PT  - JOURNAL ARTICLE
AU  - S. L. Yong
AU  - R. Xu
AU  - J. G. McLarnon
AU  - A. B. Zolotoy
AU  - G. N. Beatch
AU  - M. J. A. Walker
TI  - RSD1000: A Novel Antiarrhythmic Agent with Increased Potency under Acidic and High-Potassium Conditions
DP  - 1999 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 236--244
VI  - 289
IP  - 1
4099  - http://jpet.aspetjournals.org/content/289/1/236.short
4100  - http://jpet.aspetjournals.org/content/289/1/236.full
SO  - J Pharmacol Exp Ther1999 Apr 01; 289
AB  - This study reports the use of a novel agent, RSD1000 [(±)-trans-[2-(4-morpholinyl)cyclohexyl]naphthalene-1-acetate mono hydrochloride], to test the hypothesis that a drug with pKa close to the pH found in ischemic tissue may have selective antiarrhythmic actions against ischemia-induced arrhythmias. The antiarrhythmic ED50 for RSD1000 against ischemic arrhythmias was 2.5 ± 0.1 μmol/kg/min in rats. This value was significantly lower than doses that suppressed electrically induced arrhythmias. In isolated rat hearts, RSD1000 was approximately 40 times more potent in producing ECG changes (i.e., P–R and QRS prolongation) in acid (pHo = 6.4) and high [K+]o (10.8 mM) buffer than in normal buffer (pHo = 7.4; [K+]o = 3.4 mM). In patch-clamped, whole-cell rat cardiac myocytes, inhibition of sodium (INa) currents by RSD1000 was pH- and use-dependent. The IC50 for INa blockade was lower (P < .05) in acid (0.8 ± 0.1 μM) than in pH 7.3 (2.9 ± 0.3 μM), respectively, whereas the IC50 for blockade of transient outward potassium current (ITO) at pH = 6.4 and 7.3 was 3.3 ± 0.4 and 2.8 ± 0.1 μM, respectively. Mixed ion channel block in ischemic myocardium with minimal effects on normal cardiac tissue, as governed by the low pKa of RSD1000, may account for its antiarrhythmic activity against ischemia-induced arrhythmias. The American Society for Pharmacology and Experimental Therapeutics