Abstract
It has been established that oximes cause endothelium-independent relaxation in blood vessels. In the present study, the cardiovascular effects of the new oxime 3-hydroxy-4–(hydroxyimino)-2-(3-methylbut-2-enylnaphtalen-1(4H)-one (OximeS1) derived from lapachol were evaluated. In normotensive rats, administration of Oxime S1 (10, 15, 20 and 30 mg/Kg, i.v.) produced dose-dependent reduction in blood pressure. In isolated aorta and superior mesenteric artery rings, Oxime S1 induced endothelium-independent and concentration-dependent relaxations (10−8 M to 10−4 M). In addition, Oxime S1-induced vasorelaxations were attenuated by hydroxocobalamin or methylene blue in aorta and by PTIO or ODQ in mesenteric artery rings, suggesting a role for the nitric oxide (NO) pathway. Additionally, Oxime S1 (30 and 100 µM) significantly increased NO concentrations (13.9 ± 1.6 nM and 17.9 ± 4.1 nM, respectively) measured by nitric oxide microsensors. Furthermore, pre-contraction with KCl (80 mM) prevented Oxime S1-derived vasorelaxation in endothelium-denuded aortic rings. Of note, combined treatment with potassium channel inhibitors also reduced Oxime S1-mediated vasorelaxation suggesting a role for potassium channels, more precisely Kir, Kv and KATP channels. We observed the involvement of BKCa channels in Oxime S1-induced relaxation in mesenteric artery rings. In conclusion, these data suggest that the Oxime S1 induces hypotension and vasorelaxation via NO pathway by activating soluble guanylate cyclase (sGC) and K+ channels.
Highlights
For many years, investigators worldwide have explored the mechanisms by which nitric oxide (NO)causes vasodilatation
It has been reported that non-amino acid compounds sharing the R2C=NOH group can produce nitric oxide synthase-independent relaxation in endothelium-denuded aortic rings of rats [10,14,15,16]
The mechanisms underlying the effects of exogenous nitrovasodilators are predominantly mediated by cyclic guanosine monophosphate, as a result of the activation of soluble guanylyl cyclase [17,18]
Summary
Investigators worldwide have explored the mechanisms by which nitric oxide (NO). In addition to the classical production of NO via NOS, the existence of NOS-independent pathways for NO production from exogenous substrates is of particular pharmaceutical interest [4,5,6] In this regard, compounds presenting a R2C=NOH structural group can be metabolized by hemoproteins like horse radish peroxidase, rat liver microsomal cytochrome P450 (P450), hemoglobin, and catalase. Compounds presenting a R2C=NOH structural group can be metabolized by hemoproteins like horse radish peroxidase, rat liver microsomal cytochrome P450 (P450), hemoglobin, and catalase This biotransformation process results in nitric oxide (NO) or NO-related vasorelaxant species formation in blood vessels that are independent of nitric oxide synthase activity [7,8,9]. Tabebuia avallanedae Lor.Ex.Gris (Bignoniaceae), which formula is shown bellow
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