Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis.
This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI(2)) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.
Hong
Ting-Ting
TT
Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0632, USA.
Huang
Jinbao
J
Barrett
Terrance D
TD
Lucchesi
Benedict R
BR
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology; D002339:Carotid Arteries / Q000601:surgery; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D011464:Epoprostenol / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D008026:Ligation; D008070:Lipopolysaccharides; D009288:Naproxen / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D001572:Benzofurans; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D011422:Propionates; D011720:Pyrazoles; C515593:RO3244794; D044006:Receptors, Epoprostenol; C115461:SC 560; D013449:Sulfonamides; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D009288:Naproxen; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000109:Acetylcholine; C012655:nimesulide