HYPOXIC AND METABOLIC-REGULATION OF VOLTAGE-GATED K-ARTERY SMOOTH-MUSCLE CELLS( CHANNELS IN RAT PULMONARY)

Inhibition of voltage-gated K+ (K-V) channels by 4-aminopyridine (4-AP ) depolarizes pulmonary artery (PA) smooth muscle cells, induces Ca2+- dependent action potentials and increases [Ca2+](i). Neither charybdot oxin, which blocks Ca2+ activated K+ channels, nor glibenclamide, whic h blocks ATP-sensitive K+ channels, has such effects on membrane poten tial (E(m)) and [Ca2+](i). Hypoxia reversibly decreases the 4-AP-sensi tive K-V currents (I-K(V)) in PA myocytes. The resulting membrane depo larization caused by decreased I-K(V) induces Ca2+-dependent action po tentials and thereby raises [Ca2+](i). Thus, K-V channel activity play s a critical role in: (a) regulating E(m) and [Ca2+](i) under physiolo gical conditions; and (b) sensing O-2 alteration and transducing the h ypoxic stimulus to changes of E(m) and [Ca2+](i). The metabolic inhibi tors 2-deoxy-D-glucose (2-DOG; 10 mM) and carbonyl cyanide-p-trifluoro methoxyphenyl-hydrazone (FCCP; 3-5 mu M), the reducing agent reduced g lutathione and inhibitors of cytochrome P-450, all mimic the effects o f hypoxia on I-K(V) and E(m) in PA myocytes. Furthermore, hypoxia and 2-DOG negligibly affect I-K(V) and E(m) in mesenteric artery smooth mu scle cells. These results suggest that hypoxia, perhaps via a localize d reduction of ATP, triggers the block of K-V channels and depolarizes PA myocytes. This blockade may also be mediated by a change in cellul ar redox status, perhaps via a conformational change of a haem- (or me tal-) containing regulatory moiety that is attached to the channel pro tein.