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Am J Physiol Heart Circ Physiol (May 27, 2005). doi:10.1152/ajpheart.01250.2004
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Submitted on December 14, 2004
Accepted on May 25, 2005

Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca2+ homeostasis

Richard Balasubramaniam1*, Sangeeta Chawla2, Andrew A Grace3, and Christopher L.-H Huang4

1 Department of Physiology, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
2 Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
3 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
4 Department of Physiology, University of Cambridge, Cambridge, United Kingdom

* To whom correspondence should be addressed. E-mail: rnb25{at}cam.ac.uk.

Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular (SR) Ca2+ into the cytosol due to increased open probabilities in cardiac ryanodine receptor (RyR2)-Ca2+ release channels. Caffeine similarly increases such open probabilities and so we explored its arrhythmogenic effects in intact murine hearts. A clinically established programmed electrical stimulation (PES) protocol adapted for studies of isolated intact mouse hearts demonstrated that caffeine (1 mM) increased the frequency of ventricular tachycardia from 0 to 100%, yet left electrogram duration and latency unchanged during PES thereby excluding slowed conduction as a cause of arrhythmogenesis. Fluorescence measurements of intracellular [Ca2+] in isolated mouse ventricular cells then investigated parallel changes in Ca2+ homeostasis associated with these arrhythmias. Both 1 mM caffeine and 30 µM FK506 reduced electrically evoked cytosolic Ca2+ transients yet increased the frequency of spontaneous Ca2+ release events. Diltiazem (1 µM) but not nifedipine (1 µM) pre-treatment suppressed these increases in frequency. Identical concentrations of diltiazem but not of nifedipine correspondingly suppressed the arrhythmogenic effects of caffeine in whole hearts. These findings thus directly implicate spontaneous Ca2+ waves in triggered arrhythmogenesis in intact hearts.




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