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Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity
Author(s) -
Lidbury Paul S.,
Cirillo Rocco,
Vane John R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13805.x
Subject(s) - ex vivo , platelet , in vivo , chemistry , ischemia , ibuprofen , coronary occlusion , occlusion , pharmacology , platelet activation , medicine , anesthesia , in vitro , biochemistry , biology , microbiology and biotechnology
1 Cloricromene is a non‐anticoagulant coumarin derivative with anti‐platelet and anti‐leukocyte properties, which has beneficial effects in various models of ischaemia and shock. 2 We have assessed the effects of cloricromene on (a) ex vivo platelet aggregation, and (b) infarct size using a model of myocardial ischaemia in the anaesthetized rabbit. 3 Cloricromene (1–1000 μg kg −1 min −1 for 15 min) induced a dose‐dependent inhibition of ex vivo platelet aggregation, causing only a minimal increase in heart rate and no change in mean arterial blood pressure. The inhibitory activity was considerably stronger when platelet aggregation was induced by collagen than by ADP. 4 Cloricromene inhibited ex vivo platelet aggregation in rabbits pretreated with indomethacin (5 mg kg −1 ) and this inhibition persisted for 30–60 min. 5 The model of myocardial ischaemia involved 1 h occlusion of the first antero‐lateral branch of the left coronary artery followed by 2 h of reperfusion. Infusion of cloricromene (30 or 300 μg kg −1 min −1 ), ibuprofen (80 μg kg −1 min −1 ) or vehicle began 15 min prior to occlusion, and continued throughout the experiment. 6 While area at risk was similar for all groups studied, cloricromene (30 or 300 μg kg −1 min −1 ) or ibuprofen caused a reduction in infarct size, and decreased myeloperoxidase activity in the tissue of the infarcted myocardium. 7 Cloricromene at 300 μg kg −1 min −1 also reduced the occlusion‐induced elevation of the ST‐segment of the rabbit electrocardiogram, and inhibited platelet aggregation ex vivo . Ibuprofen or cloricromene at 30 μg kg −1 min −1 had no effect on either the ST‐elevation or platelet reactivity. 8 Thus, cloricromene exhibits a cardioprotective activity via an inhibition of leukocyte infiltration, in the presence (300 μg kg −1 min −1 ) or absence (30 μg kg −1 min −1 ) of inhibition of platelet activity ex vivo . The anti‐aggregatory activity of cloricromene acts via a mechanism that is either different from, or in addition to, inhibition of cyclo‐oxygenase, and is of long duration.