Endothelium Dependent and Independent Mechanisms of Vasorelaxant Activity of Synthesized 2,5-disubstituted-1,3,4-oxadiazole Derivatives in Rat Thoracic Aorta – Ex vivo and Molecular Docking Studies

Attari, Zenab and Mudgal, Jayesh and Nayak, Pawan G and Krishnadas, Nandakumar and Rajappan, Revathi and Kutty, Gopalan N (2016) Endothelium Dependent and Independent Mechanisms of Vasorelaxant Activity of Synthesized 2,5-disubstituted-1,3,4-oxadiazole Derivatives in Rat Thoracic Aorta – Ex vivo and Molecular Docking Studies. Letters in Drug Design & Discovery, 13 (5). pp. 441-450. ISSN 1875-628X

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Abstract

Background: Vasoconstriction is a major pathological feature of cardiovascular diseases involving endothelium dependent and independent mechanisms. Oxadiazole moiety appeared to be effective in various pathologies.Objective: The aim of the study was to synthesize and evaluate the mechanism of vasorelaxation exhibited by synthesized oxadiazole derivatives.Method: The 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized by an efficient and simple method. The derivatives were investigated for their ex-vivo vasorelaxant action on intact/denuded endothelium rat aortic rings precontracted with norepinephrine/ phenylephrine/KCl.Results: The contractions induced in the aortic rings by the addition of cumulative concentrations of norepinephrine,phenylephrine, KCl and calcium were significantly antagonized by a derivative, OXD-Z2. In another experiment, verapamil pretreatment inhibited phenylephrine and Ca2+-induced aortic contractions and OXD-Z2 did not alter verapamilinduced inhibition. This indicated the role of L-type Ca2+-channels in the OXD-Z2-induced vasorelaxation via inhibition of calcium influx. Further, atropine (muscarinic receptor antagonist), L-NAME (NO synthase inhibitor) and methylene blue (non-selective cGMP inhibitor) inhibited OXD-Z2-induced relaxation in other sets of experiments. These results indicate that OXD-Z2 also mediates vasorelaxation through NO release by muscarinic receptor activation. In addition, the molecular docking studies showed that OXD-Z2 interacts with L-type Ca2+-channel, muscarinic (M2) receptor and eNOS.Conclusion: Thus, it is deduced from the above findings that the vasorelaxant activity of OXD-Z2 involves muscarinic receptor-mediated nitric oxide release in addition to direct inhibition of L-type Ca2+-channels.

Item Type: Article
Uncontrolled Keywords: 2,5-disubstituted-1,3,4-oxadiazoles; Aortic rings; Endothelium; Vasorelaxation; Hypertension
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 03 Jun 2016 09:23
Last Modified: 03 Jun 2016 09:23
URI: http://eprints.manipal.edu/id/eprint/146285

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