Nifedipine and diltiazem suppress ventricular arrhythmogenesis and calcium release in mouse hearts.
Ventricular arrhythmogenesis leading to sudden cardiac death remains responsible for significant mortality in conditions such as cardiac failure and the long-QT syndrome (LQTS). Arrhythmias may be accentuated by beta-adrenergic stimulation and, accordingly, the present study explored the possible effects of beta-adrenergic stimulation and L-type Ca(2+) channel blockade on ventricular arrhythmogenesis and Ca(2+) handling using the mouse heart as an experimental system. Studies in whole, Langendorff-perfused hearts using programmed electrical stimulation protocols adapted from clinical practice demonstrated sustained ventricular tachycardia following addition of 0.1 microM isoprenaline (n=15), whilst no arrhythmias were observed in the absence of the drug (n=15). Arrhythmias were suppressed by nifedipine or diltiazem pre-treatment (both 1 microM) (n=8 and 4 respectively) and were also induced by elevating external [Ca(2+)] (n=3). At the cellular level, 0.1 microM isoprenaline significantly increased normalized fluorescence (F/F(0)) in field-stimulated fluo-3-loaded mouse ventricular myocytes imaged using confocal microscopy, reflecting increases in sarcoplasmic reticulum Ca(2+) release (n=8). Elevated external [Ca(2+)] also increased F/F(0) (n=4) whilst 0.1 microM nifedipine or 0.1 microM diltiazem significantly decreased F/F(0) (n=13 and 6 respectively). Pre-treatment with 0.1 microM nifedipine or 0.1 microM diltiazem suppressed the increases in F/F(0) induced by 0.1 microM isoprenaline alone (n=14 and 6 respectively). The findings thus paralleled suppression of isoprenaline-induced arrhythmias seen with nifedipine or diltiazem at the whole-heart level. Taken together, the findings may have implications for the use of L-type Ca(2+) channel blockade in conditions associated with beta-adrenergically driven ventricular arrhythmias such as cardiac failure and LQTS.
Balasubramaniam
Richard
R
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, United Kingdom. rnb25@cam.ac.uk
Chawla
Sangeeta
S
Mackenzie
Lauren
L
Schwiening
Christof J
CJ
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000318:Adrenergic beta-Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology*; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol; D051379:Mice; D008815:Mice, Inbred Strains; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D004110:Diltiazem; D009543:Nifedipine; D007545:Isoproterenol; D002118:Calcium