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1 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
2 Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: gsalama{at}pitt.edu.
Chemical uncouplers, diacetyl monoxime (DAM) and cytochalasin-D (cyto-D) are used to abolish cardiac contractions in optical studies, yet alter intracellular Ca2+ ([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 di-4- ANEPPS to map [Cai2+]i transients (
em=585 ± 20 nm) and action potentials (APs), (em > 610 nm; ex= 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 and 39.9 ± 8 ms, respectively, n=4) and refractory periods (RPs=45.14±12.1 to 82.5±3.5 and 78±4.24 ms, respectively). Cyto-D reduced conduction velocity by 20% within 5 min and DAM by 10% gradually in 1 hour (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 to controls (257 ± 30 nM, n=3). DAM prolonged [Ca2+]i transients at 75% recovery (54.3± 5 to 83.6±1.9 ms), while cyto-D had no effect (58.6±1.2 ms; n=3). Burst pacing routinely elicited long
lasting ventricular tachycardia VT but not fibrillation. Uncouplers flattened the slope of AP restitution kinetic curves and blocked VT induced by burst pacing.
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