Cold cardioplegia and the K⁺ channel modulator aprikalim (RP 52891): improved cardioprotection in isolated ischemic rabbit hearts

Abstract

Cellular potassium extrusion is now considered a natural protective mechanism following myocardial ischemia, and newly synthetized molecules mimicking cellular extrusion of K+ (potassium channel activators) appear promising for cardioprotection, although the underlying mechanisms for their beneficial effects have not been fully characterized. Indeed, the cardioprotective efficacy of K+ channel activators at low temperature or in the presence of the high K+ content of standard cardioplegic solution has never been addressed. Therefore the cardioprotective interaction of the thioformamide K+ channel activator aprikalim (RP 52891) and high K+ content, cold cardioplegia was studied in isolated ischemic rabbit hearts. Isolated hearts were perfused according to the Langendorff procedure at a constant pressure (85 cmH2O; 1 cmH2O = 98.1 Pa); systolic and diastolic left ventricular pressures, coronary flow, and heart rate were monitored throughout the study. Cardiac temperature was monitored through a thermocouple microprobe positioned in the left ventricular free wall. Global ischemia was carried out by completely shutting off the perfusate flow for 90 min, and reperfusion was monitored for 30 min. Several groups of isolated hearts (n = 6 per group) were treated before ischemia with either cold cardioplegia (St-Thomas' Hospital cardioplegic solution, 4 degrees C), aprikalim (10 microM), or glibenclamide (1 microM) alone, or with one of the following combinations: cold cardioplegia + aprikalim, cold cardioplegia + glibenclamide, or cold cardioplegia + both aprikalim and glibenclamide. A 10 microM infusion of aprikalim significantly increased coronary flow (33 to 63 mL/min, +90%) without negative chronotropic or inotropic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

BMS‐180448, A Glyburide‐Reversible Cardioprotective Agent with Minimal Vasodilator Activity

“…While depolarizing cardioplegic solutions are efficacious, further increases in protection during the bypass procedure would be useful. Previous studies indicated that KAT, openers either have a small additional protective effect when combined with depolarizing cardioplegia or no additional effect (10,26). It was not apparent in these studies if the high potassium-containing cardioplegic solutions effectively abolished the pharmacologic activity of the KATp openers by attenuating the electrochemical gradient, although the study by Pignac et al (26) suggested some efficacy.…”

Genetic Manipulation of Cardiac K + Channel Function in Mice

“…Pharmacological studies suggest a role for I KATP channels, [97][98][99] although the consensus has been that preconditioning results from activation of mitochondrial, 100 not sarcolemmal, I KATP channels. [101][102][103][104] In Langendorff perfused Kir 6.2 Ϫ/Ϫ hearts, however, the protective effect of preconditioning is abolished in spite of the fact that the infarction resulting from ( The application of transgenic and targeted deletion strategies in mouse has led to the identification of the ␣ subunits contributing to the formation of most of the K ϩ channels expressed in cardiac cells (Tables 1 and 2).…”

Prolongation of rat heart allograft survival with K+ATP-dependent channel modulators

“…In this situation, the action potential shortening is accelerated, leading to a decrease in amplitude of intracellular Ca 2+ diffusion and Ca 2+ overload. 3,4 In this study, the K + ATP-dependent channel opener, aprikalim, can significantly prolong cardiac allograft survival compared to the control group. This protective effect may be caused by vasodilation and/or cardiac protection.…”

“…They play a major role in vascular tone, 2 in cardiac depolarization, 3,4 and in insulin secretion. 5 Confirmation that ion channels are implicated in T-lymphocyte activities has been reported and transmembrane movement plays a critical role in lymphocyte activities.…”