiac arrhythmias, infections, and non-compliance with medication (Follath, 2009), the molecular mechanism(s) involved are not known. Since 6-ND is the most potent endogenous positive chronotropic and inotropic agent described (Britto-Júnior et al, 2023c), understanding its biosynthetic pathway may provide insights into the physiopathology of acute heart failure.…”

A LC–MS/MS method for the simultaneous determination of 6‐cyanodopamine, 6‐nitrodopamine, 6‐nitrodopa, 6‐nitroadrenaline and 6‐bromodopamine in human plasma and its clinical application in patients with chronic kidney disease

“…Rabbit isolated hearts show a basal release of 6-nitrodopa, 6-nitrodopamine, 6-nitroadrenaline and 6-cyanodopamine (Júnior et al, 2023). 6-Nitrodopamine (6-ND) acts as a potent vasodilator (Britto-Júnior et al, 2021) and has remarkable positive chronotropic (Britto-Júnior et al, 2022) and inotropic effects in rat and mouse isolated hearts (Britto-Júnior et al, 2023). The synthesis/release of 6-ND from vascular tissues such as the human umbilical cord vessels (Britto-Júnior et al, 2021) and the aortic rings of Panterophis guttatus (Lima et al, 2022) is significantly reduced when these tissues are pre-incubated with the inhibitor of the nitric oxide synthase (NOS) N G -nitro-L-arginine methyl ester.…”

“…The synthesis/release of 6-ND from vascular tissues such as the human umbilical cord vessels (Britto-Júnior et al, 2021) and the aortic rings of Panterophis guttatus (Lima et al, 2022) is significantly reduced when these tissues are pre-incubated with the inhibitor of the nitric oxide synthase (NOS) N G -nitro-L-arginine methyl ester. In the mouse isolated heart, the main NOS involved is endothelial nitric oxide synthase (eNOS) (Britto-Júnior et al, 2023) and endothelium-derived 6-ND is now considered a major endogenous modulator of the cardiovascular system (for a review see Zatz & De Nucci, 2023). To assess the in vivo relevance of these novel catecholamines, the development of a suitable methodology to evaluate circulating levels of 6-ND and the other novel catecholamines identified in vitro is of paramount importance.…”