Cloricromene Reduces Infarct Size and Alters Postischaemic Blood Flow Defects in Dog Myocardium

Abstract

1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia-reperfusion. 2. Dogs were instrumented to measure blood pressure, left anterior descending (LAD) coronary flow (flow probe) and regional myocardial blood flow (coloured microspheres). Two groups were studied: (i) CLO (n = 8) received an infusion of cloricromene (15 micrograms/kg per min); and (ii) VEH (n = 8) received saline. Infusions began at the onset of ischaemia (60 min) and continued through reperfusion (180 min). 3. Haemodynamic responses were not different between groups. Cloricromene reduced the area of necrosis expressed as a percentage of the area at risk from 35 +/- 3% in the VEH group to 23 +/- 4% in the CLO group (P < 0.05). Regional myocardial blood flow in the ischaemic region was different between groups; VEH dogs showed an early reperfusion hyperaemia followed by a progressive reduction in flow, while CLO dogs exhibited a gradual increase in reflow in the absence of an early hyperaemic response (P < 0.05). Left anterior descending flow was enhanced during the reperfusion period in the CLO group compared with VEH (P < 0.05). Cloricromene reduced polymorphonuclear neutrophil (PMN) infiltration (myeloperuxidase activity) in all myocardial regions when compared with VEH (non-ischaemic zone, 0.34 +/- 0.54 vs 0.05 +/- 0.01 IU/100 mg; ischaemic zone, 2.03 +/- 0.80 vs 0.24 +/- 0.08 IU/100 mg; and necrotic zone, 0.56 +/- 0.04 vs 3.59 +/- 1.09 IU/100 mg for VEH vs CLO groups, respectively; P < 0.01). In a separate in vitro preparation, cloricromene reduced adherence of platelet-activating factor (PAF)-stimulated PMN to canine coronary endothelium. Stimulation of PMN by 100 nmol/L PAF resulted in adherence of 176 +/- 36 compared with 48 +/- 12 cells/mm2 in PAF-stimulated PMN treated with 100 mumol cloricromene (P < 0.001). 4. These data indicate that cloricromene reduces myocardial infarct size in a canine model of ischaemia-reperfusion injury. Postischaemic blood flow patterns are significantly different in cloricromene-treated dogs. Cloricromene-mediated reductions in infarct size, neutrophil accumulation and adherence may play a role in this effect.

A protective effect of the synthetic coumarine derivative Cloricromene against DNB-colitis in the rat

“…In platelets and neutrophils it reduces arachidonic acid release from membrane phospholipids by interfering with phopholipase A2 activation resulting in an inhibition of platelet-activating-factor synthesis (Ribaldi et al, 1996). Cloricromene reduces neutrophil accumulation and adherence in experimental models of myocardial infarction (Groban et al, 1998) exhibiting an anti-ischaemic effect beyond its anti-platelet activity (Lidbury et al, 1993) and protects rats against endotoxin shock by reducing TNF-a synthesis (Squadrito et al, 1992).…”

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).…”

“…Since cloricromene influences TNF-a production, the drug has been recently evaluated on an animal model of inflammatory bowel disease (Fries et al, 2004), where TNF-a has a key role; the drug significantly reduced the tissue concentrations of TNF-a and myeloperoxidase activity, whereas no effect was seen on blood coagulation parameters (Fries et al, 2004). In addition, cloricromene is able to influence the release of endothelin-1 in patients with peripheral atherosclerotic arteriopathies (Saitta et al, 1996) and it possesses a notable inhibitory effect on polymorphonuclear neutrophil function (Groban et al, 1998;Zatta and Bevilacqua, 1999). In our experience, cloricromene is able to regenerate rabbit aortic endothelium after cryoinduced vascular damage, as demonstrated by morphological features at scanning electron microscopy (Aliev et al, 1999).…”

“…Cloricromene is a semi-synthetic coumarin derivative (ethyl({8-chloro-3-[2-(diethylamino) ethyl]-4-methyl-2-oxo-2H-1-benzopyran-7-yl}oxy) acetate) used as an antiplatelet drug with vasodilating and endothelium-protective activity (Squadrito et al, 1991;Hoult and Paya, 1996). The drug has been found to decrease myocardial infarct size after ischemic reperfusion injury (Squadrito et al, 1993;Zvara et al, 1997;Groban et al, 1998;Corsini et al, 2001) by inhibiting tumor necrosis factor-alpha (TNF-a) and plateletactivating factor. Cloricromene has been also found to protect rats from lipopolysaccharide-induced endotoxemia by blocking nuclear factor-nB activation, leading to inhibition of NO and TNF-a overproduction (Ianaro et al, 2004), reversing the lipopolysaccharide-induced vascular hyporeactivity.…”