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

BackgroundThe 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.MethodsTension experiments were conducted on the pulmonary artery from male Wistar rats.ResultsTRPV4 channel agonist GSK1016790A (GSK) caused concentration-dependent relaxation (Emax 86.9 ± 4.6%; pD2 8.7 ± 0.24) of the endothelium-intact rat pulmonary artery. Combined presence of apamin and TRAM-34 significantly attenuated the relaxation (Emax 61.1 ± 6.0%) to GSK. l-NAME (100 μM) 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 alongwith l-NAME revealed the GSK-mediated EDHF-response (Emax of 28.5 ± 5.2%; Emax 24.5 ± 4.3%) in this vessel, respectively. Further, these two TxA2 modulators (ICI/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 pD2 (8.1 ± 0.03) of the TRPV4 channel agonist in comparison to controls (Emax, 92.4 ± 4.3% and pD2, 8.3 ± 0.06).ConclusionThe 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.