Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on ischemic myocardium

Objective

We explored effects of nonselective cyclooxygenase and selective cyclooxygenase 2 inhibition on collateral development in a model of chronic myocardial ischemia. We hypothesized that cyclooxygenase 2 inhibitors would negatively effect angiogenic and inflammatory pathways.

Methods

Yorkshire swine were made chronically ischemic by placing an ameroid constrictor on the left circumflex coronary artery. Swine were divided into 3 groups and given no drug (control, n = 7), a nonselective cyclooxygenase inhibitor (naproxen 400 mg daily, n = 7), or a selective cyclooxygenase 2 inhibitor (celecoxib 200 mg daily, n = 7). After 7 weeks, coronary angiography was performed. Myocardial function and microvascular reactivity were assessed. Serum and myocardial tissue were analyzed for prostaglandin levels and markers of inflammation and angiogenesis.

Results

The celecoxib group demonstrated significantly increased mean arterial pressure and decreased left ventricular function. Myocardial perfusion in the celecoxib group was similar to control value but less than in the naproxen group. Coronary microvascular contraction in the collateral-dependent territory was increased in the naproxen group but minimally affected in the celecoxib group. Oxidative stress and apoptosis were increased in the celecoxib group. Expression of angiogenic markers vascular endothelial growth factor and phospho–endothelial nitric oxide synthase (ser1177) and tissue levels of prostacyclin were decreased in both celecoxib and naproxen groups. The naproxen group had diminished endostatin expression.

Conclusions

Selective and nonselective cyclooxygenase inhibition are more complex in effect than previously published, but they did not decrease collateral-dependent blood flow to the myocardium in our model of chronic myocardial ischemia.

CTSNet classification: 17, 38.2

Abbreviations and Acronyms: ADP, adenosine diphosphate, COX, cyclooxygenase, JNK, c-Jun N-terminal kinase, LCx, left circumflex coronary artery, NSAID, nonsteroidal anti-inflammatory drug, PGF_1α, prostaglandin F_1α, PGI2, prostacyclin, TX, thromboxane