Effects of Cloricromene on Ischemia-Reperfusion Myocardial Damage in the Rabbit

Abstract

Cloricromene, a compound with several biological activities which suggest a therapeutic role in thrombosis or ischemic disease, has been studied for its effects on the extension of myocardial damage and the production of oxygen free radicals during periods of ischemia and reperfusion. In twenty rabbits the left anterior descending coronary artery (LAD) was occluded and cloricromene (3.6 µg /kg /min; n = 10) or placebo (n = 10) were continuously infused. After 50 min the artery was reopened and after 20 min of reperfusion a biopsy was obtained from the anterior wall of the heart in the LAD area and from the posterior wall (control myocardium) prior to sacrifice. Both samples were used for chemiluminescence measurement (free-radical production) and ultrastructural studies. In the placebo group all rabbits showed ST-segment changes during ischemia and reperfusion arrhythmias, while in the cloricromene group there were transient ST elevations in 4 animals which reverted at higher infusion rates of the drug. The chemiluminescence values were 18,017 ± 1,956 and 8,583 ± 918 cpm/mg protein (p < 0.001) in the anterior and posterior walls of the left ventricle, respectively, for the placebo group, and 7,767 ± 992 and 8,333 ± 832 cpm/mg protein (NS), respectively, for the cloricromene group. The ratio between the anterior and posterior wall was 2.27 ± 0.37 for the placebo group versus 0.95 ± 0.11 for the cloricromene group (p < 0.001). In ultrastructural studies, the anterior wall in the placebo group showed irreversible myocyte injury and infarction as well as mitochondrial damage. Samples from the cloricromene-treated group showed, in general, preservation of myocyte architecture or minor signs of injury. These results illustrate clearly the protective effect of cloricromene during damage induced by ischemia and reperfusion in the rabbit.

Beneficial Effects of Cloricromene in Ischemic Reperf used Myocardium

“…Increasing the infusion rate of Clo from 0.45 to 0.75 mg/kg reversed 2/4 ventricular fibrillations. The re sults further emphasize previous data ob tained with a model of mild ischemia-reperfusion injury in which the left arterior descend ing coronary artery was occluded [4,5].…”

“…Here, a total of 70 min of ischemia-reperfusion resulted in focal subendocardial necrosis involving the coronary bed at risk. Ultrastructural studies reported in detail previously [4,5] showed that the subendocardial zone is the area most susceptible to an ischeniia-reperfusion insult. As already suggested, triphenyltetrazolium chloride may underestimate the ultimate ex tent of myocardial damage [8] when the time course of coronary occlusion is less than 3 h. Because of this, in the present study, micro scope sections were used for the assessment of myocardial damage.…”

“…Prevention of myocardial damage or pres ervation of cardiac functions during periods of ischemia and reperfusion would be beneficial following acute myocardial infarc tion, early thrombolytic therapy, surgical aor tic-coronary bypass or coronary angioplasty rabbit followed by reperfusion periods of 10 and 20 min, respectively [4,5], However, in this model, the damage induced by ischemiareperfusion is relatively small, since the left anterior descending coronary artery supplies only the proximal zones of the anterior wall of the left ventricle [6],…”

Cloricromene effect on the enzyme activities of the tryptophan–nicotinic acid pathway in diabetic/hyperlipidemic rabbits

“…Several mechanisms of action of the drug have been proposed and mainly focused on cell-to-cell interactions at the endothelial level; the drug blunts polymorphonuclear superoxide gener- ation and influences leukocyte function (Groban et al, 1998;Zatta and Bevilacqua, 1999;Bertocchi et al, 1989). The drug has been studied for its effects on the extension of myocardial damage and the production of oxygen free radicals during periods of ischemia and reperfusion; evidence has been found for a protective effect of cloricromene against myocardial ischemia -reperfusion injury (Zvara et al, 1997;Groban et al, 1998;Corsini et al, 2001;Milei et al, 1992) and for a regenerating property on rabbit aortic endothelium after cryoinduced vascular damage (Aliev et al, 1999). Another interesting field of application emerged from clinical studies suggesting a possible role of cloricromene for the treatment of intermittent claudication, in patients with moderate walking impairment (Gresele et al, 2000).…”