Inhibitory Effect of Nitric Oxide on Intimal Hyperplasia after Rat Carotid Artery Intima Injury

ABSTRACT

Intimal hyperplasia is considered to be a most frequent cause attributing to occlusion of a blood flow after vascular surgeries such as endarterectomy, bypass surgery and angioplasty. Clearly this response is a significant cause of morbidity in patients undergoing vascular procedures and studies to find out the strategy for avoid intimal hyperplasia are of great importance. The precise pathophysiologic pathways leading to the development of intimal hyperplasia have not been yet clear. The initial event is thought to be damage to the vascular intimal endothelium. Intimal hyperplasia is the characteristic fibromuscular cellular response on intimal injury and some author advocated the "response-to-injury" hypothesis of atherogenesis to be inducing factors of intimal hyperplasia. Endothelial cells release a number of vasoactive substances such as relaxing factor, including nitric oxide(NO). The NO has not only relaxing effect to the smooth muscle cells, but also inhibitory effect to intimal hyperplasia. In this study, we investigated on rat inhibitory effect of NO donor(SNAP, SNP) to intimal hyperplasia on endothelial denudation and reversed by coadministration of the NO synthase inhibitor, L-NAME. Balloon catheter denudation of common carotid artery was performed in 35 rats pharmacologically treated from 3 days before to 14 days after surgery(5 mg/kg/day, intraperitoneally) and divided into 5 groups control group, without any medical treatment; SNAP group, S-Nitroso-N- acetylpenicillamine; SNP group, sodium nitroprusside; SNAP+L group, both SNAP and N(G)-Nitro-L-arginine methylester; SNP+L group, both sodium nitroprusside and N(G)-Nitro-L-arginine methylester. Animals were killed and left common carotid arteries were perfused and fixed with 10% formalin solution at 14 days after endothelial denudation. Cross sectional intima-to-media area ratios(I-M ratio, intimal area/[intimal area medial area]x100) were calculated by an image analyzer system and serum level of NO was measured directly by electrochemical methods. The results of the this experimental study were as follows 1) Morphometric analysis of cross sections showed marked intimal thickening in the control group with an mean I-M ratio of 64.71+/-4.96%. In contrast, the I-M ratios in the SNAP group were significantly reduced by 53.14+/-7.86%(P<0.05) and in the SNP group by 43.43+/- 9.32%(P<0.05). The IM ratios of animals treated with L-NAME in group SNAP-L and group SNP-L were 68.43+/-3.91% and 67.71+/-5.50% respectively(P=NS). No significant change was noted when L-NAME was coadministered with SNAP and SNP compared to control group. 2) The serum level of NO in SNAP group(2509.7+/-354.95 nM) and SNP group(3430.4+/-236.70 nM) were significantly increased compare to control group(1339.2+/-101.04 nM)(P<0.05). Coadministration of L-NAME in group SNAP-L(1719.8+/-483.65 nM) and group SNP-L(1415.7+/-219.04 nM)were no significant changed compare to control group(1339.2+/-101.04 nM). These experiments suggest that SNAP and SNP reduced intimal hyperplasia and increased serum level of NO, reversed by coadministration of L-NAME. The relation between the intimal hyperplasia suppression and NO increase should be speculated.