title: Slowly inactivating component of sodium current in ventricular myocytes is decreased by diabetes and partially inhibited by known Na(+)-H(+)Exchange blockers.
abstract: Recent evidence has suggested a major role for a slowly inactivating component of Na(+)current (I(NaL)) as a contributor to ischemic Na(+)loading. The purposes of this study were to investigate veratrine and lysophosphatidylcholine (LPC)-induced I(NaL)in single ventricular myocytes of normal and diabetic rats and to analyse the effects on this current of three pharmacological agents, known as Na(+)/H(+)exchange inhibitors, whose selectivity has been questioned in several studies. A decrease in Na(+)/H(+)exchange activity has been previously shown to be associated with diabetes, and this has been found to confer some protection to the diabetic heart after an episode of ischemia/reperfusion. Recordings were made using the whole-cell patch-clamp technique. I(NaL)was stimulated either by veratrine (100 mg/ml) or by LPC (10 micromol/l) applied extracellularly. Veratrine as well as LPC-induced I(NaL)was found to be significantly decreased in ventricular myocytes isolated from diabetic rat hearts. Veratrine- and LPC-induced I(NaL)in ventricular myocytes of normal rats was significantly (in the range 10(-7)to 10(-4)mol/l) inhibited 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 and 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.
authors.affiliation: Laboratoire de Physiologie Cellulaire, UFR dOrsay, France.
authors.forename: S
authors.initials: S
authors.lastname: Chattou
authors.forename: A
authors.initials: A
authors.lastname: Coulombe
authors.forename: J
authors.initials: J
authors.lastname: Diacono
authors.forename: B
authors.initials: B
authors.lastname: Le Grand
authors.forename: G
authors.initials: G
authors.lastname: John
authors.forename: D
authors.initials: D
authors.lastname: Feuvray
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013311:Streptozocin; D013450:Sulfones / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014702:Veratrine / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D008244:Lysophosphatidylcholines; D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D013779:Tetrodotoxin; D013311:Streptozocin; D000584:Amiloride; C093373:cariporide; D014702:Veratrine; C039614:ethylisopropylamiloride