Different responses of non-ischemic and post-ischemic myocardium towards Ca2+ sensitization.
We tested whether decreased Ca2+ sensitivity is a major cause for dysfunctional stunned myocardium. The experiments employed a novel Ca2+ sensitizing agent: the thiadiazinone derivative EMD 60 263. Experiments were done on 14 isolated, blood-perfused rabbit hearts. After control, seven hearts were subjected to 20 min no-flow ischemia, and then allowed to recover during 30 min reperfusion. Thereafter, EMD 60 263 was administered (3, 10 and 30 microm). For comparison, the effect of the same doses was investigated in seven non-ischemic hearts. At the low dose, the agent improved ventricular systolic function in the post-ischemic group significantly (LVPmax: 65+/-13 v 91+/-17 mmHg; dP/dtmax: 845+/-235 v 1300+/-350 mmHg/s), and non-significantly in the non-ischemic group (LVPmax: 115+/-35 v 132+/-39 mmHg; dP/dtmax: 1415+/-545 v 1885+/-720 mmHg/s). Early relaxation (dP/dtmin) was slightly improved in both groups (800+/-225 v 1050+/-220 mmHg/s post-ischemic; 1120+/-315 v 1205+/-285 mmHg/s non-ischemic). Heart rate was increased (151+/-35 v 175+/-45 beats/min) in the post-ischemic group and was unaffected in the non-ischemic group. At the higher dose, systolic ventricular function in the post-ischemic group was further improved (LVPmax: 109+/-17 mmHg, dP/dtmax: 1330+/-180 mmHg/s), but tended to decrease in the non-ischemic group (LVPmax: 121+/-40 mmHg, dP/dtmax: 1605+/-680 mmHg/s). This dose decreased heart rate in both groups (133+/-34 and 134+/-23 beats/min). 30 microm EMD 60 263 had deleterious effects in both groups. The different responses towards Ca2+ sensitization suggest that a decrease in Ca2+ sensitivity might play a role in dysfunctional stunned myocardium. Therefore, Ca2+ sensitizing agents of the thiadiazinone type could be useful to recruit a positive inotropic reserve in stunned myocardium.
Korbmacher
B
B
Institute of Experimental Surgery, University of Düsseldorf, Düsseldorf, Germany.
Sunderdiek
U
U
Selcan
G
G
Arnold
G
G
Schipke
J D
JD
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D001919:Bradycardia / Q000139:chemically induced; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000633:toxicity; D004351:Drug Resistance; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D017682:Myocardial Stunning / Q000209:etiology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D013599:Systole / Q000187:drug effects; D013829:Thiadiazines / Q000494:pharmacology* / Q000633:toxicity
D002316:Cardiotonic Agents; D013829:Thiadiazines; C088204:EMD 60263; D002118:Calcium