Vol. 303, Issue 2, 673-680, November 2002

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

Weiqun Shen, Robert M. Gill, Bonita D. Jones, Jian-Ping Zhang, Angela K. Corbly and Mitchell I. Steinberg

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

We compared the cardiac inotropic, chronotropic, and myocardial O₂ consumption (MVO₂) 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 -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 µg/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 µg/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 µg/kg/min) increased MVO₂ by 23 ± 7% (P < 0.05), whereas LY341311 (100 µg/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO₂ 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 O₂ utilization in the failing heart while providing inotropic support comparable to a -receptor-mediated agonist.