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

Abstract

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 micromol/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 microM) than in pH 7.3 (2.9 +/- 0.3 microM), 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 microM, 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.

• Authors: S L Yong, R Xu, J G McLarnon, A B Zolotoy, G N Beatch, M J Walker
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 289 Issue 1 Pg. 236-44 (Apr 1999) ISSN: 0022-3565 [Print] United States
• PMID: 10087010 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Buffers
• Calcium Channels
• Morpholines
• Potassium Channel Blockers
• RSD 1000
• Sodium Channel Blockers
• Potassium

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arrhythmias, Cardiac (drug therapy, etiology, physiopathology)
• Buffers
• Calcium Channels (drug effects)
• Dose-Response Relationship, Drug
• Electric Stimulation
• Electrophysiology
• Heart Ventricles (drug effects, pathology)
• Hemodynamics (drug effects)
• Hydrogen-Ion Concentration
• In Vitro Techniques
• Male
• Morpholines (pharmacology)
• Myocardial Ischemia (complications, physiopathology)
• Patch-Clamp Techniques
• Potassium (metabolism)
• Potassium Channel Blockers
• Rats
• Rats, Sprague-Dawley
• Sodium Channel Blockers