Inhibitory effect of n-acetylcysteine on intimal hyperplasia and proliferation of smooth muscle cells in anastomosis performed on the carotid artery of rabbit

Other than occurence of acute thrombosis leading to sudden occlusion after reconstructive vascular procedures, neointimal hyperplasia, which is accounted for the recurrence of occlusion at late period and which is the result of proliferation and migration of smooth muscle cells together with accmulation of extracellular matrix, plays an important role. It was shown in arterial injury models of animal and human studies that the principal reason for luminal narrowing was smooth muscle cell proliferation and connective tissue accumulation in the intimal layer.N-Acetylcysteine, shows a direct antioxydant characteristic with its free tiyole (-SH) group through an interaction with the electrophilic groups of oxydant radicals. It triggers the synthesis of glutation. As for glutation, which is a high reactive tripeptide, while it protects cells from the harmful effects of endogenous or exogenous cytotoxic substances and oxydant radicals, it also has an important role in endocellular mechanisms for the continuity of the structure and the functionality of cells. N-Acetylcysteine constitudes as a resource for sulphydrile groups. The sulphydril groups has many biologic functions, such as clearance of free oxygen radicals and regulation of the half life of nitric oxide. N-Acetylcysteine also potentialize the vasodilatatory effects of nitroglycerine on coronary arteries and inhibitory effects of it to the aggregation of thrombocytes. It was shown that N-Acetylcysteine regulates the cell cycle and proliferation of smooth muscle cells. Through the activation of nuclear factor Kappa-Beta (NF-kB), the upregulation of specific adesion molecules on endotel and smooth muscle cells support the activation of vascular cells after injury. Recently performed studies of N-Acetylcysteine showed that it has been an important regulator of the activity of NF-kB in endotel and smooth muscle cells. N-Acetylcysteine regulates the progression and proliferation of smooth muscle cells and potentializes the antithrombotic and antiplatelet activation in endotel cells. Due to the all abovementioned effects of N-Acetylcysteine, we aimed to investigate the inhibitory effects of N-Acetylcysteine on intimal hyperplasia and endothelial proliferation in the anastomosis models of rabbit carotid arteries.Material and MethodIn this study, randomly selected fourteen New Zealand type male rabbits were used. As for anesthesia, 50 mg/kg intramuscular ketamine and 5 mg/kg intramuscular Ksilazine were used. Right common carotid artery for anastomozis and left common carotid artery for control was used. Common carotid artery was explored with vertical neck incision in all rabbits. 100 IU/kg intravenous heparin were used. After the proximal and distal carotid arterial segments were clamped, it was transected and anastomozed end-to-end with 8/0 polipropilene sutures. Group 1 pertained the control group. First dose of N-Acetylcysteine was given intravenously initially after the surgical procedure, and the remaining doses intramuscularly with total of 150 mg/kg/day. At the end of twentyeighth day, carotid artery segments of both sides (anastomozis side and opposing control side) were removed and transfered to the hystology laboratory. Specimens were cut as paraphine blocks of 5 µm and painted with Hematoxylene-Eosine in order to be evaluated under microscobe.ResultsThe comparison of luminal area in group 1 and 2 revealed that, the luminal area was significantly higher in group 2 [z=3,13, p=0,002]. This comparison between contrlateral control groups (Group 1K and 2K) was not significantly different [z=-0,57, p=0,56]. While the intimal area was significantly lower in group 2 [z=-2,49, p=0,013], no significant difference was found on the comparison of control groups [z=0,96, p=0,34]. The comparison of the ratio of intimal to medial area showed that it was significantly lower in group 2 [z=-2,236, p=0,025].ConclusionIntimal hyperplasia has an influence on15-30% of all arterial revascularizations. Improvements in management strategies in order to control the healing process to injury have a great clinical importance. Until today, either after anastomozis or after PTCA or stenting, many articles have been published regarding the inhibition of intimal hyperplasia and smooth muscle cell proliferation.In our study, significant improvements in parameters of luminal area, intimal area and ratio of intimal-to-media were achieved in groups which were given N-Acetylcysteine. This favorible influence of N-Acetylcesteine was thought to be achieved with the direct antioxydant effect, induction of synthesis of glutation, regulation of the half life of nitric oxide, regulation of the activities of chemoattractants and regulation of the proliferation and migration of smooth muscle cells. With this manner, in our opinion, the usage of N-Acetylcysteine after surgical and interventional revascularizations lessen the load of intimal hyperplasia, improve the remodelling process and finally increase the patency period of revascularizations procedures.Key words: N-Acetylcysteine, intimal hyperplasia, smooth muscle cell proliferation, anastomosis, rabbit.