title: Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart.
abstract: Cardiac contractility may be enhanced via multiple cellular mechanisms resulting in varied effects on cardiac energetics. The mechanisms that account for the varied energetic responses are not well understood. The purpose of this investigation was to compare the effects of the calcium sensitizing agent ORG 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride, a calcium sensitizing agent which increases contractility without increasing calcium transients significantly), dobutamine and high perfusate calcium on contractility and energetics. Langendorff-perfused rat hearts were stimulated with ORG 30029, dobutamine and high perfusate calcium in graduated concentrations while myocardial oxygen consumption (MVO2) and force-time integral were measured. ORG 30029, dobutamine and high perfusate calcium increased contractility in a dose-dependent manner. Despite an increase of 50% in systolic pressure and a 17% increase in force-time integral from control, ORG 30029 had no significant effect on MVO2 at the lower concentrations (n = 6). However, dobutamine (n = 4) and high perfusate calcium (n = 4) caused a 65% increase in systolic pressure and a 17% increase in force-time integral and a 50% and 41% increase in MVO2 respectively (P < 0.05). High energy phosphates (by 31P NMR), and lactate production were unaltered by these agents, suggesting that metabolism was steady state. Basal metabolism tended to increase slightly with dobutamine but not with ORG 30029 or high perfusate calcium. ORG 30029, dobutamine, and high perfusate calcium increase contractility in perfused rat hearts with disparate effects on energetics. These differences may be accounted for, in part, by differences in energy expenditure for calcium handling.
authors.affiliation: Pittsburgh NMR Center for Biomedical Research, Carnegie-Mellon University, PA 15213, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Grandis
authors.forename: G A
authors.initials: GA
authors.lastname: MacGowan
authors.forename: A P
authors.initials: AP
authors.lastname: Koretsky
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000096:biosynthesis; D008274:Magnesium / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009930:Organic Chemicals; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole