INFLUENCE OF LONG-CHAIN ACYLCARNITINES ON VOLTAGE-DEPENDENT CALCIUM CURRENT IN ADULT VENTRICULAR MYOCYTES

Long-chain acylcarnitines (LCAC) increase 3.5-fold within 2 min in ischemic myocardium in vivo, and previous studies have suggested, through indirect evidence, that LCAC can stimulate the voltage-dependent L-type Ca2+ current [I(Ca(L))] in both cardiac and smooth muscle cells. In the present study, whole cell voltage-clamp procedures were performed in isolated adult guinea pig ventricular myocytes to assess the direct effect of LCAC on I(Ca(L)). The intracellular solution contained (in mM) 80 CsCl, 40 K-aspartic acid, and 5 ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). Maximal current density of I(Ca(L)) at 0 mV was 10.1 +/- 0.5 pA/pF (n = 22) at extracellular Ca2+ concentration ([Ca2+]o) = 2.7 mM. LCAC induced a concentration (1-25-mu-M, n = 23)- and time-dependent, reversible decrease in I(Ca(L)). When delivered extracellularly for 10 min, LCAC (5-mu-M) inhibited the maximal current of I(Ca(L)) by 48.1 +/- 1.3% (n = 9, P < 0.01) and shifted the half-maximal voltage of steady-state activation and inactivation from -13.1 +/- 0.5 to -6.8 +/- 0.4 mV (n = 4; P < 0.05) and from -21.8 +/- 0.2 to -16.5 +/- 0.6 mV (n = 4; P < 0.01), respectively. Intracellular delivery of LCAC (5-mu-M) also suppressed I(Ca(L)) to a similar degree (47.5 +/- 1.5%, n = 4; P < 0.05). Despite the marked decrease in I(Ca(L)), LCAC (greater-than-or-equal-to 5-mu-M) induced both early and delayed afterdepolarizations resulting in triggered activity (n = 9) when the concentration of EGTA in the intracellular solution was <0.2 mM in the absence of Cs+. Thus LCAC suppresses rather than stimulates the I(Ca(L)) but also induces afterdepolarizations and triggered activity, which likely contribute to its arrhythmogenic effects during ischemia.