CaM Kinase II and Ca2+ sensitization mediate enhanced KCl constriction in collateral‐dependent coronary arteries of both sedentary and exercise‐trained pigs

Abstract

The purpose of this study was to determine mechanisms underlying enhanced KCl‐mediated constriction in collateral‐dependent coronary arteries of sedentary (SED) and exercise‐trained (ET) pigs subjected to chronic occlusion. Ameroid constrictors were surgically placed around the left circumflex artery of female Yucatan miniature swine. Eight weeks post‐operatively, pigs were randomized into SED (pen‐confined) or ET (treadmill run; 5 days/week; 14 weeks) groups. Arteries (150–300μm luminal diameter) were isolated from the collateral‐dependent and control (nonoccluded) myocardial regions. Contractile tension and simultaneous measures of tension and intracellular free Ca2+ levels ([Ca2+]i; fura‐2) were measured in response to increasing concentrations of KCl. Chronic occlusion enhanced contractile responses to KCl and increased tension at comparable levels of [Ca2+]i in collateral‐dependent compared to control arteries of both SED and ET pigs. Inhibition of CaMKII (1μM), but not of Rho‐kinase (Y27632; 10μM or hydroxyfasudil; 30μM) or PKC (calphostin C; 1μM), abolished the enhanced contractile responses to KCl. Taken together, these data reveal that chronic coronary occlusion leads to enhanced contractile responses to KCl in collateral‐dependent coronary arteries likely via an increase in CaMKII‐mediated Ca2+ sensitization that is not corrected with ET.