Pretreatment with Pinacidil Promotes Arrhythmias in an Isolated Tissue Model of Cardiac Ischemia and Reperfusion

Abstract

It is not clear whether activation of ATP-sensitive potassium channels (K ATP ) with pinacidil in advance of ischemia and reperfusion promotes or suppresses arrhythmias. This study determines the effects of pinacidil pretreatment on arrhythmias and the changes in cellular electrophysiological parameters in segments of guinea pig right ventricular free walls exposed to simulated ischemia and reperfusion. Microelectrode recordings were made from endo-and epicardium during endocardial pacing. Preparations were superfused with Tyrode's solution and then exposed for 5 min to either 100 M pinacidil or its solvent. After a 5-min washout, preparations were exposed to 15 min of ischemic conditions (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, and glucose-free) followed by reperfusion with Tyrode's solution. Pinacidil pretreatment increased ischemia-induced abbreviation of endo-and epicardial action potential durations and effective refractory periods. Pinacidil had no effect on endocardial conduction times but greatly prolonged transmural conduction during ischemia and early reperfusion, and it increased the incidence of transmural conduction block. Pinacidil pretreatment caused a significant increase in the incidence of arrhythmias in ischemia and reperfusion. Reperfusion arrhythmias in control preparations had electrophysiological characteristics of activity initiated by afterpotentials; however, arrhythmias with these characteristics were absent in pinacidil-pretreated preparations, and all reperfusion arrhythmias exhibited characteristics of reentry. The increased incidence of re-entrant arrhythmias is likely explained by pinacidil-induced reduction in effective refractory periods in combination with prolonged transmural conduction times. Thus, pinacidil pretreatment enhanced the effects of ischemia and reperfusion on action potential duration, effective refractory period, and transmural conduction, and it promoted re-entrant arrhythmias.

Consequences of cardiac myocyte-specific ablation of KATPchannels in transgenic mice expressing dominant negative Kir6 subunits

“…Furthermore, the progressive shortening of the effective refractory period characteristic of atrial fibrillation has been argued to be due to activation of the K ATP channels during rapid atrial rates (39). Conversely, K ATP channel opening by pinacidil or cromakalim has been described to be associated with a reduction in effective refractory periods in experimental models (4,35). Taken together, the lengthened effective refractory period and possible dispersion of refractoriness caused by the absence of K ATP channel may be responsible for an increased susceptibility to arrhythmias.…”

Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: A potential anti-arrhythmic agent

“…In addition, increased oxidation directly activates SarcKATP (sarcolemmal-ATPdependent potassium) channels (Tokube et al, 1996(Tokube et al, , 1998 and changes the inactivation kinetics of L-type calcium channels (Belevych et al, 2009). SarcKATP channels opening reduces the action potential duration and effective refractory period (Aidonidis et al, 2009;Ferrier & Howlett, 2005) which in turn increases the incidence of cardiac arrhythmia (Billman, 2008;Billman et al, 2004). There is credible evidence that during reperfusion, production of oxygen free radicals increase in ischemic tissue (Bolli et al, 1989;Manning et al, 1988) and the use of ROS (reactive oxygen species) scavengers is associated with successful decrease in the reperfusion-induced arrhythmias (Cho et al, 2007;Hicks et al, 2007;Konya et al, 1992).…”

Temporal differences in the influence of ischemic factors and deformation on the metabolism of engineered skeletal muscle

“…1B), which was continuously flushed with a 95% N 2 and 5% CO2 gas mixture over the 5-day period. Evaporation was prevented by overlaying the medium with mineral oil (Sigma, Zwijndrecht, The Netherlands), which was previously shown not to hinder oxygen diffusion (13). This layer of oil was also placed on medium of the normoxic (20% oxygen) samples that were kept in the incubator.…”

“…However, hypoxia cannot be considered to be the only adverse environmental event occurring during ischemia. In addition, other factors, such as acidosis, hyperkalemia, hypercapnia, lactate build-up, and glucose depletion will take place in ischemic tissues (13,22). Apart from these phenomena, calcium overload and accumulation of free radicals play important roles in damage development in ischemic skeletal muscle (15).…”