We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na⁺ channel enhancer LY368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats per minute for 3-4 weeks. LY368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY368052 in heart failure was not altered by either ganglionic or -adrenergic receptor blockade. LY368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure, but not in normal dogs. The negative chronotropic effect of LY368052 was eliminated by ganglion blockade, but not -blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY368052. Thus, the sodium channel enhancer LY368052 maintains its -receptor independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.