Role of potassium channels and nitric oxide in the relaxant effects elicited by beta-adrenoceptor agonists on hypoxic vasoconstriction in the isolated perfused lung of the rat

1 The aims of this study were to compare, in the rat isolated perfused lung preparation, the antagonist effects of a nonselective P-adrenoceptor agoni st (isoprenaline), a selective beta(2)-adrenoceptor agonist (salbutamol) an d a selective beta(3)-adrenoceptor agonist (SR 59104A) on the hypoxic pulmo nary pressure response, and to investigate the role of KC channels, endothe lium derived relaxing factor and prostaglandins in these effects. KC channe ls were inhibited by glibenclamide, charybdotoxin or apamin, NO synthase an d cyclo-oxygenase were inhibited by N-G-nitro-L-arginine methyl ester (L-NA ME) and indomethacin, respectively. 2 Hypoxic ventilation produced a significant increase in perfusion pressure (+ 65%, P < 0.001) and L-NAME significantly increased this response furthe r (+ 123%, P < 0.01). After apamin, L-NAME, indomethacin, post-hypoxic basa l pressure did not return to baseline values (P < 0.001). 3 Glibenclamide partially inhibited the relaxant effects of isoprenaline (P < 0.05) and salbutamol (P < 0.001) but not that of SR 59104A. In contrast, charybdotoxin and apamin partially inhibited the relaxant effects of SR 59 104A (P = 0.053 and < 0.01, respectively) but did not modify the effects of isoprenaline and salbutamol. L-NAME partially inhibited the dilator respon se of salbutamol (P < 0.01) and SR 59104A (P < 0.05) but not that of isopre naline. 4 We conclude that (a) EDRF exerts a significant inhibition of the hypoxic pulmonary response, (b) SKca channel activation, EDRF and prostaglandins co ntribute to the reversal of the hypoxic pressure response, (c) the vasodila tion induced by isoprenaline is mediated in part by activation of K-ATP cha nnels, that of salbutamol by activation of K-ATP channels and EDRF. In cont rast, SR 59104A partly operates through BKca SKca channels and EDRF activat ion, differing in this from the pi and Pz-adrenoceptor agonists.