Chronic hypoxia alters effects of endothelin and angiotensin on K⁺ currents in pulmonary arterial myocytes

We tested the hypothesis that chronic hypoxia alters the regulation of K⁺ channels in intrapulmonary arterial smooth muscle cells (PASMCs). Charybdotoxin-insensitive, 4-aminopyridine-sensitive voltage-gated K⁺ (K(V,CI)) and Ca²⁺activated K⁺ (K(Ca)) currents were measured in freshly isolated PASMCs from rats exposed to 21 or 10% O₂ for 17-21 days. In chronically hypoxic PASMCs, K(V,CI) current was reduced and K(Ca) current was enhanced. 4-Aminopyridine (10 mM) depolarized both normoxic and chronically hypoxic PASMCs, whereas charybdotoxin (100 nM) had no effect in either group. The inhibitory effect of endothelin (ET)-1 (10^-7 M) on K(V,CI) current was significantly reduced in PASMCs from chronically hypoxic rats, whereas inhibition by angiotensin (ANG) II (10^-7 M) was enhanced. Neither ET-1 nor ANG II altered K(Ca) current in normoxic PASMCs; however, both stimulated K(Ca) current at positive potentials in chronically hypoxic PASMCs. These results suggest that although modulation of K(V,CI) and K(Ca) channels by ET- 1 and ANG II is altered by chronic hypoxia, the role of these channels in the regulation of resting membrane potential was not changed.