title: 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.
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.
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: Bonita D
authors.initials: BD
authors.lastname: Jones
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zhang
authors.forename: Angela K
authors.initials: AK
authors.lastname: Corbly
authors.forename: Mitchell I
authors.initials: MI
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002908:Chronic Disease; D003326:Coronary Circulation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D062687:Sodium Channel Agonists; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D001384:Azetidines; D002316:Cardiotonic Agents; D062687:Sodium Channel Agonists; C071117:BDF 9148; D004280:Dobutamine; D000242:Cyclic AMP