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

Author(s): Zenab Attari, Jayesh Mudgal, Pawan G Nayak, Nandakumar Krishnadas, Revathi Rajappan, N. Gopalan Kutty

Journal Name: Letters in Drug Design & Discovery

Volume 13 , Issue 5 , 2016

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Graphical 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.

Keywords: 2, 5-disubstituted-1, 3, 4-oxadiazoles, aortic rings, endothelium, vasorelaxation, hypertension.

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Article Details

Year: 2016
Published on: 14 April, 2016
Page: [441 - 450]
Pages: 10
DOI: 10.2174/1570180812666150907203634
Price: $65

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