Reducing electrical defibrillation thresholds with glibenclamide in an isolated rabbit heart preparation

Glibenclamide has been shown to prevent ischemia-induced shortening of action-potential duration (APD) and to prolong effective refractory period (ERP). Glibenclamide also has been shown to prolong APD under normal conditions. The aim of this study was to test the hypothesis that glibenclamide would prolong APD and ERP in the nonischemic heart by blocking adenosine triphosphate-sensitive K+ (K(ATP)) channels in myocardium, thus reducing defibrillation energy requirements. Hearts from 15 adult male New Zealand White rabbits, weight 3.1 +/- 0.1 kg, were perfused with a Krebs-Henseleit solution containing either no drugs (five hearts) or glibenclamide (10 hearts) at six concentrations ranging from 30 nM to 10 microM. Two 140-mm2 Pt-Ir mesh patch electrodes were sutured onto the ventricles. A 3.5/2.5-ms biphasic pulse (impedance, 95 +/- 16 omega) with randomly selected voltages of 20, 30, 50, 70, 90, or 110, defibrillated the heart after 10 s of fibrillation. The APD, ERP, fibrillation threshold (FT), and defibrillation threshold (DFT) were determined from monophasic action potentials, computer-controlled pacing, 50-Hz sinusoidal pacing, and multiple defibrillation shocks, respectively. Defibrillation thresholds were determined from a total of 180 fibrillation and defibrillation sequences, conducted in each preparation, and the results were fitted to a sigmoid dose-response curve by logistic regression analysis. Five repeated observations of APD, ERP, FT, and DFT showed no change over a 5-h period, whereas for DFT, there was a significant increase between first and next four determinations. With glibenclamide (100 and 300 nM, and 1 and 10 microM), a dose-dependent difference (p < 0.05) compared with controls was observed. There was an increase in APD, ERP, and FT and a decrease in DFT at 50% success (V50). The maximal effect for each parameter occurred at 300 nM. Glibenclamide dose-dependently reduced DFT and increased FT in an isolated nonischemic rabbit heart preparation. A probable mechanism is through APD and ERP prolongation by blocking ATP-sensitive K+ channels, suggesting that these channels may be important in modifying the APD and ERP during electrical defibrillation. This might be of particular interest in reducing electrical-defibrillation thresholds, thereby minimizing heart damage.