Bolus doses (4-128 micromolkg(-1)) and infusions (2-32 micromolkg(-1)min(-1)) of the novel arylpiperazine drug RSD992 produced bradycardia in rats and guinea pigs but had minimal effect on ECG variables. RSD992 (2-32 micromolkg(-1)min(-1)) increased threshold current (I(T)) for induction of extra-systoles and induction of sustained ventricular fibrillation (VF(T)) and also increased the effective refractory period (ERP) and decreased the maximum following frequency (MFF) in rat and guinea pig hearts. RSD992 (32-512 microM) significantly increased PR and QRS intervals in isolated rat hearts subjected to conditions that mimic ischaemia (pH 6.4, K(+) 11mM) but not in isolated hearts under normal perfusion conditions (pH 7.4, K(+) 3mM). RSD992 (0.1-3.0mM) reduced peak sodium current in rat cardiac (rNa(v)1.5) sodium channels more potently than neuronal (rNa(v)1.2a) sodium channels expressed in Xenopus oocytes. The voltage-dependence of sodium channel activation was unaffected whereas inactivation was shifted in a hyperpolarized direction thus suggesting RSD992 may preferentially interact with the inactive state of the sodium channel, a state usually associated with myocardial cell depolarization in ischaemic myocardium. RSD992 (2-24 micromolkg(-1)min(-1)) decreased the incidence of ventricular arrhythmias and mortality in rats subject to coronary artery ligation. RSD992 exhibits frequency- and ischaemia-selective actions on myocardial sodium currents and antiarrhythmic actions in ischaemic rat myocardium.
