NO production and potassium channels activation induced by Crotalus durissus cascavella underlie mesenteric artery relaxation.

Autor: Santos SS; Department of Bioregulation, Federal University of Bahia, Salvador, BA, 40110-902, Brazil., Jesus RLC; Department of Bioregulation, Federal University of Bahia, Salvador, BA, 40110-902, Brazil., Simões LO; Department of Bioregulation, Federal University of Bahia, Salvador, BA, 40110-902, Brazil., Vasconcelos WP; Department of Pharmaceutical Sciences, Federal University of Paraiba, João Pessoa, Paraíba, 58059-900, Brazil., Medeiros IA; Department of Pharmaceutical Sciences, Federal University of Paraiba, João Pessoa, Paraíba, 58059-900, Brazil., Veras RC; Department of Pharmaceutical Sciences, Federal University of Paraiba, João Pessoa, Paraíba, 58059-900, Brazil., Casais-E-Silva LL; Department of Bioregulation, Federal University of Bahia, Salvador, BA, 40110-902, Brazil., Silva DF; Department of Bioregulation, Federal University of Bahia, Salvador, BA, 40110-902, Brazil. Electronic address: darizy@gmail.com.
Jazyk: angličtina
Zdroj: Toxicon : official journal of the International Society on Toxinology [Toxicon] 2017 Jul; Vol. 133, pp. 10-17. Date of Electronic Publication: 2017 Apr 18.
DOI: 10.1016/j.toxicon.2017.04.010
Abstrakt: Animal toxins are natural resources for pharmacological studies. The venom of Crotalus durissus cascavella (C.d. cascavella) may be a source in the bio-prospecting of new anti-hypertensive agents. The aim of this study was to investigate vascular effects of the venom of C.d. cascavella in normotensive rats. Studies were performed using isolated mesenteric artery segments and aortic endothelial cells. The cumulative administration of the venom of C.d. cascavella (0.001-30 μg/mL) on phenylephrine (Phe; 10 μM) pre-contracted rings induced a concentration-dependent vasorelaxation in the presence of vascular endothelium (E max  = 47.9 ± 5.0% n = 8), and its effect was almost abolished in the absence of endothelium (E max  = 5.8± 2.4% n = 5 ( ∗∗∗ p < 0.001)). Tissue viability was maintained as there was no difference in the contractile capacity of rings before and after the administration of venom. The vasorelaxant effect of the venom was also abolished when arteries were pre-contracted with potassium chloride (KCl; 80 mM) (E max  = 6.4± 0.9% n = 5, ∗∗∗ p < 0.001). When assessing the participation of endothelium-derived relaxing factors, it was noted that non-selective COX inhibition with indomethacin (10 μM) caused a significant reduction in the vasorelaxant effect of C.d. cascavella (*p < 0.05). When investigating the participation of NO released by endothelium, there was a significant reduction of the vasorelaxant effect of venom in rings treated with L-NAME (100 μM; E max  = 17.5± 2.2% n = 6; **p < 0.01). Similar results were noted in the presence of ODQ (10 μM), an inhibitor of soluble guanylyl cyclase (E max  = 11.2± 3.5%, n = 6) and PTIO (100 μM), a stable radical scavenger for nitric oxide (E max  = 10.77± 3.6%, n = 6). Moreover, the venom induced the release of NO by isolated aortic endothelial cells through amperometric studies. When assessing the participation of K + channels on the vasodilatory response of the venom, tyrode solution with 20 mM of KCl caused a significant reduction in the relaxation response (p < 0.001) (E max  = 21.3 ± 8%, n = 7), as did inhibitor of delayed rectifier K + channels (4-amynopiridine 1 mM; E max  = 9.5 ± 1.3, %, n = 5, ***p < 0.001), and vasorelaxation was almost abolished in the presence of Iberiotoxin (IbTx 100 nM). Therefore, these results suggest that the venom of C.d. cascavella induces vasorelaxation in superior mesenteric artery rings of normotensive rats in an endothelium-dependent manner. Specifically, the venom stimulates the generation of endothelium-derived relaxing factors, especially NO, and activates vascular smooth muscle hyperpolarization through K + channels. These data illustrate that C.d. cascavella is a source of bioactive molecules and therefore has therapeutic potential in the treatment of cardiovascular diseases such as hypertension.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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