Differential effects of small and big Ca2+‐sensitive K+ channel agonists and antagonists during cardiac ischemia and reperfusion injury (648.10)

Abstract

Small and big conductance Ca2+‐sensitive K+ channel (SKCa, BKCa) agonists have been shown to provide preconditioning protection against cardiac ischemia reperfusion (IR) injury. We tested if activation or block of SKCa vs. BKCa channels, initiated before ischemia through initial reperfusion, differently reduce or worsen cardiac global IR injury in isolated rodent hearts, and if these drugs are effective if given IV in vivo before and during regional (LAD) coronary artery occlusion. We found that activating SKCa or BKCa channels by DCEB or NS1619 reduced infarct size (IS) after 35 min of ischemia by 26 and 39% in vivo, and by 56 and 62% in vitro vs. IR alone respectively; BKCa and SKCa blockers paxilline+NS8593, respectively, increased IS by 17% in vivo and by 30% in vitro vs. IR alone. In vitro the two agonists also increased LVP by 90 and 88% and the blockers reduced it by 45% vs. IR alone. Activation of SKCa and BKCa channels improved the respiratory control index (state3/4), increased Ca2+ retention capacity, and restored membrane repolarization in mitochondria isolated after IR. Our results show similar effects of these drugs when given in vivo or in vitro indicating their bioavailability in the heart when given IV. Since each of SKCa ‐ BKCa agonists/antagonists exert effects on isolated cardiac mitochondria, our data also suggest that activation of KCa channels endogenously protects against cardiac injury in part by improving mitochondrial function.Grant Funding Source: R01 HL 089514