Sex Differences in Hydrogen Peroxide‐Induced K+ Channel Activation in Arterioles of Ischemic Myocardium after Exercise Training

Abstract

The objective of this study was to determine sex differences in potassium (K+) channel contribution to H2O2‐mediated dilation after exercise training in arterioles distal to chronic coronary artery occlusion. We tested the hypothesis that females would have enhanced H2O2‐mediated vasodilation compared to males through enhanced coupling of H2O2 with large‐conductance, calcium‐dependent K+ (BKCa; iberiotoxin 100 nM) channels and 4‐aminopyridine (4‐AP; 1 mM)‐sensitive voltage‐gated K+ (Kv). Adult Yucatan miniature swine were surgically instrumented with an Ameroid constrictor around the proximal left circumflex coronary artery, which gradually induced occlusion and created a collateral‐dependent vascular bed. Arterioles from the left anterior descending artery myocardial region served as nonoccluded control vessels. Pigs of each sex were separated into two groups: one that underwent a progressive exercise training program (treadmill run; 5 days/week for 14 weeks) and another that remained sedentary and was limited to normal pen activity. Collateral‐dependent arterioles from female, sedentary pigs were significantly less sensitive to H2O2‐induced dilation compared with nonoccluded arterioles (EC50: ‐4.55 ± 0.15 vs. ‐4.91 ± 0.15 log M, respectively; P<0.05), whereas exercise training reversed the impaired dilation so that collateral‐dependent and nonoccluded arterioles responded similarly to H2O2 (EC50: ‐4.86 ± 0.16 vs. ‐4.95 ± 0.18 log M, respectively). Conversely, male pigs demonstrated enhanced vasodilation to H2O2 in collateral‐dependent compared with nonoccluded arterioles (‐4.92 ± 0.16 vs. –4.35 ± 0.16 log M, respectively) of sedentary pigs, which persisted after exercise training (‐4.94 ± 0.11 vs. ‐4.50 ± 0.21 log M, respectively). In female sedentary pigs, H2O2‐mediated dilation in nonoccluded or collateral‐dependent arterioles was not altered by inhibitors of BKCa or Kv channels. In contrast, after exercise training, Kv channels contributed significantly to dilation in nonoccluded arterioles and both BKCa and Kv channels played a significant role in dilation of collateral‐dependent arterioles in female pigs. Blockade of BKCa or Kv channels in nonoccluded or collateral‐dependent arterioles from male pigs had no effect on H2O2‐mediated vasodilation, independent of exercise‐training. Taken together, our studies suggest that coronary arterioles in females compensate for impaired H2O2‐mediated vasodilation by modulating BKCa and 4‐AP‐sensitive Kv channels after exercise‐training. Males do not appear to utilize the particular pathway involving H2O2 action on BKCa or 4‐AP‐sensitive Kv channels.