Novos derivados da isatina causam vasorrelaxamento em artéria mesentérica cranial de ratos Wistar

• Ano de defesa: 2015
• Autor(a) principal: Monteiro, Matheus Morais de Oliveira
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos; UFPB
• Palavras-chave em Português: Vasorrelaxamento; Vasorelaxation; Pressão arterial; Canais para potássio; Artéria mesentérica; Blood pressure; Potassium channels; Mesenteric artery; CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/tede/8067

The process of discovering new drugs that act on the smooth muscle layer causing vascular relaxation is of fundamental importance in the treatment of cardiovascular diseases. In this context highlights the isatin, a versatile substance found in various tissues of mammals and plants which can easily undergo structural changes to yield new substances. The pharmacological effects of four novel drugs derived from isatin (IS-AK1, IS-BK1, B-001 and D-001) on the cardiovascular system using techniques in vivo and in vitro. In in vitro studies, cranial mesenteric rings from rat were kept in vats containing Tyrode at 37 ° C gassed with carbogen then they were fixed to a force transducer (PowerLab™, ADInstruments, MA, EUA) and coupled to a data acquisition system (WinDaq/XL, DI 148-U, Insight, Brasil) under tension 0.75 g, for 1 hour. After this period, the preparations were pre-contracted with phenylephrine (PHE, 10 μM) and KCl (60 mM) and then increasing concentrations of isatin derivatives were added cumulatively. All tested compounds showed vasorelaxant effect and IS-AK1 the most promising compound for presenting higher power when both in presence and in absence of endothelium compared to others (pD2 = 7.99 ± 0.11 and 7.95 ± 0.15, respectively), but these vasorelaxant responses were not different (Emax = 85.69 ± 5.18% vs. 74.62 ± 5.33%) in presence or in absence of endothelium. Therefore, IS-AK1 was then was selected for further studies in order to investigate its mechanism of action of the compound by concentration-response curves in the presence of blockers ODQ (10 μM), cyclase blocker soluble guanylyl; TEA 3 (mM) nonspecific blocker of K+ channels; TEA (1 mM) BKCa blocker; GLIB (1 μM), KATP blocker; 4-AP (1 mM) KV blocker and BaCl2 (30 μM), KIR blocker. In the presence of ODQ vasorelaxation was significantly attenuated (Emax = 39.68 ± 6.56%; pD2 = 5.07 ± 0.2, n = 6). In addition, in the presence of TEA 3 mM (Emax = 43.53 ± 8.16%, 6.72 pD2 ± 0.2, n = 6) and presence of TEA 1 mM (Emax = 39 72 ± 7.86%; pD2 = 5.63 ± 0.2, n = 6) vasorelaxant response were reduced. There was reduction in the power of the IS-AK1 when blocked by GLIB (pD2 = 7.23 ± 0.17, n = 5), 4-AP (pD2 = 7.1 ± 0.17, n = 5) and BaCl2 (pD2 = 6.23 ± 0.16, n = 5), suggesting the participation of different types of K+ channels in this response. For in vivo studies, changes in blood pressure and heart rate were investigated in non-anesthetized rats treated acutely with the IS-AK1. The IS-AK1 administration (10 mg/kg) produced blood pressure and bradycardia both in normotensive (-50 ± 12 mmHg -258 ± 40 bpm, n = 7) and hypertensive rats (-99 ± 7 mmHg, -278 ± 40 bpm, n = 6) with effects more pronounced in hypotensor effect in hypertensive rats. Thus, the vasorelaxant response promoted by IS-AK1 possibly involves the participation of sGC enzyme, thereby leading to the activation of PKG causes activation of K+ channels, KATP, KV, KIR and especially BKCa types. This mechanism of action may be contributing to hypotension and bradycardia observed in non-anesthetized rats.