Similar oxygen cost of myocardial contractility between DPI 201-106 and epinephrine despite different subcellular mechanisms of action in dog hearts.
The effects of DPI 201-106 (a novel, cyclic AMP-independent positive inotropic agent with Ca(2+)-sensitizing and Na(+)-channel agonistic mechanisms) on myocardial mechanics and energetics were assessed in the excised cross-circulated dog left ventricle. In the first protocol, the relation between left ventricular oxygen consumption (VO2) and systolic pressure-volume area (PVA) was analyzed before and during administration of DPI 201-106. The reciprocal of the slope of the VO2-PVA relation has been shown to reflect the contractile efficiency, and the VO2-intercept consists of the oxygen cost of contractility-dependent excitation-contraction coupling and basal metabolism. DPI 201-106 increased Emax (contractility index) and elevated the VO2-PVA relation in a parallel manner, i.e., the VO2-intercept increased without a change in the slope. In the second protocol, the increase in the VO2-intercept of the VO2-PVA relation for a unit increase in Emax (i.e., oxygen cost of enhanced contractility) was compared between DPI 201-106 and epinephrine in a paired manner in each heart. Epinephrine significantly abbreviated the time to end systole, whereas DPI 201-106 did not, suggesting that the mechanism of inotropic action differed between the two drugs. However, the oxygen cost of enhanced contractility was the same between the two drugs in each heart. Therefore, DPI 201-106 did not alter the contractile efficiency nor spare the oxygen cost of enhanced contractility as compared to epinephrine under the present experimental conditions. This suggests that the Ca(2+)-sensitizing effect of DPI 201-106, if any, is too small to spare the oxygen cost of contractility in the blood-perfused, non-failing dog heart.
Futaki
S
S
Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Osaka, Japan.
Goto
Y
Y
Ohgoshi
Y
Y
Yaku
H
H
Suga
H
H
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002395:Catecholamines / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D002395:Catecholamines; D010879:Piperazines; D015222:Sodium Channels; C046261:DPI 201-106; D011433:Propranolol; D004837:Epinephrine