Exercise Training Rescues Impaired HO-mediated Vasodilation in Porcine Collateral-dependent Coronary Arterioles Through Enhanced K Channel Activation

We previously reported that exercise training drives enhanced agonist-stimulated hydrogen peroxide (HO) levels and restores endothelium-dependent dilation via an increased reliance on HO in arterioles isolated from ischemic porcine hearts. In this study, we tested the hypothesis that exercise training would correct impaired HO-mediated dilation in coronary arterioles isolated from ischemic myocardium through increases in protein kinase G (PKG) and protein kinase A (PKA) activation and subsequent colocalization with sarcolemmal K channels. Female adult Yucatan miniature swine were surgically instrumented with an ameroid constrictor around the proximal left circumflex coronary artery, gradually inducing a collateral-dependent vascular bed. Arterioles (∼125 µm) supplied by the left anterior descending artery served as nonoccluded control vessels. Pigs were separated into exercise (treadmill; 5 days/wk for 14 wk) and sedentary groups. Collateral-dependent arterioles isolated from sedentary pigs were significantly less sensitive to HO-induced dilation compared with nonoccluded arterioles, whereas exercise training reversed the impaired sensitivity. Large conductance calcium-activated potassium (BK) channels and 4AP-sensitive voltage-gated (K) channels contributed significantly to dilation in nonoccluded and collateral-dependent arterioles of exercise-trained but not sedentary pigs. Exercise training significantly increased HO-stimulated colocalization of BK channels and PKA, but not PKG, in smooth muscle cells of collateral-dependent arterioles compared with other treatment groups. Taken together, our studies suggest that with exercise training, nonoccluded and collateral-dependent coronary arterioles better use HO as a vasodilator through increased coupling with BK and 4AP-sensitive K channels; changes that are mediated in part by enhanced colocalization of PKA with BK channels. The current study reveals that coronary arterioles distal to stenosis display attenuated dilation responses to HO that are restored with endurance exercise training. Enhanced HO dilation after exercise is dependent on K and BK channels and at least in part on in colocalization of BK channel and PKA and independent of PKA dimerization. These findings expand our earlier studies which demonstrated that exercise training drives beneficial adaptive responses of reactive oxygen species in the microvasculature of the ischemic heart.