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

Abstract

1 The aims of this study were to compare, in the rat isolated perfused lung preparation, the antagonist eects of a nonselective b-adrenoceptor agonist (isoprenaline), a selective b 2 -adrenoceptor agonist (salbutamol) and a selective b 3 -adrenoceptor agonist (SR 59104A) on the hypoxic pulmonary pressure response, and to investigate the role of K + channels, endothelium derived relaxing factor and prostaglandins in these eects. K + channels were inhibited by glibenclamide, charybdotoxin or apamin, NO synthase and cyclo-oxygenase were inhibited by N G -nitro-L-arginine methyl ester (L-NAME) and indomethacin, respectively. 2 Hypoxic ventilation produced a signi®cant increase in perfusion pressure (+65%, P50.001) and L-NAME signi®cantly increased this response further (+123%, P50.01). After apamin, L-NAME, indomethacin, post-hypoxic basal pressure did not return to baseline values (P50.001).3 Glibenclamide partially inhibited the relaxant eects of isoprenaline (P50.05) and salbutamol (P50.001) but not that of SR 59104A. In contrast, charybdotoxin and apamin partially inhibited the relaxant eects of SR 59104A (P=0.053 and 50.01, respectively) but did not modify the eects of isoprenaline and salbutamol. L-NAME partially inhibited the dilator response of salbutamol (P50.01) and SR 59104A (P50.05) but not that of isoprenaline. 4 We conclude that (a) EDRF exerts a signi®cant inhibition of the hypoxic pulmonary response, (b) SK Ca channel activation, EDRF and prostaglandins contribute to the reversal of the hypoxic pressure response, (c) the vasodilation induced by isoprenaline is mediated in part by activation of K ATP channels, that of salbutamol by activation of K ATP channels and EDRF. In contrast, SR 59104A partly operates through BK Ca , SK Ca channels and EDRF activation, diering in this from the b 1 and b 2 -adrenoceptor agonists.

Role of NO in the systemic hemodynamic response to β2-adrenoceptor stimulation

“…Blockade of NO synthesis decreased vasodilation [8]. Other authors [7][8][9] reported that blockade of NO synthesis had no effect on the degree of β 2 -adrenergic vasodilation.…”

“…Little is known about the NO-dependent endothelial mechanism of systemic vasodilation. The role of NO in the vascular response to β 2 -adrenoceptor stimulation was studied only on isolated vessels [6][7][8][9][10][11][12].…”

Endogenous Nitric Oxide Attenuates Β‐adrenoceptor‐mediated Relaxation in Rat Aorta

“…Indeed, the effect of various potassium channel blockers on isoprenalinemediated relaxation in rat aorta suggests that BK Ca channels, 11,42 K Ca channels, 42 ATP-sensitive potassium channels 44,45 and voltagesensitive potassium channels 46 may be involved in mediating the b-adrenoceptor relaxant response. Thus, in the present study, the non-selective potassium channel blocker TEA, which has some selectivity for BK Ca channels, 47 was used to examine the involvement of potassium channels in isoprenaline-mediated relaxation.…”

Transient relaxation of rat mesenteric microvessels by ceramides

“…In the present study, the broad‐spectrum K + channel inhibitors BaCl 2 and tetraethylammonium did not have major effects on vasodilation by sodium nitroprusside, isoprenaline or C2‐ceramide. Although the K ATP channel blocker glibenclamide has been reported to partially inhibit isoprenaline‐induced vasodilation in the hypoxic pulmonary circulation (Dumas et al ., 1999), it did not affect vasodilation by isoprenaline in the present study and also had little if any effect on vasodilation by sodium nitroprusside or C2‐ceramide. Apamine is an inhibitor of SK Ca small conductance K + channels and has been shown to inhibit e.g.…”

“…Apamine is an inhibitor of SK Ca small conductance K + channels and has been shown to inhibit e.g. β 3 ‐adrenoceptor‐mediated vasodilation in a perfused hypoxic lung preparations (Dumas et al ., 1999). However, in the present study apamine did not affect vasodilation by isoprenaline or sodium nitroprusside and surprisingly even enhanced vasodilation by C2‐ceramide.…”