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J Pharmacol Exp Ther. 2002 Nov;303(2):673-80.

Combined inotropic and bradycardic effects of a sodium channel enhancer in conscious dogs with heart failure: a mechanism for improved myocardial efficiency compared with dobutamine.

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  • 1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. SHEN_WEIQUN@Lilly.com

Abstract

We compared the cardiac inotropic, chronotropic, and myocardial O(2) consumption (MVO(2)) responses to the sodium (Na(+)) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenyl-methyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the beta-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10-100 microg/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt(max) (55 +/- 7%), and fractional shortening (62 +/- 9%), accompanied by increases in cardiac stroke work (111 +/- 18%) and minute work (34 +/- 10%) and decreases in heart rate (33 +/- 4%). Dobutamine (2-15 microg/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 +/- 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 microg/kg/min) increased MVO(2) by 23 +/- 7% (P < 0.05), whereas LY341311 (100 microg/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO(2) was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O(2) utilization in the failing heart while providing inotropic support comparable to a beta-receptor-mediated agonist.

PMID:
12388650
[PubMed - indexed for MEDLINE]
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