Differential effects of OPC-18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea-pig isolated ischaemic heart.
1. The effects of OPC-18790, a novel positive inotropic agent, on cardiac function and myocardial energy metabolism in the guinea-pig isolated heart with ischaemia were studied by 31P-magnetic resonance spectroscopy (MRS) and compared with those of amrinone and dobutamine. 2. Cardiac ischaemia was induced by intracoronary infusion of 15 microns microspheres to reduce coronary perfusion flow (CPF) by 50%. Microsphere embolisation caused a 40% decrease in left ventricular systolic pressure (LVSP), cardiac contractility measured by peak of ventricular pressure development (LVdP/dt) and slightly reduced heart rate. There was also a decrease in ATP and creatine phosphate (PCr) by 20%, an increase in inorganic phosphate (Pi) by 25% and an acidic shift of intracellular pH in the ischaemic heart. 3. In the ischaemic heart, OPC-18790, amrinone and dobutamine were applied at concentrations which increased LVdP/dt by about 60%. These compounds increased LVP by 15% to 30% and increased CPF by about 10%. Amrinone and dobutamine but not OPC-18790 increased heart rate. When these drugs produced the haemodynamic changes described above, amrinone and dobutamine reduced ATP and PCr, increased Pi and produced further intracellular acidosis, whereas, OPC-18790 did not change these parameters. 4. Cardiac pacing at 285 beats min-1 produced decreases in LVP, LVdP/dt and CPF by about 30%, 20%, 5%, respectively and an increase in Pi, decreases in PCr and ATP, and intracellular acidosis. 5. These results suggest that degradation of high energy phosphate compounds closely relates to increase in heart rate in the ischaemic heart. Positive inotropic agents without chronotropic action seem to be beneficial in support of the ischaemic heart.
Itoh
S
S
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Japan.
Mori
T
T
Tominaga
M
M
Ishikawa
M
M
Koga
K
K
Yabuuchi
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000676:Amrinone / Q000494:pharmacology*; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004280:Dobutamine / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010725:Phosphocreatine / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D015363:Quinolones; D010725:Phosphocreatine; C077543:toborinone; D004280:Dobutamine; D000255:Adenosine Triphosphate; D000676:Amrinone