We identified two strains of mice in which the 3–5th generation pulmonary artery smooth muscles cells (PASMCs) possess different outward current responses to hypoxia: hypoxia decreases the outward current in PASMC in CF1 mice and does not change the outward currents in CAF1 mice. During normoxia, outward currents were significantly larger in the CF1 compared to the CAF1 mice at a voltage step of +60mV (33.9±23.1pA/pF vs. 17.9±17.5pA/pF; p<0.05). Analysis of tail currents showed that the reversal potential did not differ between the strains (−63.98±10.18mV vs. −67.30±14.39mV; p>0.05); therefore the outward current can be attributed to K+ leaving the cell - not Cl− entering the cell. PASMCs were exposed to normoxia (N), 3% hypoxia (H), H + 10mM 4-aminopyridine (HAP), and HAP + 20nM charybdotoxin (HAPCTX) while the changes in K+ currents were measured. At a holding potential of +60mV, CF1 current (I/Imax) was N: 1.00±.0.48; H: 0.83±0.31; HAP: 0.40±0.18; HAPCTX: 0.34±0.16 (p<0.05 for all values compared to N). In the CAF1 mice the values were N: 1.00±.0.79; H: 1.13±0.84; HAP: 0.43±0.33; HAPCTX: 0.41±0.42 (p<0.05 for HAP and HAPCTX compared to N). Total outward current (pA/pF) was different (p< 0.05) between the two strains at a voltage step to +60mV during N (87.92±42.00 vs. 42.68±33.90) and during H (72.83±29.91 vs. 48.38±35.87), but not during HAP or HAPCTX. The hypoxia plus drug data indicate that the differences between strains cannot be attributed to hypoxia-sensitive Kv channels, but may be related to strain differences in calcium-activated K+ channels. Support from Albert J. Ryan Foundation