Pinacidil's Effects on Defibrillation Outcomes: Role of Increased Potassium Conductance Via the KATP Channel

Abstract

Background: It has been shown that the inhibition of potassium ion conductance decreases defibrillation threshold. We postulated that if potassium conductance is a primary mechanism affecting defibrillation threshold values, then increasing potassium ion conductance will increase defibrillation values. The primary objective of this study was to determine if the ATP-dependent potassium (KATP) channel opener pinacidil would increase defibrillation threshold values. The second objective was to prove that the observed changes were due to potassium conductance by using the KATP inhibitor, glyburide, to reverse the electrophysio logic actions of pinacidil. The third objective was to determine if the electrophysiology actions of pinacidil correlate with changes in defibrillation threshold value. Methods and Results: Domestic farm swine (n = 14) were anesthetized and intubated. Subsequently, they were instrumented with monophasic action potential catheters and epi cardial defibrillation patches. Defibrillation threshold values, action potential duration, effective refractory period, and ventricular fibrillation cycle length were determined at base line and during treatment phase 1 and treatment phase 2. Pigs were randomized into 2 groups: group 1 (n = 6) received D5W in treatment phase one followed by D5W in treatment phase 2 and group 2 (n = 8) received pinacidil in treatment phase one followed by the addi tion of glyburide in treatment phase two. DFTED50 did not change at baseline, treatment phase one or treatment phase two for group 1 (10.5 ± 2, 11.1 ± 1.7, 10.5 ± 1.0 J) or for group 2 (10.1 ± 2.2, 11.4 ± 4.2, 11.4 ± 3.0 J). Electrophysiologic parameters (QRS, effec tive refractory period, action potential duration 90, and ventricular fibrillation cycle length) were not significantly changed from baseline in group 1. In contrast, effective refractory period, action potential duration90, and ventricular fibrillation cycle length significantly decreased at all recorded sites after the administration of pinacidil in group 2 (range of 7-13%, 6-9%, and 12-17%, respectively). However, pinacidil did not change the basal level of dispersion in effective refractory period, action potential duration, and ventricular fibrillation cycle length during paced rhythm or ventricular fibrillation. Glyburide reversed pinacidil's electrophysiologic actions. Conclusions: Pinacidil does not alter defibrillation threshold, but it reduces effective refractory period, action potential duration, and ventricular fibrillation cycle length and does not increase electrical heterogeneity. Therefore, changes in potassium channel conductance as well as short ening repolarization are unlikely primary mechanisms for elevating defibrillation threshold.