title: Mechanisms underlying the vascular relaxation induced by a new nitric oxide generator.
abstract: Nitric oxide (NO) is a potent vasodilator and it can be generated by the ruthenium complex cis-[Ru(H-dcbpy(-))(2)(Cl)(NO(2)(-))] (DCBPY). The present study aimed to investigate the NO specie generated and to characterize the cellular mechanisms involved on the vasodilatation induced by DCBPY. It was found that at pH 7.4 and 9.4, the NO(+) coordinated to ruthenium (Ru-NO(+)) is converted to NO(2)(-) (Ru-NO(2)(-)), which remains stable. However, the configuration Ru-NO(+) is stable at pH 5.4. It was also verified that the DCBPY complex (Ru-NO(2)(-) configuration) induces vascular relaxation of contracted rat aortic rings in a concentration-dependent manner. Therefore, the potency (pD(2) values) and the maximum relaxant effect (ME) were compared. It was observed that relaxation is more pronounced to Ru-NO(+) configuration, compared with Ru-NO(2)(-), with no difference in ME. On the other hand, the potency of DCBPY (Ru-NO(2)(-)) is lower than that of SNP and higher than that of NITRITE, with no difference in ME for all the compounds. Further experiments were conducted using DCBPY in the Ru-NO(2)(-) configuration. It was noted that the relaxation induced by DCBPY is completely blocked by the soluble guanylyl cyclase (sGC) enzyme inhibitor. The non-selective K(+) channel blocker (TEA) diminishes the potency of DCBPY, but it does not change the ME. Incubation with selective radicalar NO (NO()) and extracellular NO scavengers almost abolishes the relaxation induced by DCBPY. The use of a selective nitroxyl (NO(-)) scavenger decreases the potency of DCBPY, but it does not alter the ME. By using confocal microsopy, it was found that DCBPY, SNP, and NITRITE raise the cytosolic NO concentration and reduce the cytosolic Ca(2+) concentration [Ca(2+)]c in rat aortic smooth muscle cells. These effects are not different when DCBPY and SNP are compared, but they are lower for NITRITE. Taken together, our results demonstrate that the compound DCBPY (Ru-NO(2)(-)) is an NO generator that promotes relaxation of rat aortic rings due to a reduction in [Ca(2+)]c. The vascular smooth muscle relaxation is dependent on sGC activation.
authors.affiliation: School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
authors.forename: G J
authors.initials: GJ
authors.lastname: Rodrigues
authors.forename: S A
authors.initials: SA
authors.lastname: Cicillini
authors.forename: R S
authors.initials: RS
authors.lastname: Silva
authors.forename: L M
authors.initials: LM
authors.lastname: Bendhack
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D009942:Organometallic Compounds; D009569:Nitric Oxide; D002118:Calcium