Pharmacological Characterization of the Vasodilating Effect Induced by the Ruthenium Complex cis-[Ru(NO)(NO2)(bpy)2].(PF6)2

Abstract

Nitric oxide (NO) can be found in different species and is a potent vasodilator. The ruthenium compound cis-[Ru(NO)(NO2)(bpy)2].(PF6)2 (BPY) can generate NO. This study aimed to investigate the BPY stability at physiological pH, the cellular mechanisms involved in BPY effect, NO species originating from BPY, and to verify how BPY affects blood pressure. Our results has shown that at pH 7.4 and 9.4, the NO coordinated to ruthenium (Ru-NO) is converted to nitrite (Ru-NO2) and remains stable. In aortic rings, the stable configuration of BPY (Ru-NO2) induces vascular relaxation in a concentration-dependent manner. Thus, further experiments were made with stable configuration of BPY (Ru-NO2). The relaxation induced by BPY was abolished in the presence of guanylyl cyclase inhibitor and decreased in the presence of potassium channel blocker. By using radicalar (NO) and nitroxyl (NO) scavenger, our results suggest that the BPY mainly release the radicalar species. By using fluorescence probes to detect intracellular NO concentration ([NO]i) and cytosolic Ca concentration ([Ca]c), we verified that in smooth muscle cells, BPY induces an increase in [NO]i and a decrease in [Ca]c. The intravenous bolus injection of 1.25, 2.5, and 5.0 mg/kg from stable configuration of BPY results in a decrease on basal blood pressure values. Taken together, our results indicated that the stable configuration of the compound BPY induces vascular relaxation in aorta because of NO release and decrease of [Ca]c in vascular smooth muscle cells. Also, the stable configuration is able to reduce the blood pressure in a dose-dependent manner.

Ruthenium-based nitric oxide-donating and carbon monoxide-donating molecules

“…Likewise, activation of sGC and K + channels is the underlying mechanism of Ca 2+ decrease and vasorelaxation. Moreover, this stable configuration has shown to dose‐dependently reduce blood pressure …”

Ru(ii) based dual nitric oxide donors: electrochemical and photochemical reactivities and vasorelaxant effect with no cytotoxicity

“…Among the few metal-nitrosyls being synthesized and evaluated as exogenous NO donors, 13–16 nitrosyl ruthenium complexes have attained remarkable progress and are recognized as promising exogenous NO donors 8,17–19 that have vasodilation activity. 7,20–23 These complexes are also promising antimicrobial agents by aggregating the recognized microbicidal and microbiostatic effects of the nitric oxide (NO). 24,25 Nitric oxide improves cisplatin cytotoxicity in head and neck squamous cell carcinoma.…”

Phenotypic switching prevention and proliferation/migration inhibition of vascular smooth muscle cells by the ruthenium nitrosyl complex trans-[Ru(NO)Cl(cyclam](PF6)2

“…The biological importance of NO had launched searches for NO carriers capable to deliver NO efficiently and in a controlled manner in physiological medium and aiming biological applications . NO donors are pharmacologically active substances that release NO, spontaneously or induced by chemical or photochemical reactions, differing by varied chemical and photochemical reactivities in physiological milieu and NO‐release kinetics . Among these NO donors, ruthenium tetraammine and tetraazamacrocycle nitrosyl complexes have favourable features, such as water solubility, stability even in aqueous solutions, low toxicity and for the possibility to control the reactivity of the coordinated NO by the careful choice of ligands around the RuNO moiety .…”

“…[19][20][21][22][23][24][25][26][27][28][29] NO donors are pharmacologically active substances that release NO, spontaneously or induced by chemical or photochemical reactions, differing by varied chemical and photochemical reactivities in physiological milieu and NO-release kinetics. [19][20][21][22][23][24][25][26][27][28][29][30][31] Among these NO donors, ruthenium tetraammine and tetraazamacrocycle nitrosyl complexes have favourable features, such as water solubility, stability even in aqueous solutions, low toxicity and for the possibility to control the reactivity of the coordinated NO by the careful choice of ligands around the RuNO moiety. [22,24,29,32] Such features make them attractive candidates as NO delivery agents, not only for therapeutic applications, as in cardiovascular devices, but also as pharmacological tools to investigate the role of NO in physiology and pathophysiology.…”