ROLES OF K- CHANNELS IN CAMP-INDUCED PULMONARY VASODILATION( AND CL)

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 (E-m), 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 te sted using isolated rat PA rings. Raising extracellular K+ concentrati on from 20 to 142.7 mM increased the K+-evoked contraction, but signif icantly decreased the relaxation induced by the adenylate cyclase acti vator, forskolin (FSK, 2.5 mu M), suggesting that FSK-induced PA relax ation depended on transmembrane K+ gradient. Indeed, the FSK-induced r elaxation was inhibited by 4-aminopyridine (4-AP, 10 mM), a voltage-ga ted K+ (K-V) channel blocker. Neither the Ca2+-activated K+ channel bl ocker, charybdotoxin, nor the ATP-sensitive K+ channel blocker, gliben clamide, had this effect. Furthermore, reducing extracellular Cl- conc entration from 142.7 to 50 mM sinificantly decreased the FSK-induced r elaxation in PA rings precontracted with 142.7 mM K+ (E-K approximate to 0 mV), but negligibly affected the evoked contraction. This indicat es that transmembrane Cl- gradient also regulates FSK-induced PA relax ation. Indeed, the Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino )benzoic acid (NPPB, 10 mu M), 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 K-V channels an d stimulation of the NPPB-sensitive Cl- channels.