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Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the electrophysiology of perfused mouse hearts

¹Department of Cell Biology and Physiology and the Department of Medicine, ²Division of Cardiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Submitted 11 March 2004 ; accepted in final form 7 June 2004

Chemical uncouplers diacetyl monoxime (DAM) and cytochalasin D (cyto-D) are used to abolish cardiac contractions in optical studies, yet alter intracellular Ca²⁺ concentration ([Ca²⁺]_i) handling and vulnerability to arrhythmias in a species-dependent manner. The effects of uncouplers were investigated in perfused mouse hearts labeled with rhod-2/AM or 4-[-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) to map [Ca²⁺]_i transients (emission wavelength = 585 ± 20 nm) and action potentials (APs) (emission wavelength > 610 nm; excitation wavelength = 530 ± 20 nm). Confocal images showed that rhod-2 is primarily in the cytosol. DAM (15 mM) and cyto-D (5 µM) increased AP durations (APD₇₅ = 20.0 ± 3 to 46.6 ± 5 ms and 39.9 ± 8 ms, respectively, n = 4) and refractory periods (45.14 ± 12.1 to 82.5 ± 3.5 ms and 78 ± 4.24 ms, respectively). Cyto-D reduced conduction velocity by 20% within 5 min and DAM by 10% gradually in 1 h (n = 5 each). Uncouplers did not alter the direction and gradient of repolarization, which progressed from apex to base in 15 ± 3 ms. Peak systolic [Ca²⁺]_i increased with cyto-D from 743 ± 47 (n = 8) to 944 ± 17 nM (n = 3, P = 0.01) but decreased with DAM to 398 ± 44 nM (n = 3, P < 0.01). Diastolic [Ca²⁺]_i was higher with cyto-D (544 ± 80 nM, n = 3) and lower with DAM (224 ± 31, n = 3) compared with controls (257 ± 30 nM, n = 3). DAM prolonged [Ca²⁺]_i transients at 75% recovery (54.3 ± 5 to 83.6 ± 1.9 ms), whereas cyto-D had no effect (58.6 ± 1.2 ms; n = 3). Burst pacing routinely elicited long-lasting ventricular tachycardia but not fibrillation. Uncouplers flattened the slope of AP restitution kinetic curves and blocked ventricular tachycardia induced by burst pacing.

optical action potentials; action potentials; intracellular calcium; restitution kinetics

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