title: Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure.
abstract: 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 beta-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 beta-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 beta-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. shen_weiqun@lilly.com
authors.forename: Weiqun
authors.initials: W
authors.lastname: Shen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gill
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.forename: Bonita D
authors.initials: BD
authors.lastname: Jones
authors.forename: Angela K
authors.initials: AK
authors.lastname: Corbly
authors.forename: Mitchell I
authors.initials: MI
authors.lastname: Steinberg
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure; D001919:Bradycardia / Q000188:drug therapy / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003243:Consciousness; D004285:Dogs; D004562:Electrocardiography; D005730:Ganglionic Blockers / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D000319:Adrenergic beta-Antagonists; D001384:Azetidines; D002316:Cardiotonic Agents; D005730:Ganglionic Blockers; C499717:LY368052; D008333:Mandelic Acids; D011943:Receptors, Adrenergic, beta; D015222:Sodium Channels