Vol. 289, Issue 1, 236-244, April 1999

RSD1000: A Novel Antiarrhythmic Agent with Increased Potency under Acidic and High-Potassium Conditions

S. L. Yong, R. Xu, J. G. McLarnon, A. B. Zolotoy, G. N. Beatch¹ and M. J. A. Walker

Department of Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada

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 pK_a 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 (pH_o = 6.4) and high [K⁺]_o (10.8 mM) buffer than in normal buffer (pH_o = 7.4; [K⁺]_o = 3.4 mM). In patch-clamped, whole-cell rat cardiac myocytes, inhibition of sodium (I_Na) currents by RSD1000 was pH- and use-dependent. The IC₅₀ for I_Na 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 (I_TO) 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 pK_a of RSD1000, may account for its antiarrhythmic activity against ischemia-induced arrhythmias.