Late sodium current inhibition in human isolated cardiomyocytes by R 56865.
R 56865, a cytoprotective agent, has been shown to prevent myocardial ischemia and reperfusion injury by blockade of the late sodium current (I(Nal)). The effect of R 56865 on I(Nal) in isolated human atrial myocytes was investigated by using the whole-cell patch-clamp technique. I(Nal) recorded at the end of a 350-ms test pulse evoked from -100 to +20 mV was significantly increased by the addition of veratrine (100 microg/ml: quantity of charge corresponding to total I(Nal): 6.1 +/- 1.2 at baseline vs. 86.9 +/- 15; p < 0.001). Tetrodotoxin (TTX; 1 microM) fully prevented veratrine-induced increases in I(Nal). R 56865 (0.1-10 microM, n = 14) significantly and reversibly decreased veratrine-induced I(Nal) (42.01 +/- 8.6%, n = 6; p < 0.001 at 10 microM). Moreover, R 56865 reduced I(Nal) without significantly affecting kinetic parameters of inactivation [tau1 = 1.04 +/- 0.1 ms and tau2 = 119.3 +/- 2.3 ms (baseline) vs. tau1 = 1.57 +/- 0.5 ms and tau2 = 134.4 +/- 14 ms in the presence of 10 microM R 56865; NS]. The data indicate that R 56865 is a potent blocker of the late inducible component of sodium current in human cardiomyocytes.
Le Grand
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B
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases II, Castres, France.
Coulombe
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A
John
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GW
D052160:Benzothiazoles; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D010880:Piperidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013844:Thiazoles; C054551:R 56865