Improvement of vascular function by chronic administration of a cyclo-oxygenase inhibitor in cholesterol-fed rabbits

Abstract

1. Atherosclerotic cardio- and cerebrovascular disease is a leading cause of mortality in Western countries. Aspirin-like drugs are widely used to prevent and treat these occlusive cardio- and cerebrovascular diseases. The beneficial effects of these drugs have been largely attributed to inhibition of platelet cyclo-oxygenase activity and thromboxane (TX) A2 production. We investigated the effect of an aspirin-like drug, namely indomethacin, on endothelial function, plaque and platelet aggregation and the formation of vasoactive substances during the development of atherosclerosis in cholesterol-fed rabbits. 2. Rabbits were fed 1% cholesterol (n = 8), 1% cholesterol plus 25 mg/day indomethacin (n = 8) or normal rabbit chow (control group; n = 8) for 12 weeks. Urinary excretion rates of 2,3-dinor-TXB2, 6-keto-prostaglandin (PG) F1α, 8-iso-PGF2α, and nitrate were analysed at the beginning of dietary intervention and at 4 weekly intervals thereafter. At the end of the study period, platelet aggregation, aortic plaque formation and endothelium-dependent and -independent vascular functions of isolated aortic rings ex vivo were assessed. 3. Compared with control, in the cholesterol-fed group, urinary 2,3-dinor-TXB2, 6-keto-PGF1α and 8-iso-PGF2α excretion and platelet aggregation were significantly increased (P < 0.05), but urinary excretion of nitrate was decreased (P < 0.05). Treatment with indomethacin significantly reduced platelet aggregation, urinary 2,3-dinor-TXB2, 6-keto-PGF1α, and 8-iso-PGF2α excretion (P < 0.05 vs the cholesterol-fed group) and attenuated the reduction in urinary nitrate excretion. 4. Cholesterol feeding progressively increased aortic intimal thickening and impaired endothelium-dependent vasodilator function (P < 0.05 vs control), whereas indomethacin partially prevented aortic plaque formation and restored endothelium-dependent vasodilation (P < 0.05 vs the cholesterol-fed group). 5. The present study demonstrates that indomethacin reduces the progression of atherosclerotic lesions and improves endothelium-mediated vascular responses ex vivo in cholesterol-fed rabbits. The beneficial effects of indomethacin may be due to its ability to prevent the elevation of platelet aggregation, TXA2 (measured as urinary 2,3-dinor-TXB2 excretion) and 8-iso-PGF2α, formation and to retard the decrease in endogenous nitric oxide synthesis (assessed as urinary excretion of nitrate). Despite indomethacin treatment leading to the suppression of prostacyclin biosynthesis (assessed as urinary 6-keto-PGF1α excretion), according to our data, indomethacin appears to preserve endothelial function.