REVERSAL OF HYPOTHERMIA-INDUCED ACTION-POTENTIAL LENGTHENING BY THE K-ATP CHANNEL AGONIST BIMAKALIM IN ISOLATED GUINEA-PIG VENTRICULAR MUSCLE

1. ATP-sensitive potassium (K-ATP) channel openers shorten cardiac ven tricular muscle action potential duration (APD), reduce resting and de veloped contractile force, and have been shown to provide cardioprotec tion when given before, during, and after either short-term ischemia o r longterm hypothermia. The authors' aim was to determine the concentr ation-dependent effect of the potent K-ATP channel opener bimakalim on transmembrane action potential changes induced by mild (27 degrees C) and moderate (20 degrees C) hypothermia in isolated guinea pig ventri cular muscle. 2. Conventional microelectrode techniques were used to r ecord action potentials (APs) in single myocytes during normothermia ( 37 degrees C) and hypothermia in the presence and absence of 0.1 to 30 mu mol.l(-1) bimakalim. 3. Hypothermia alone increased APD and depola rized the diastolic membrane potential (DMP): APD(90)=141.7+/-7.0 msec and DMP -86.2+/-1.4 mV (n=6) at 37 degrees C versus 235.7+/-7.8 msec and -75.6+/-1.0 mV at 20 degrees C (n=7). At 37 degrees C, bimakalim ( 0.1-10 mu mol l(-1)) shortened APD in a concentration-dependent fashio n. 4. APD(90) was markedly reduced from 141.7+/-7.0 msec without bimak alim to 9.5+/-2.6 msec with 10 mu mol l(-1) bimakalim (n=6); this effe ct was blocked by glibenclamide. DMP was hyperpolarized by bimakalim. More bimakalim was required to shorten APs during mild and moderate hy pothermia. The 50% effective concentration (EC50) of bimakalim require d to maximally shorten APD(90) was 0.96+/-0.10 mu mol l(-1) at 37 degr ees C; this increased to 3.96+/-0.24 mu mol.l(-) at 27 degrees C, and to 12.34+/-0.72 mu mol.l(-1) at 20 degrees C. Relative to hypothermia- induced depolarization, bimakalim hyperpolarized DMP toward drug-free values obtained at 37 degrees C. 5. These results indicate that hypoth ermia shifts the bimakalim concentration APD(90) response curve to the right such that 13 times more bimakalim is required at 20 degrees C s horten APD by the same amount as at 37 degrees C. Bimakalim also rever ses hypothermia-induced AP lengthening and tends to reverse the hypoth ermia induced decrease in DMP. 6. These findings aid in our understand ing of the cardioprotective effects of K-ATP channel openers during hy pothermia. (C) 1998 Elsevier Science Inc.