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 °C), aprikalim (10 μM), or glibenclamide (1 μM) alone, or with one of the following combinations: cold cardioplegia + aprikalim, cold cardioplegia + glibenclamide, or cold cardioplegia + both aprikalim and glibenclamide. A 10 μM infusion of aprikalim significantly increased coronary flow (33 to 63 mL/min, +90%) without negative chronotropic or inotropic effects. Aprikalim also completely reversed the coronary vasoconstrictive and cardiodepressant effects of glibenclamide, the ATP-sensitive K+ channel blocker, an indication of aprikalim's interaction on both coronary and myocardial K+ channels. Pretreatment with aprikalim significantly improved post-ischemic left ventricular function, compared with ischemia alone (93 ± 8 vs. 78 ± 6 mmHg (1 mmHg = 133.3 Pa) for ischemia alone, at 30 min of recovery), while at reperfusion, hyperemic coronary flow values were similar. Experiments carried out in the presence of glibenclamide suggested that the cardioprotective effects of aprikalim were related to activation of myocardial K+ channels rather than change in coronary perfusion. Cold cardioplegia alone significantly improved post-ischemic left ventricular recovery (99 ± 6 mmHg or 89% of pre-ischemic value at 30 min of reperfusion) despite the absence of hyperemic coronary flow. Aprikalim further improved, for the entire duration of reperfusion, the cardioprotection afforded by cold cardioplegia (post-ischemic systolic left ventricular pressure values were similar to pre-ischemic values). The latter additional improvement was blunted by glibenclamide, independently of coronary flow changes. These results indicated that the K+ channel activator aprikalim affords significant cardioprotection either alone or in the presence of cold cardioplegia; these beneficial properties appear to be independent of its coronary vasodilator effects. We thus conclude that aprikalim might be a significant addition to standard cardioprotection in cardiac surgery.Key words: aprikalim, glibenclamide, potassium channels, cardioprotection, coronary flow.