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Different responses of non-ischemic and post-ischemic myocardium towards Ca2+ sensitization
B Korbmacher1, U Sunderdiek, G Selcan
1Institute of Experimental Surgery, University of Düsseldorf, Düsseldorf, Germany.
Abstract:
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.
Insights
A novel calcium sensitizer, EMD 60 263, improved cardiac function in stunned rabbit hearts. This suggests reduced calcium sensitivity contributes to myocardial stunning and thiadiazinone agents may aid recovery.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Myocardial stunning, a post-ischemic dysfunction, is often linked to impaired cardiac contractility.
- Reduced calcium (Ca2+) sensitivity of myocardial contractile proteins is a potential contributor to this dysfunction.
Purpose of the Study:
- To investigate if decreased Ca2+ sensitivity is a primary cause of stunned myocardium.
- To evaluate the efficacy of a novel Ca2+ sensitizing agent, EMD 60 263, in improving cardiac function post-ischemia.
Main Methods:
- Experiments utilized isolated, blood-perfused rabbit hearts (n=14).
- Hearts underwent a 20-minute no-flow ischemia followed by 30 minutes of reperfusion.
- The thiadiazinone derivative EMD 60 263 was administered at varying doses (3, 10, 30 µM) to both ischemic and non-ischemic hearts.
Main Results:
- Low-dose EMD 60 263 significantly improved ventricular systolic function in post-ischemic hearts.
- Early relaxation and heart rate were also positively affected by low-dose EMD 60 263 in stunned hearts.
- Higher doses showed diminished benefits in non-ischemic hearts and deleterious effects at 30 µM in both groups.
Conclusions:
- The differential response to Ca2+ sensitization suggests reduced Ca2+ sensitivity plays a role in stunned myocardium.
- Thiadiazinone-type Ca2+ sensitizing agents show potential for enhancing contractility in stunned myocardial tissue.