NO synthase inhibition attenuates EDHF-mediated relaxation induced by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery: Role of TxA2

Background: The aim of the present study was to observe the concomitant activation of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways by TRPV4 channel agonist GSK1016790A in the rat pulmonary artery and explore the mechanism by which NO synthase inhibition attenuates EDHF-mediated relaxation in endothelium-intact rat pulmonary artery. Methods: Tension experiments were conducted on the pulmonary artery from male Wistar rats. Results: TRPV4 channel agonist GSK1016790A (GSK) caused concentration-dependent relaxation (E-max 86.9 +/- 4.6%; pD(2) 8.7 +/- 0.24) of the endothelium-intact rat pulmonary artery. Combined presence of apamin and TRAM-34 significantly attenuated the relaxation (E-max 61.1 +/- 6.0%) to GSK. L-NAME (100 mu M) significantly attenuated (8.2 +/- 2.9%) the relaxation response to GSK that was resistant to apamin plus TRAM 34. However, presence of ICI192605 or furegrelate along with L-NAME revealed the GSK-mediated EDHF-response (E-max of 28.5 +/- 5.2%; E-max 24.5 +/- 4.3%) in this vessel, respectively. Further, these two TxA(2) modulators (ICl/furegrelate) alongwith L-NAME had no effect on SNP-induced endothelium-independent relaxation in comparison to L-NAME alone. This EDHF-mediated relaxation was sensitive to inhibition by K+ channel blockers apamin and TRAM-34 or 60 mM K+ depolarizing solution. Further, combined presence of apamin and TRAM-34 in U46619 pre-contracted pulmonary arterial rings significantly reduced the maximal relaxation (Emax 71.6 +/- 6.9%) elicited by GSK, but had no effect on the pD(2) (8.1 +/- 0.03) of the TRPV4 channel agonist in comparison to controls (Emax, 92.4 +/- 4.3% and pD2, 8.3 +/- 0.06). Conclusion: The present study suggests that NO and EDHF are released concomitantly and NO synthase inhibition attenuates GSK-induced EDHF response through thromboxane pathway in the rat pulmonary artery. (C) 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.