Effects of folic acid on vascular reactivity in a rat model of hyperhomocystenemia

Effects of Folic Acid on Vascular Reactivity in a Rat Model of Hyperhomocystenemia Introduction and Background: Homocysteine is a member of sulfhydril group amainoacids formed by remethyletion of dietary methionine and which does not participate in protein structure. Homocysteine has potent mitogenic effects on vascular smooth muscle cells. In addition; homocysteine reduces expression of endothelial nitric oxide synthase and nitric oxide production and causes endothelial dysfunction. Homocysteine increases the lipid peroxidation. The mechanisms of hyperhomocystenemia induced atherosclerosis include endothelial dysfunction, vasodilatation caused by impaired flow, increased vascular smooth muscle proliferation and coagulation. Folic acid takes part in single carbon metabolism by providing single carbon units for the synthesis of purine and timidilate and the methylation of essential biological substances such as phospholipids, proteins, DNA and neurotransmitters. Folic acid deficiency may not cause symptoms in the early period. However, increment of metabolites including homocysteine results in accumulation of toxic substrates. Rapidly proliferating cells are more sensitive to defificiency of folic acid. It has been shown that folic acid deficiency is the primary cause of hyperhomocystenemia. Recent studies have indicated that the interaction between folate homeostasis and homocysteine metabolism plays important role in various types of vascular disease. Materials and Method: Thirty four male Wistar Albino rats were allocated into four groups each containing nine animals. Sham group rats had orogastric saline for 30 days whic was followed by intraperitoneal (i.p) injection of saline for another 7 days. Rats in the hyperhomocyestenemia (HHcy) group recieved 1g/kg/day methionine via orogastric gavage for 30 days and then injected with intraperitoneal (i.p) saline for the next 7 days. In the hyperhomocystenemia+folic acid (HHcy+Fa) group, following the administration of methionine for 30 days, folic acid (4mg/kg/day) was delivered via i.p route for 7 days. Animals which were allocated in the folic acid (Fa) group had orogastric saline for 30 days and i.p folic acid for 7 days. After the treatment period of 5 weeks blood samples were obtained, all animals were sacrificed and hearts was harvested. Thoracic aortic segments were dissected free from the surrounding tissues, suspended on individual organ baths and acethylcholine (ACh)-induced (endothelium dependent) relaxation responses of isolated rat aortic rings were evaluated. The levels of antioxidants were assesed in serum and myocardial tissue samples. Findings:m In the HHcy group serum catalase was significantly reduced as compared to HHyca+Fa group. Serum homocysteine level was moderately increased in groups which were fed with methionine. The levels of tissue GSH, catalase, GPX and serum GR were found to be significantly decreased in HHcy group as compared with sham group. In HHcy group tissue GPX and GR and serum catalase levels were also significantly reduced as compared to Fa group. There was significant decrement in the levels of tissue GSH, GR, catalase and serum catalase but significant increment in serum GR level in HHcy+Fa group when compared with sham group. In the HHcy + Fa group tissue GR, tissue GSH and serum catalase levels were significantly reduced in comparision with Fa group. There were no significant differences regarding the relaxation responses in organ bath between the four study groups. Conclusion:Hyperhomocystenemia resulted in reduction of both serum and myocardial antioxidant levels. However, hyperhomocystenemia did not cause any difference in endothelium dependent vasorelaxation responses of isolated aortic rings in organ bath. Administration of folic acid in hyperhomocystenemic rats did not preserve serum and myocardial antioxidant levels. Folic acid therapy also did not cause a difference in vasorelaxation responses of aortic rings when compared wit other groups. Further investigations with application of different folic acid treatment regimens might be needed in order to determine the exact role of this agent on vascular reactivity.