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  • Title: Pharmacologic inhibition of nitric oxide synthases and cyclooxygenases enhances intimal hyperplasia in balloon-injured rat carotid arteries.
    Author: Fischer JW, Hawkins S, Clowes AW.
    Journal: J Vasc Surg; 2004 Jul; 40(1):115-22. PubMed ID: 15218471.
    Abstract:
    OBJECTIVE: Extensive proliferation and migration of smooth muscle cells (SMCs) contribute to development of fibromuscular intimal hyperplasia in response to balloon catheter-induced injury of the left carotid artery in Fischer 344 rats. The purpose of the present study was to test the hypothesis that endogenously generated nitric oxide (NO) and prostaglandins act synergistically to limit the extent of neointimal hyperplasia. METHODS: The left carotid artery of Fischer 344 rats was injured with a 2F balloon catheter. The following treatment was initiated 24 hours before arterial injury, and was continued for 2 weeks: N-nitro-l-arginine (L-NA; 10 mg/kg/d, in drinking water), indomethacin (1.5 mg/kg/d per gavage), and L-NA (10 mg/kg/d) plus indomethacin (1.5 mg/kg/d). After application of an overdose of pentobarbital animals were formalin-fixed. Subsequently, paraffin-embedded cross sections of the uninjured and injured carotid arteries were analyzed morphometrically. SMC proliferation was determined by incorporation of 5-bromo-2'-deoxyuridine. RESULTS: Two weeks after injury, L-NA caused a 1.29-fold +/- 0.29-fold (mean +/- SD; n = 14; P <.05) increase in the intima-media ratio, compared with control animals, whereas indomethacin had no effect. Combined treatment with L-NA plus indomethacin further increased intima-media ratio (1.65-fold +/- 0.5-fold over control; n = 14; P <.05). SMC proliferation in the neointima of rats treated with L-NA and L-NA plus indomethacin was elevated. Furthermore, neointimal cell density (nuclei per square millimeter) was reduced after combined inhibition of cyclooxygenases and NO synthases. CONCLUSION: The present results of pharmacologic NO synthase and cyclooxygenase inhibition suggest that NO and prostaglandins are part of an endogenous growth inhibitory mechanism that synergistically suppresses intimal thickening. CLINICAL RELEVANCE: The role of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) during vascular recurrent stenosis and atherosclerosis is not clear yet. In particular, the effects of selective COX2 inhibitors on the frequency of cardiovascular events is still controversial. It is shown here in rats that the application of a non-selective COX inhibitor does not affect arterial stenosis. However, the concurrent inhibition of endogenous nitric oxide generation and COX1 or COX2 causes overshooting neointimal hyperplasia. These results suggest that increased vascular stenosis can result from administration of drugs that pharmacologically block 2 or more inhibitory pathways that normally counterbalance the effect of promotors of neointimal hyperplasia.
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