Pharmacologic inhibition of nitric oxide synthases and cyclooxygenases enhances intimal hyperplasia in balloon-injured rat carotid arteries

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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.

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Fischer, J. W., Hawkins, S., & Clowes, A. W. (2004). Pharmacologic inhibition of nitric oxide synthases and cyclooxygenases enhances intimal hyperplasia in balloon-injured rat carotid arteries. Journal of Vascular Surgery, 40(1), 115–122. https://doi.org/10.1016/j.jvs.2004.03.037

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