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 (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). 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. © 2016 institute of pharmacology,polish academy of sciences.