TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 673 LP - 680 DO - 10.1124/jpet.303.2.673 VL - 303 IS - 2 AU - Weiqun Shen AU - Robert M. Gill AU - Bonita D. Jones AU - Jian-Ping Zhang AU - Angela K. Corbly AU - Mitchell I. Steinberg Y1 - 2002/11/01 UR - http://jpet.aspetjournals.org/content/303/2/673.abstract N2 - 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 β-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/dtmax(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 β-receptor-mediated agonist. The American Society for Pharmacology and Experimental Therapeutics ER -