We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (+/-)isoprenaline (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA2 of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats, ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125+/-15 bpm, n=6, P<0.001) by a mechanism apparently unrelated to blockade of beta1- or beta2-adrenoceptors. Cumulative incremental doses of (+/-)isoprenaline (0.63 ng/kg to 0.16 mg/kg i.v.) administered to pithed rats induced concomitant depressor and chronotropic responses. Animals received either vehicle (saline 0.9% i.v., n=12), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/kg i.v., n=6 or 7 per dose), (+/-)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.

BACKGROUND AND PURPOSEMyocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (INap) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on INap and in integrative models of INap-induced arrhythmias. EXPERIMENTAL APPROACHSodium current was investigated using patch clamp technique on wild-type and DKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia-and aconitine-induced arrhythmias in the rat. KEY RESULTSWe demonstrated that F 15845 is a potent blocker of INap acting from the extracellular side of the channel. Blockade of INap was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the INap activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where INap is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias. CONCLUSIONS AND IMPLICATIONSF 15845, a novel anti-anginal drug targeting INap, demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias Abbreviations AP, action potential; APD50, APD90, action potential duration at 50% and 90% repolarization; DAD, delayed afterdepolarization; EAD, early afterdepolarization; INap, persistent sodium current.

Hearts from CFR exhibited markedly improved recovery upon reperfusion compared to age-matched controls, strongly suggesting increased myocardial resistance to ischaemic injury.

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