Abstract
The pentamidine analog PA‐6 was developed as a specific inward rectifier potassium current (IK 1) antagonist, because established inhibitors either lack specificity or have side effects that prohibit their use in vivo. We previously demonstrated that BaCl2, an established IK 1 inhibitor, could prolong action potential duration (APD) and increase cardiac conduction velocity (CV). However, few studies have addressed whether targeted IK 1 inhibition similarly affects ventricular electrophysiology. The aim of this study was to determine the effects of PA‐6 on cardiac repolarization and conduction in Langendorff‐perfused guinea pig hearts. PA‐6 (200 nm) or vehicle was perfused into ex‐vivo guinea pig hearts for 60 min. Hearts were optically mapped with di‐4‐ANEPPS to quantify CV and APD at 90% repolarization (APD 90). Ventricular APD 90 was significantly prolonged in hearts treated with PA‐6 (115 ± 2% of baseline; P < 0.05), but not vehicle (105 ± 2% of baseline). PA‐6 slightly, but significantly, increased transverse CV by 7%. PA‐6 significantly prolonged APD 90 during hypokalemia (2 mmol/L [K+]o), although to a lesser degree than observed at 4.56 mmol/L [K+]o. In contrast, the effect of PA‐6 on CV was more pronounced during hypokalemia, where transverse CV with PA‐6 (24 ± 2 cm/sec) was significantly faster than with vehicle (13 ± 3 cm/sec, P < 0.05). These results show that under normokalemic conditions, PA‐6 significantly prolonged APD 90, whereas its effect on CV was modest. During hypokalemia, PA‐6 prolonged APD 90 to a lesser degree, but profoundly increased CV. Thus, in intact guinea pig hearts, the electrophysiologic effects of the IK 1 inhibitor, PA‐6, are [K+]o‐dependent.
Highlights
The inward rectifier potassium current (IK1) is an important regulator of the cardiac action potential, serving to stabilize the resting membrane potential (Sakmann and Trube 1984; Tourneur 1986), and contributing to late repolarization (Kass et al 1990; Ibarra et al 1991)
To investigate the effects of IK1 inhibition on ventricular repolarization, Langendorff-perfused guinea pig hearts were treated with 200 nmol/L PA-6 for 60 min and APD90 was measured from optical action potentials recorded at 0, 30, and 60 min
The results from PA-6 treated hearts (n = 8) were compared to time (TC, n = 3) and vehicle control hearts (Veh, n = 5) to assess the effects of preparation stability and the vehicle solvent (DMSO + Pluronic) on APD90
Summary
The inward rectifier potassium current (IK1) is an important regulator of the cardiac action potential, serving to stabilize the resting membrane potential (Sakmann and Trube 1984; Tourneur 1986), and contributing to late repolarization (Kass et al 1990; Ibarra et al 1991). Hypokalemia is known to shift the reversal potential for IK1 to a more negative potential and reduce the slope conductance of the inward current (resulting in a decreased peak density of IK1), as well as hyperpolarize the resting membrane potential (Scamps and Carmeliet 1989; Shimoni et al 1992; Hirota et al 2000), which together alters sodium channel availability and cardiac excitability. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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