Alleviation of contractile dysfunction in ischemic hearts by slowly inactivating Na+ current blockers

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes

Pages H511–H520: H. Ichikawa, D. J. Hearse, and W. A. Coetzee. “Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes.” The concentration of R-56865 should be 1 μM and not 1 mM as stated in the paper.

Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes

Pages H511–H520: H. Ichikawa, D. J. Hearse, and W. A. Coetzee. “Effects of R-56865 on transient inward current, Na+-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes.” The concentration of R-56865 should be 1 μM and not 1 mM as stated in the paper.

Effects of R-56865 on transient inward current, Na(+)-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes

Voltage-clamp studies were performed on guinea pig ventricular myocytes to clarify the action of N-(1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl)-N-methyl-2-benzothiazo lamine (R-56865), an inhibitor of cardiac glycoside-induced arrhythmias. Transient inward current ((Iti)) was induced using low-K+/high-Ca2+ Tyrode solution. R-56865 (1 mM) was found to abolish I(ti). R-56865 had no influence on the peak Ca2+ current, steady-state current during the clamp, holding current, or the Ni(2+)-sensitive electrogenic Na(+)-Ca2+ exchange current. Fluorescence transients after repolarization (temporally related to the I(ti)) were abolished by R-56865 without affecting the fluorescence transients during depolarization. In separate experiments, the threshold of Ca2+ release from sarcoplasmic reticulum (SR) by the Ca2+ current was found to be unchanged, whereas Ca2+ transients (presumably triggered by Ca2+ entry through the Na(+)-Ca2+ exchanger) were depressed. Our results suggest that R-56865 inhibits spontaneous Ca2+ release from the SR when it is mediated by Ca2+ entry through the Na(+)-Ca2+ exchanger but that it has no direct effect on the well-known “physiological” Ca(2+)-induced Ca(2+)-release mechanism from SR.