Exercise Training-Enhanced, Endothelium-Dependent Dilation Mediated by Altered Regulation of BKCa Channels in Collateral-Dependent Porcine Coronary Arterioles

Microcirculation (Impact Factor: 2.57). 02/2013; 20(2). DOI: 10.1111/micc.12016


Test the hypothesis that exercise training increases the contribution of BKCa channels to endothelium‐mediated dilation in coronary arterioles from collateral‐dependent myocardial regions of chronically occluded pig hearts and may function downstream of H2O2. Methods
An ameroid constrictor was placed around the proximal left circumflex coronary artery to induce gradual occlusion in Yucatan miniature swine. Eight weeks postoperatively, pigs were randomly assigned to sedentary or exercise training (treadmill; 14 week) regimens. ResultsExercise training significantly enhanced bradykinin‐mediated dilation in collateral‐dependent arterioles (~125 μm diameter) compared with sedentary pigs. The BKCa‐channel blocker, iberiotoxin alone or in combination with the H2O2 scavenger, polyethylene glycol catalase, reversed exercise training‐enhanced dilation in collateral‐dependent arterioles. Iberiotoxin‐sensitive whole‐cell K+ currents (i.e., BKCa‐channel currents) were not different between smooth muscle cells of nonoccluded and collateral‐dependent arterioles of sedentary and exercise trained groups. Conclusions
These data provide evidence that BKCa‐channel activity contributes to exercise training‐enhanced endothelium‐dependent dilation in collateral‐dependent coronary arterioles despite no change in smooth muscle BKCa‐channel current. Taken together, our findings suggest that a component of the bradykinin signaling pathway, which stimulates BKCa channels, is enhanced by exercise training in collateral‐dependent arterioles and suggest a potential role for H2O2 as the mediator.

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    ABSTRACT: Exercise training of coronary artery disease patients is of considerable interest since it has been shown to improve vascular function and thereby enhance blood flow into compromised myocardial regions. However, the mechanisms underlying exercise-induced improvements in vascular function have not been fully elucidated. In the current study, we tested the hypothesis that exercise training increases the contribution of multiple mediators to endothelium-dependent relaxation of coronary arteries in the underlying setting of chronic coronary artery occlusion. To induce gradual occlusion, an ameroid constrictor was placed around the proximal left circumflex coronary (LCX) artery in Yucatan miniature swine. Eight weeks postoperatively, pigs were randomly assigned to sedentary or exercise (treadmill; 5 days/week) regimens for 14 weeks. Exercise training significantly enhanced the contribution of nitric oxide, prostanoids, and large-conductance, Ca(2+)-dependent K(+) (BKCa) channels to endothelium-dependent, bradykinin-mediated relaxation in both nonoccluded and collateral-dependent arteries. Combined nitric oxide synthase (NOS), prostanoid, and BKCa channel inhibition ablated the enhanced relaxation associated with exercisetraining. Exercise training significantly increased nitric oxide levels in response to bradykinin in endothelial cells isolated from both nonoccluded and collateral-dependent arteries. Bradykinin treatment significantly increased prostacyclin (PGI2) levels in all artery treatment groups and tended to be further enhanced after NOS inhibition in exercise-trained pigs. No differences were found in whole-cell BKCa channel currents, BKCa channel protein levels, or arterial cyclic nucleotide levels. Although redundant, upregulation of parallel vasodilator pathways appears to contribute to enhanced endothelium-dependent relaxation, potentially providing a more refined control of blood flow after exercise training.
    No preview · Article · Aug 2013 · AJP Heart and Circulatory Physiology
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    ABSTRACT: Myosin phosphatase (MP) is a key target of signaling pathways that regulate smooth muscle tone and blood flow. Alternative splicing of MP targeting subunit (MYPT1) exon 24 (E24) generates isoforms with variable presence of a C-terminal leucine zipper (LZ) required for activation of MP by NO/cGMP. Here we examined the expression of MP and associated genes in a disease model in the coronary circulation. Female Yucatan miniature swine remained sedentary or were exercise-trained beginning eight weeks after placement of an ameroid constrictor around the left circumflex (LCX) artery. Fourteen weeks later epicardial arteries (~ 1 mm) and resistance arterioles (~ 125 μm) were harvested and assayed for gene expression. MYPT1 isoforms were distinct in the epicardial arteries (E24-/LZ +) and resistance arterioles (E24 +/LZ-) and unchanged by exercise training or coronary occlusion. MYPT1, CPI-17 and PDE5 mRNA levels were not different between arteries and arterioles while Kir2.1 and eNOS were 6.6-fold and 3.9-fold higher in the arterioles. There were no significant changes in transcript abundance in epicardial arteries of the collateralized (LCX) vs. non-occluded left anterior descending (LAD) territories, or in exercise-trained vs. sedentary pigs. There was a significant 1.2 fold increase in CPI-17 in collateral-dependent arterioles, independent of exercise, and a significant 1.7 fold increase in PDE5 in arterioles from exercise-trained pigs, independent of occlusion. We conclude that differences in MYPT1 E24 (LZ) isoforms, eNOS, and Kir2.1 distinguish epicardial arteries and resistance coronary arterioles. Up-regulation of coronary arteriolar PDE5 by exercise and CPI-17 by chronic occlusion could contribute to altered vasomotor responses and requires further study.
    No preview · Article · Feb 2014 · Microvascular Research