| Abstract: |
TRPV4 was first identified as a channel activated by hypotonicity, but, TRPV4 is also sensitive to a wide variety of physical and chemical stimuli. TRPV4 is widely expressed in blood vessels, ranging from the aorta, over large and small arteries, up to capillaries.The aim of the study is to demonstrate the in vivo effects of TRPV4 activation on HR and arterial blood pressure, and the in vitro effects of TRPV4 activation on isolated rat aortic strips and the possible role of NO and SKCa in the mechanism of action .Material and Methods: The present study was carried out on a total number of 88 healthy, adult, male albino rats. In vivo studies: The rats (n = 56) were divided into two main groups: Group I: It was subdivided into four equal subgroups to study the hemodynamic effects before and after I.V. administration of different doses (0.1, 0.5, 1, and 2 µg/kg body weight) of the TRPV4 agonist; GSK1016790A. Group II: It was subdivided into three equal subgroups to study the hemodynamic effects of GSK1016790A (1 µg/kg body weight) in presence of either the TRPV4 blocker (RuR), nitric oxide synthase inhibitor (L-NAME) or SKCa blocker (Apamin). In vitro isolated aortic strips studies: The rats (n = 32) were divided into two main groups: Group A: To study the effects of different doses (10-10, 10-9, 10-8, 10-7 and 10-6 M) of the TRPV4 agonist; GSK1016790A on PE -induced contraction in isolated aortic strips. Group B: To study the effects of the submaximal dose of GSK1016790A (10-8 M) on PE-induced contraction in isolated rat aortic strips in presence of either the TRPV4 blocker (RuR), nitric oxide synthase inhibitor (L-NAME) or SKCa blocker (Apamin).Results: I.V. injection of TRPV4 agonist, GSK1016790A in anesthetized male albino rats caused a significant dose- dependent reduction in MAP and insignificant change in HR followed by cardiovascular collapse at the highest dose. The reduction in MAP induced by GSK1016790A was nearly abolished in presence of RuR, moderately attenuated in presence of L-NAME and slightly attenuated in presence of Apamin. The in vitro results showed that GSK1016790A induced a significant dose-dependant reduction in amplitude of PE-induced contraction of isolated rat aortic strips. The relaxation induced by GSK1016790A was markedly attenuated in presence of RuR, moderately attenuated in presence of L-NAME and slightly attenuated in presence of Apamin.Conclusion: Activation of the TRPV4 by GSK1016790A induced a dose-dependent hypotensive effect associated with a concentration-dependant vasorelaxant effect in isolated rat aortic strips. Evidence suggests that the circulatory collapse produced by the lethal dose of GSK1016790A was the result of profound disruption of the endothelial permeability barrier in the lung revealed by histopathological examination. The TRPV4 effects were mediated to great extent by NO, partially by SKca, and still other mechanisms may be involved.
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