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Clentiazem given at reperfusion improves subendocardial reflow and reduces myocardial infarct size in the dog
G Rousseau1, P Provost, D Tran
1Laboratory of Experimental Pathology, Montreal Heart Institute, University of Montreal, Quebec, Canada.
Insights
Clentiazem, a calcium channel blocker, significantly reduced heart attack size in dogs by nearly 50%. It also decreased neutrophil accumulation and improved blood flow in reperfused heart tissue.
Area of Science:
- Cardiology
- Pharmacology
- Ischemic Heart Disease
Background:
- Calcium antagonists are known to offer cardioprotection post-ischemia.
- The interaction between neutrophils and myocardial blood flow is crucial in reperfusion injury.
Purpose of the Study:
- To investigate the cardioprotective effects of clentiazem, a novel calcium channel blocker.
- To examine the role of clentiazem in modulating neutrophil activity and regional myocardial blood flow during reperfusion.
Main Methods:
- Anesthetized dogs underwent 90-minute coronary artery occlusion followed by 6-hour reperfusion.
- Clentiazem was administered before reperfusion, with controls receiving saline.
- Infarct size, regional myocardial blood flow, and neutrophil accumulation were quantified.
Main Results:
- Clentiazem reduced infarct size by approximately 50% compared to controls.
- Regional myocardial blood flow decline during reperfusion was attenuated in clentiazem-treated dogs, particularly in the subendocardium.
- Neutrophil accumulation in the infarct area was reduced by 50% in the clentiazem group.
Conclusions:
- Clentiazem demonstrates significant post-ischemic cardioprotection by reducing infarct size.
- The cardioprotective mechanism involves interference with neutrophil accumulation and the development of subendocardial no-reflow.
- Clentiazem holds promise for managing myocardial reperfusion injury.
Abstract:
The postischemic cardioprotection by calcium antagonists and the interplay between neutrophils and regional myocardial blood flow were investigated further, using clentiazem, a new potent calcium channel blocker derived from diltiazem. A 90-min occlusion of the interventricular coronary artery was followed by 6 hr of reperfusion in anesthetized dogs. One group was given clentiazem: 100 micrograms/kg at 5 min before reperfusion followed by a perfusion of 1 microgram/kg/min until sacrifice; controls received saline. Infarct size (% of area at risk) estimated with triphenyltetrazolium staining and by histology was reduced by nearly 50% (P < .05) in treated (16.6 +/- 3.0%), as compared to control (31.6 +/- 6.3%) dogs. Regional and collateral myocardial flows estimated with radioactive microspheres were similar between groups before and during occlusion. However, after an initial recovery to preocclusion values at 30-min reperfusion in both groups, flow declined to 50% normal (P < .05) in control animals after 3 and 6 hr in midwall and subendocardium, but the change was remarkably attenuated (P < .05) in subendocardium of clentiazem-treated dogs. Also, neutrophil accumulation at the epicardial side of the infarct, at the edge of salvaged myocardium, and estimated by tissue myeloperoxidase measurement, was reduced by 50% in treated dogs (clentiazem: 17.2 +/- 2.8; controls: 32.3 +/- 2.7 x 10(6) neutrophils/g). We conclude that administration of clentiazem at reperfusion reduces infarct size by interfering with both neutrophil accumulation and development of subendocardial no reflow in reperfused myocardium.