Roles of K+ and Cl-Channels in Camp-Induced Pulmonary Vasodilation

Abstract

Increase in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) is a common pathway for many clinically used drugs to cause pulmonary artery (PA) relaxation. Activity of sarcolemmal K+ and Cl--channels is an important determinant of membrane potential (Em), which, in turn, plays a critical role in regulating pulmonary vascular tone. Whether K+ and Cl-channels were involved in cAMP-induced PA relaxation was tested using isolated rat PA rings. Raising extracellular K+ concentration from 20 to 142.7 mM increased the K+-evoked contraction, but significantly decreased the relaxation induced by the adenylate cyclase activator, forskolin (FSK, 2.5 μM), suggesting that FSK-induced PA relaxation depended on transmembrane K+ gradient. Indeed, the FSK-induced relaxation was inhibited by 4-aminopyridine (4-AP, 10 mM), a voltage-gated K+ (KV) channel blacker. Neither the Ca2+-activated K+ channel blacker, charybdotoxin, nor the ATP-sensitive K+ channel blocker, glibenclamide, had this effect. Furthermore, reducing extracellular Cl-concentration from 142. 7 to 50 mM significantly decreased the FSK-induced relaxation in PA rings precontracted with 142. 7 mM K+ (EK ± 0 mV), but negligibly affected the evoked contraction. This indicates that transmembrane Cl-gradient also regulates FSK-induced PA relaxation. Indeed, the Cl-channel blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 10 μM), significantly inhibited the FSK-induced relaxation, in PA rings preconstricted by 142.7 mM K+. In summary, the data suggest that the cAMP-induced PA relaxation is attributable, at least partly, to both activation of the 4-AP-sensitive KV channels and stimulation of the NPPB-sensitive Cl-channels.