Slowly inactivating component of sodium current in ventricular myocytes isdecreased by diabetes and partially inhibited by known Na+-H+ exchange blockers

Recent evidence has suggested a major role for a slowly inactivating compon ent of Na+ current (I-NaL) as a contributor to ischemic Na+ loading. The pu rposes of this study were to investigate veratrine and lysophosphatidylchol ine (LPC)-induced I-NaL in single ventricular myocytes of normal and diabet ic rats and Co analyse the effects on this current of three pharmacological agents, known as Na+/H+ exchange inhibitors, whose selectivity has been qu estioned in several studies, A decrease in Na+/H+ exchange activity has bee n previously shown to be associated with diabetes, and this has been found to confer some protection to the diabetic heart after an episode of ischemi a/reperfusion. Recordings were made using the whole-cell patch-clamp techni que. I-NaL was stimulated either by veratrine (100 mg/ml) or by LPC (10 mu mol/l) applied extracellularly. Veratrine as well as LPC-induced I-NaL was found to be significantly decreased in ventricular myocytes isolated from d iabetic rat hearts. Veratrine- and LPC-induced I-NaL in ventricular myocyte s of normal rats was significantly (in the range 10(-7) to 10(-4) mol/l) in hibited by the Na+/H+ exchange blockers HOE 694, EIPA and HOE 642. HOE 694 was the most potent inhibitor, followed by the amiloride derivative EIPA an d HOE 642. The sensitivity of veratrine-induced I-NaL to inhibition by HOE 694 and EIPA was markedly reduced in diabetic ventricular myocytes, with no observed inhibition by HOE 642. These data may have important implications as to the protection that may be afforded against ischemic and reperfusion injury, especially during ischemia and when ischemia occurs in a diabetic situation. (C) 2000 Academic Press.