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The pharmacology and antiarrhythmic actions of RSD 1000

University of British Columbia

In an attempt to develop a pathologically-specific antiarrhythmic agent, a series of arylacetamide derivatives have been synthesized. One of these compounds, RSD 1000 is very efficacious against arrhythmias produced during myocardial ischaemia and possesses limited toxicity. This thesis provides a preliminary pharmacological profile and investigates the possible mechanisms responsible for the antiarrhythmic actions of RSD 1000. The pharmacological profile of RSD 1000 was determined by in vivo and in vitro experiments in rats and mice. Drug effects were monitored using measurements of blood pressure (BP), heart rate (HR) and electrocardiogram (ECG) in pentobarbitone-anaesthetised rats. Additionally, isolated rat hearts were used to investigate the selectivity for "ischaemic" versus normal myocardial tissue. Lethality was tested using both rats and mice. Two models for arrhythmogenesis were used to investigate the antiarrhythmic activity of RSD 1000 in unconscious rats and these were electrically-induced and ischaemia-induced arrhythmias via coronary ligation. RSD 1000 produced a dose-dependent prolongation of P-R, QRS, RSh and Q-T intervals at higher doses. The estimated effective dose for a 25% change (ED25%) from pre-drug for PR, RSh and Q-T were 20, 12, and = 20 umole/kg/min, respectively. The effective dose range of RSD 1000 on electrically-induced arrhythmias was much lower. RSD 1000 increased the threshold currents for induction of ventricular fibrillo-flutter (VFt) (ED25% = 3.0 umoles/kg/min), extrasystoles (iT) (ED25% = 4.5 umoles/kg/min) and effective refractory period (ERP) (ED25% = 4.0 umoles/kg/min) in a dose-related manner. The effect of RSD 1000 on ischaemia-induced arrhythmias was tested between 1.0 and 8.0 umoles/kg/min and an antiarrhythmic ED50% value (or AA50%) of 2.5 umole/kg/min was determined. The highest dose, 8.0 umoles/kg/min, provided the greatest protection, since it reduced the incidence of both ventricular tachyarrhythmias and fibrillations from a control value of 95% to 0%. Unlike many antiarrhythmic agents, complete protection against ischaemia-induced arrhythmias with RSD 1000 was conferred with minimal toxicity on the cardiovascular system. Effects on blood pressure and heart rate were minimal. This finding was substantiated with time-effect data from sham-occlusions by infusing with RSD 1000 at 8.0 umoles/kg/min. RSD 1000 showed selectivity for conditions simulating myocardial ischaemia in isolated rat hearts. RSD 1000 was approximately 64 times more potent in terms of ECG changes (presumed due to channel blockade) in conditions of low pH (6.4) and high [K+] (10mM) than in normal (pH=7.4; [K+]=4mM) buffer conditions. Studies on morbidity and lethality in both rats and mice indicate that RSD 1000 is well tolerated at doses which provided complete antiarrhythmic protection. The LD50 value in rats and mice were 64 and 67 umole/kg, respectively. The same experiments were completed for lidocaine for the purpose of comparing its effects with those of RSD 1000. The results of this study suggest that RSD 1000 is more cardiac selective and produces greater channel blockade in "ischaemia"-simulated conditions than lidocaine. RSD 1000 and its effects on both the sodium and potassium channels suggest that the observed antiarrhythmic effect is the result of a combination of class I and III actions such that the prolongation of the cardiac action potential duration was sufficiently lengthened to provide antiarrhythmic protection while limiting the susceptibility for an arrhythmogenic substrate by the same action. It is possible that this proposed mechanism of antiarrhythmic activity for RSD 1000 acts independently or in combination with the observed cardiac and/or "ischaemia'-selectivity to contribute to the overall antiarrhythmic action. The results from this study suggests that RSD 1000 possesses strong antiarrhythmic properties and may perhaps be a good candidate for the next generation of antiarrhythmic agents.

Thesis/Dissertation

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2009-01-17

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http://hdl.handle.net/2429/3752

Pharmacology and Therapeutics

University of British Columbia

UBCV

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