RESUMO
This study describes the synthetic route and molecular computational docking of LQFM 021, as well as examines its biological effects and toxicity. The docking studies revealed strong interaction of LQFM 021 to phosphodiesterase-3 (PDE-3). In isolated arteries, the presence of endothelium potentiates the relaxation for LQFM 021 and the inhibition cyclic nucleotides reduced the relaxation. Pre-contraction with KCl (45 mM), the treatment with tetraethylammonium (TEA) (5 mM) and inhibition of reticular Ca(2+)-ATPase showed an inhibitory effect on relaxation. Moreover, the compound reduced the contraction evoked by the Ca(2+) influx. Acute toxicity tests revealed that the compound was practically nontoxic. In conclusion, this study showed that a new synthetic derivative of pyrazole is a possible PDE-3 inhibitor and has vasorelaxant activity and low toxicity.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Inibidores Enzimáticos/farmacologia , Nucleotídeos Cíclicos/antagonistas & inibidores , Pirazóis/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Tetrazóis/farmacologia , Células 3T3 , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Nucleotídeos Cíclicos/metabolismo , Pirazóis/síntese química , Pirazóis/química , Ratos , Ratos Wistar , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/químicaRESUMO
This study's aim was to determine the effect of hydroalcoholic extract of M. cauliflora (HEMC) on vascular tension and blood pressure in rats. In our in vitro studies using precontracted isolated aortas from rats, HEMC and acetylcholine (positive control) induced relaxation only in vessels with endothelium. Pretreatment with L-NAME (NO synthase inhibitor) or ODQ (soluble guanylyl cyclase (sGC) inhibitor) abolished the HEMC-induced relaxation. The treatment with MDL-12,330A (adenylyl cyclase (AC) inhibitor) or diclofenac (COX inhibitor) reduced HEMC-induced vasorelaxation. The blockade of muscarinic and ß-adrenergic receptors (by atropine and propranolol, resp.) did not promote changes in HEMC-induced vasorelaxation. In our in vivo studies, catheters were inserted into the right femoral vein and artery of anesthetized rats for HEMC infusion and the measurement of blood pressure, heart rate, and aortic blood flow. The intravenous infusion of HEMC produced hypotension and increased aortic blood flow with no changes in heart rate. These findings showed that HEMC induces endothelium-dependent vascular relaxation and hypotension with no alteration in heart rate. The NO/sGC/cGMP pathway seems to be the main cellular route involved in the vascular responsiveness.
RESUMO
Grapes and its derivatives (wines and juices) are rich in polyphenols that have high antioxidant and vasodilator capacity. These biological activities may vary in the juices marketed and produced in different regions of Brazil. Objectives: To determine the antioxidant and vasorelaxant effects of grape juice samples produced in different regions of Brazil. Methods: The content of phenolic compounds and antioxidant capacity were evaluated by the methods of Folin-Ciocalteau, DPPH, ABTS and a new electroanalytical approach (differential pulse voltammetry - DPV). Vasodilator effects were analyzed in isolated aorta from rats in an organ bath. Results: The samples from RJ and SP presented respectively the higher and lower phenolic content and also antioxidant capacity by the methods used (ABTS and DPPH). The results of the electrochemical index corroborate to the other tests, with the best results to RJ (21.69 ± 3.15 µA/V) and worse to the SP sample (11.30 ± 0.52 µA/V). In the vascular reactivity studies, the relaxation induced by each sample presented more distinct differences, following the order: RJ (87.9 ± 4.8%) > RS1 (71.6 ± 8.6%) > GO (56.2 ± 7.2%) > SP (39.9 ± 7.8%) > PR (39.4 ± 9.5%) > RS2 (19.5 ± 6.2%). Inhibition of endothelial NO practically abolished (p < 0.001) the relaxation for all samples, except one. Conclusion: The phenolic content and antioxidant capacity vary greatly among samples. The results obtained for the order of antioxidant activity were: RJ > RS1 > GO > RS2 > PR > SP. The juices were able to induce vascular relaxation at quite varied levels, and the RJ sample the most effective. The L-NAME practically blocked all samples except one (RS2)