Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

Abstract

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis. Am J Physiol Heart Circ Physiol 294: H145-H155, 2008. First published October 5, 2007 doi:10.1152/ajpheart.00646.2007.-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.inflammation; vascular reactivity CONVENTIONAL NONSELECTIVE anti-inflammatory drugs (NSAIDs), such as naproxen, ibuprofen, and aspirin, inhibit both cyclooxygenase (COX)-1 and COX-2. COX-1, the COX isoform expressed constitutively in platelets, mediates the synthesis of thromboxane A 2 (TxA 2 ), a prostaglandin known to activate platelets and cause vasoconstriction. The second isoform of COX, COX-2, with ϳ50% sequence homology to COX-1, is an inducible form of COX during inflammation (30, 46). Despite considerable study, the functionally important COX isoform or isoforms present in the normal vascular endothelium has been uncertain. On the basis of earlier studies that failed to demonstrate ...

Renal and cardiovascular characterization of COX-2 knockdown mice

“…Our results strongly support the hypothesis that COX-2-dependent mechanisms are protective in thrombosis and that a reduction of COX-2 activity may pose a prothrombotic hazard in certain settings. These data are consistent with other findings in a canine model of electrolytic vessel wall injury (16,17).…”

Estrogen Protects the Heart From Ischemia-Reperfusion Injury via COX-2-Derived PGI2

“…The compound nimesulide has been widely studied and has shown COX-2 specificity similar to the commercially available celecoxib. 34 Moreover, in our studies and previous studies in our laboratory, 35 the dose of nimesulide used in the study was able to inhibit LPS-induced maximal PGE 2 synthesis (COX-2) without altering arachadonic acid-induced platelet aggregation (COX-1). We feel confident that the effects observed after nimesulide treatment were due to inhibition of COX-2 and not nonselective inhibition of both cyclooxygenases.…”

Differential involvement of COX1 and COX2 in the vasculopathy associated with the α-galactosidase A-knockout mouse

“…Inhibition of COX2 worsened the existing endothelial dysfunction. This particular observation has clinical relevance, since COX2 inhibitors have been demonstrated to increase the risk of cardiovascular complications (6,25), probably by inhibiting the production of endothelium-derived prostacyclin in vessels such as the coronary arteries (16,18). Inhibition of COX2 could also increase the risk of cardiovascular events by not only affecting endothelium-dependent relaxation, but by also increasing the likelihood of a thrombotic episode (18) such as stroke.…”