Vascular Response of Ruthenium Tetraamines in Aortic Ring from Normotensive Rats

Abstract

BackgroundRuthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved.ObjectiveTo evaluate the vascular response of the tetraamines trans-[RuII(NH3)4(Py)(NO)]3+, trans-[RuII(Cl)(NO) (cyclan)](PF6)2, and trans-[RuII(NH3)4(4-acPy)(NO)]3+.MethodsAortic rings were contracted with noradrenaline (10−6 M). After voltage stabilization, a single concentration (10−6 M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10−6 M and sodium nitroprusside at 10−6 M as well as by histological examination.ResultsHistological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect.ConclusionThe results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10−6 M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used in the formulation of the compound.

The versatile ruthenium(II/III) tetraazamacrocycle complexes and their nitrosyl derivatives

“…In aortic rings with endothelium, inhibition of eNOS, cyclooxygenase, and sGC inhibition, by L-NAME, indometacine, and ODQ, respectively, caused reduction of the contractile effect of trans-[Ru(NO)(py)(NH 3 ) 4 ](BF 4 ) 3 and trans-[Ru(NO)Cl(cyclam)](PF 6 ) 2 on the pre-contracted rings, but still the effect was smaller than with noradrenaline alone [209]. The results clearly show that that vascular effect is related to the complexes, and very likely by NO release [209]. On the other hand, in rings without endothelium only inhibition of sGC significantly impacted the contractile response of trans-[Ru(NO)(py)(NH 3 ) 4 ](BF 4 ) 3 and trans-[Ru(NO)Cl(cyclam)](PF 6 ) 2 with both compounds leading to a relaxing effect.…”

“…Recent results on the vascular response of trans- [209]. Smooth muscle integrity was maintained and endothelium was present after the assays according to histological tests and after pharmacological assays with acetylcholine and SNP.…”

“…Noradrenaline alone induced contractile behavior in both aortic rings with or without endothelium, resulting in tonus increase followed by relaxation. Upon addition of the complexes, the contractile response of pre-contracted rings was much smaller meaning that the effect of noradrenaline was decreased by the presence of the complexes [209]. In aortic rings with endothelium, inhibition of eNOS, cyclooxygenase, and sGC inhibition, by L-NAME, indometacine, and ODQ, respectively, caused reduction of the contractile effect of trans-[Ru(NO)(py)(NH 3 ) 4 ](BF 4 ) 3 and trans-[Ru(NO)Cl(cyclam)](PF 6 ) 2 on the pre-contracted rings, but still the effect was smaller than with noradrenaline alone [209].…”

“…Upon addition of the complexes, the contractile response of pre-contracted rings was much smaller meaning that the effect of noradrenaline was decreased by the presence of the complexes [209]. In aortic rings with endothelium, inhibition of eNOS, cyclooxygenase, and sGC inhibition, by L-NAME, indometacine, and ODQ, respectively, caused reduction of the contractile effect of trans-[Ru(NO)(py)(NH 3 ) 4 ](BF 4 ) 3 and trans-[Ru(NO)Cl(cyclam)](PF 6 ) 2 on the pre-contracted rings, but still the effect was smaller than with noradrenaline alone [209]. The results clearly show that that vascular effect is related to the complexes, and very likely by NO release [209].…”

History of vascular reactivity models and their involvement in hypertension pathogenesis

“…In this fashion, many complexes with relaxing factors and endothelial contractile action were synthesized and tested in order to formulate new drugs to aid hypertension treatment [38,39], starring the importance of substances released by the endothelium.…”