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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/H1508    most recent 00337.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Shen, W. Articles by Steinberg, M. I. Search for Related Content PubMed PubMed Citation Articles by Shen, W. Articles by Steinberg, M. I.

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

Submitted 12 April 2004 ; accepted in final form 18 November 2004

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na⁺ channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 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/min for 3–4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or -adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not -adrenergic 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 LY-368052. Thus the Na⁺ channel enhancer LY-368052 maintains its -receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.

bradycardia; cardiac inotropic response