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

Zenab Attari, Jayesh Mudgal, Pawan G. Nayak, Nandakumar Krishnadas, Revathi Rajappan, N. Gopalan Kutty

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)441-450
Number of pages10
JournalLetters in Drug Design and Discovery
Volume13
Issue number5
DOIs
Publication statusPublished - 01-06-2016

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Phenylephrine
Muscarinic Receptors
Thoracic Aorta
Vasodilator Agents
Vasodilation
Oxadiazoles
Endothelium
Norepinephrine
Muscarinic M2 Receptors
Calcium
Muscarinic Antagonists
Methylene Blue
NG-Nitroarginine Methyl Ester
Verapamil
Vasoconstriction
Atropine
Nitric Oxide Synthase
Nitric Oxide
Cardiovascular Diseases
Pathology

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

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title = "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",
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.",
author = "Zenab Attari and Jayesh Mudgal and Nayak, {Pawan G.} and Nandakumar Krishnadas and Revathi Rajappan and {Gopalan Kutty}, N.",
year = "2016",
month = "6",
day = "1",
doi = "10.2174/1570180812666150907203634",
language = "English",
volume = "13",
pages = "441--450",
journal = "Letters in Drug Design and Discovery",
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TY - JOUR

T1 - 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

AU - Attari, Zenab

AU - Mudgal, Jayesh

AU - Nayak, Pawan G.

AU - Krishnadas, Nandakumar

AU - Rajappan, Revathi

AU - Gopalan Kutty, N.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

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