Mechanisms of Ca2+ antagonism in imipramine-induced toxicity of isolated adult rat cardiomyocytes.
Classic explanations of cyclic antidepressant toxicity often focus on Na+ channel blockade; however, cyclic antidepressant toxicity often causes decreased myocardial contractile function. The present experiments first examine inhibition of cytosolic Ca2+ signals by imipramine. Second, the experiments test if alkalinization prevents the inhibition of Ca2+ signals. Cardiomyocytes from adult rat hearts were loaded with fura-2 dye, and intracellular calcium, [Ca2+]i, was quantified using ratio fluorescence techniques. Changes in [Ca2+]I were induced by electrical pacing, depolarization with KCl (84 mM), or treatment with caffeine (10 mM). Imipramine (10-30 microM) inhibited [Ca2+]i transients in electrically paced cardiomyocytes. Imipramine (7.5-30 microM) also inhibited Ca2+ signals in KCl depolarized cells. These inhibitory effects were similar to those observed with nisoldipine (100-2000 nM), a selective L-channel blocker. The rise in [Ca2+]i that was triggered with caffeine (10 mM) was not significantly changed by imipramine (30 microM). Inhibition of KCl-induced Ca2+ signals by imipramine was prevented by alkalinization of the medium (tris(hydroxymethyl)aminomethane, pH 7.6), but not by elevation of extracellular sodium to 170 mM. Alkalinization was effective in the presence of HOE642, a selective Na+/H+ (NHE) subtype 1 inhibitor. These data show that imipramine causes Ca2+ antagonism in heart cells which is independent of sarcoplasmic reticulum Ca2+, and that alkaline treatment prevents this Ca2+ antagonism rather than stimulating an alternate source of Ca2+ via Na+/H+ and subsequent Na+/Ca2+ exchange.
Watts
J A
JA
Department of Emergency Medicine, Carolinas Medical Center, Charlotte, North Carolina 28232, USA.
Yates
K M
KM
Badar
S K
SK
Marcengill
M B
MB
Kline
J A
JA
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000633:toxicity*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007099:Imipramine / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000929:Antidepressive Agents, Tricyclic; D002110:Caffeine; D007099:Imipramine; D011188:Potassium; D002118:Calcium