Sexually dimorphic mechanisms of HO-mediated dilation in porcine coronary arterioles with ischemia and endurance exercise training.

We determined the impact of sex on HO-mediated dilation in coronary arterioles and the contribution of K channels after exercise training in ischemic heart disease. We hypothesized that arterioles from male and female swine would similarly display impaired HO-induced dilation after chronic occlusion that would be corrected by exercise training. Yucatan miniswine were surgically instrumented with an ameroid constrictor around the proximal left circumflex artery, gradually inducing occlusion and a collateral-dependent myocardium. Arterioles from the left anterior descending artery myocardial region served as nonoccluded controls. Eight weeks postoperatively, swine of each sex were separated into sedentary and exercise-trained (progressive treadmill regimen; 5 days/wk for 14 wk) groups. Collateral-dependent arterioles of sedentary female pigs displayed impaired sensitivity to HO that was reversed with exercise training. In contrast, male pigs exhibited enhanced sensitivity to HO in collateral-dependent versus nonoccluded arterioles in both sedentary and exercise-trained groups. Large-conductance, calcium-dependent K (BKCa) and 4-aminopyridine (AP)-sensitive voltage-gated K (Kv) channels contributed to HO-mediated dilation in nonoccluded and collateral-dependent arterioles of exercise-trained females, but not in arterioles of sedentary female or sedentary or exercise-trained male swine. BKCa channel, protein kinase A (PKA), and protein kinase G (PKG) protein levels were not significantly different between groups, nor were kinase enzymatic activities. Taken together, our studies suggest that in female swine, exercise training stimulates the coupling of HO signaling with BKCa and 4-AP-sensitive Kv channels, compensating for impaired dilation in collateral-dependent arterioles. Interestingly, coronary arterioles from neither sedentary female or male swine, regardless of training status, depended upon BKCa or 4-AP-sensitive Kv channels for HO-mediated dilation. The current studies reveal sexually dimorphic adaptations to HO-mediated dilation, and unique contributions of K channels, in coronary arterioles from swine subjected to chronic ischemia and exercise training; findings important for development of therapeutic strategies. In female swine, chronic ischemia attenuates dilation, which is reversed by exercise training via BKCa and Kv channel stimulation. In male swine, ischemia enhances dilation to HO, which is further augmented by exercise training and independent of BKCa and Kv channels.