Efeito vasorrelaxante de novos nitrocomplexos de rutênio FOR703 e FOR777A em anéis de aorta isolados de ratos Wistar

Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, with hypertension (HTN) being a major risk factor associated with genetic, environmental, and social components. The endothelium and vascular smooth muscle regulate vascular tone through mechanisms dependent on intracellular calcium, nitric oxide (NO), guanylate cyclase (GC), cyclic guanosine monophosphate (cGMP), and K⁺ channels. Ruthenium complexes have been widely trained due to their potential for controlled nitric oxide release.The aim was to investigate the vasodilatory potential of the ruthenium nitrocomplexes cis-[Ru(bpy)2(Bzim)NO2](PF6) (FOR703) and cis- [Ru(NO2)(bpy)2(4-pybz)](PF6) (FOR777A) in isolated rat aortas, evaluating the role of the endothelium and the involvement of the NO/GC, IP3K/Akt pathways and K⁺ channels. This study was approved under the CEUA protocols 46051222-0 (FOR777A) and 53060323-0 (FOR703). For the experiment, aortic rings from Wistar rats, with intact or denuded endothelium, were pre-contracted with phenylephrine (PHE) or potassium chloride (KCl) and subjected to concentration-effect curves of the ruthenium complexes FOR703 and FOR777A. Inhibitors/blockers (L-NAME, ODQ, TEA, BaCl2, hydroxocobalamin, 4-aminopyridine, glibenclamide, L-cysteine, wortmannin) were used to investigate the possible mechanisms of action. According to the results, in the PHE-precontracted preparations, both nitrocomplexes were able to induce concentration-dependent relaxation, reversing 100% of the contraction, but without a difference between their efficacies (EMAX), FOR703 (EMAX = 114.80±1.16%) and 777ª (114.10±4.08%). Regarding their potencies, a significant difference was observed between the two, with FOR777A being more potent, having the lowest (EC50), FOR703 (1.390 [1.031- 1.872]) and 777A (0.148 [0.104 - 0.210]). FOR703 showed a greater effect in rings without endothelium, while FOR777A was more potent in preparations with endothelium. The blockers indicate that both act predominantly via the NO/GC pathway, with possible involvement of NOS and K⁺ channels. These findings reinforce the pharmacological potential of ruthenium nitrocomplexes as promising vasodilator candidates.