RSD1000: A novel antiarrhythmic agent with increased potency under acidic and high-potassium conditions

This study reports the use of a novel agent, RSD1000 [(+/-)-trans-[2-(4-mor pholinyl)cyclohexyl]naphthalene-1-acetate mono hydrochloride], to test the hypothesis that a drug with pK(a) close to the pH found in ischemic tissue may have selective antiarrhythmic actions against ischemia-induced arrhythm ias. The antiarrhythmic ED50 for RSD1000 against Ischemic arrhythmias was 2 .5 +/- 0.1 mu mol/kg/min in rats. This value was significantly lower than d oses that suppressed electrically induced arrhythmias. In isolated rat hear ts, RSD1000 was approximately 40 times more potent in producing ECG changes (i.e., P-R and QRS prolongation) in acid (pH(o) = 6.4) and high [K+](o) (1 0.8 mM) buffer than in normal buffer (pH(o) = 7.4; [K+](o) = 3.4 mM). In pa tch-clamped, whole-cell rat cardiac myocytes, inhibition of sodium (I-Na) c urrents by RSD1000 was pH- and use-dependent. The IC50 for I-Na blockade wa s lower (P < .05) in acid (0.8 +/- 0.1 mu M) than in pH 7.3 (2.9 +/- 0.3 mu M), respectively, whereas the IC50 for blockade of transient outward potas sium current (I-TO) at pH = 6.4 and 7.3 was 3.3 +/- 0.4 and 2.8 +/- 0.1 mu M, respectively. Mixed ion channel block in ischemic myocardium with minima l effects on normal cardiac tissue,as governed by the low pK(a) of RSD1000, may account for its antiarrhythmic activity against ischemia-induced arrhy thmias.