Purpose: The ruthenium complex cis-[Ru(H-dcbpy-)2(Cl)(NO)] (DCBPY) is a nitric oxide (NO) donor and  studies suggested that the ruthenium compounds can inactivate O2-. The aim of this study is to test if DCBPY can revert and/or prevent the endothelial dysfunction. Methods: Normotensive (2K) and hypertensive (2K-1C) wistar rats were used. To vascular reactivity study, thoracic aortas were isolated, rings with intact endothelium were incubated with: DCBPY: 0.1; 1 and 10μM, DCBPY plus hydroxocobalin (NO scavenger) or tempol during 30 minutes, and concentration effect curves to acetylcholine were performed. The potency values (pD2) and maximum effect (ME) were analyzed. The O2- was generated using hypoxantine xantine oxidase and the reduction of cytochrome c, NO consumption by O2- and the effect in avoid NO consumption was measured. Results: In 2K-1C DCBPY at 0.1; 1 or 10μM improved the relaxation endothelium dependent induced by acetylcholine in aortic rings compared to control 2K-1C, and also improved ME. In rings from 2K incubation with DCBPY (0.1; 1.0 and 10 μM) did not change pD2 or ME. Incubation with 0.1 μM of DCBPY plus hydroxocobalamin did not modify the potency and ME in 2K-1C compared to DCBPY (0.1 μM). DCBPY and SOD inhibits the reduction of cytochrome c and inhibited the NO consumption by O2-, showing that O2- has been removed from the solution. Conclusion: Our results suggest that DCBPY at a lower concentration (0.1 µM) is not an NO generator, but can inactivate superoxide and improves the endothelial function. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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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.

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-Purpose. In endothelial cells, investigate if the soluble guanylate cyclase (sGC) activation or stimulation is able to potentiate the relaxation in vessels. Methods. Aortic and coronary rings with and without endothelium were placed in a myograph and cumulative concentration-effect curves for DETA-NO or ataciguat were performed. Nitric oxide (NO) were measured by fluorescence or by selective electrode in human umbilical endothelial cells (HUVECs) in response to some treatments, including ataciguat, 8-BrcGMP and A23187. Results. The presence of the endothelium potentiated the relaxation induced by DETA-NO in aortic and coronary rings. In addition, in aortic rings the endothelium potentiated the relaxation induced by ataciguat. In the presence of nitric oxide synthase (NOS) inhibitor, the endothelium effect was abolished to DETA-NO or ataciguat, in both vessels. Ataciguat, 8-Br-cGMP and A23187 were able to induce NO production in HUVECs cells. In the presence of NOS inhibitor, the NO production induced by ataciguat and 8-Br-cGMP was abolished. Conclusions. Our results suggest that in aortic and coronary rings the endothelium potentiates the relaxation induced by activation or stimulation of sGC through a mechanism dependent of NOS activation.

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BackgroundThe endothelium is a monolayer of cells that extends on the vascular inner surface, responsible for the modulation of vascular tone. By means of the release of nitric oxide (NO), the endothelium has an important protective function against cardiovascular diseases.ObjectiveVerify if cis- [Ru(bpy)2(NO2)(NO)](PF6)2 (BPY) improves endothelial function and the sensibility of conductance (aorta) and resistance (coronary) to vascular relaxation induced by BPY.MethodsNormotensive (2K) and hypertensive (2K-1C) Wistar rats were used. For vascular reactivity study, thoracic aortas were isolated, rings with intact endothelium were incubated with: BPY(0.01 to10 µM) and concentration effect curves to acetylcholine were performed. In addition, cumulative concentration curves were performed to BPY (1.0 nM to 0.1 µM) in aortic and coronary rings, with intact and denuded endothelium.ResultsIn aorta from 2K-1C animals, the treatment with BPY 0.1µM increased the potency of acetylcholine-induced relaxation and it was able to revert the endothelial dysfunction. The presence of the endothelium did not modify the effect of BPY in inducing the relaxation in aortas from 2K and 2K-1C rats. In coronary, the endothelium potentiated the vasodilator effect of BPY in vessels from 2K and 2K-1C rats.ConclusionOur results suggest that 0.1 µM of BPY is able to normalize the relaxation endothelium dependent in hypertensive rats, and the compound BPY induces relaxation in aortic from normotensive and hypertensive rats with the same potency. The endothelium potentiate the relaxation effect induced by BPY in coronary from normotensive and hypertensive rats, with lower effect on coronary from hypertensive rats.

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