Organic Nitrate Benzoate 4-Nitrooxybutyl Does Not Develop Ex Vivo Tolerance And Induces Vasorelaxation Via NO/Gcs/PKG Pathway And Inhibition Of Ca2+ Influx Through Cav1

Organic Nitrate Benzoate 4-Nitrooxybutyl Does Not Develop Ex Vivo Tolerance And Induces Vasorelaxation Via NO/Gcs/PKG Pathway And Inhibition Of Ca2+ Influx Through Cav1

• Autor
• Patrícia Keytth Lins Rocha
• Co-autores
• Mickael Souza da Luz , Danilo Duarte de Assis Gadelha , Helivaldo Diógenes da Silva Souza , Priscila Santos Vieira de Lima , Petrônio Filgueiras Athayde-Filho , Juliana Franco Almeida , Valdir Andrade Braga
• Resumo

• Nitric oxide (NO) is an important messenger that regulates the vascular tone. A chronic deficiency of NO bioavailability results in an abnormal elevating in vascular resistance, leading to increased blood pressure. Organic nitrates are widely used in hypertensive therapies, but their prolonged use can develop tolerance. In this context, this study aims to evaluate the underlying molecular mechanism of benzoate 4-nitrooxybutyl(BBN)-induced vasodilator effect and to verify the development of tolerance and toxicological risk. For this, male mesenteric arteries rings of Wistar Kyoto rats (200-300g; 14 weeks; CEUA/UFPB-000463) were pretreated for 30min with ODQ (10uM), a soluble guanylyl cyclase (sGC) inhibitor; or TEA (3mM), channel inhibitor for K+; and submitted to a tonic contraction with PE (1µM) to build BBN concentration-response curves (10-12-10-4M) in an organ bath. To verify the participation of Ca2+ channels in BBN vasorelaxant-response, contractions were induced by KCl (60mM) or Bay-K8644 (200nM), a Cav1 channel agonist. In order to verify the occurrence of tolerance, the rings were pre-exposed to BBN (10-4 M) for 30min, washed, and pre-contracted with PE (1µM). Toxicity tests were conducted according to OECD-423. Statistical analyzes were performed using two-way ANOVA with Bonferroni's post-test. It has been demonstrated that BBN acts via NO/GCs/PKG pathway due to the significant reduction of the maximum effect (Emax) in the presence of ODQ vs. in the absence of inhibitor (Emax=67.41±6%vs.111.1±3%;n=10;p<0.05). There was no involvement of K+ channels (Emax=119.59±6%vs.111.1±3%;n=7;p<0.05). Inhibition of Ca2+ influx occurred in the assays with KCl (Emax=124.65±5%vs.111.1±3%;n=8;p<0.05), confirmed in the assays with Bay-K8644 (Emax=124.4±3%vs.111.1±3%;n=5;p<0.05). Tolerance was not developed (Emax=109.45±3%vs.111.1±3%;n=8;p<0.05). BBN did not cause any animal deaths or even show any sign of toxicity. Based on these findings, BBN acts by the classic NO/sGC/PKG pathway with inhibition of Ca2+ influx through Cav1, and in addition, BBN proved to have a promising advantage and to be safe.

• Palavras-chave
• hypertension, nitric oxide, vasodilator
• Modalidade
• Comunicação oral
• Área Temática
• Produtos naturais