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Cardiovascular Effects of Pyridoxamine in Type 1 Diabetic Female Rats

The formation of advanced glycation end products (AGEs) is an important pathway involved in cardiovascular complications of diabetes mellitus (DM). The pharmacologic approaches in clinical use have remained unsatisfactory in preventing the diabetic cardiovascular complications and more innovative therapies are needed. Therefore, the aim of the study was to investigate the coronary vascular responsiveness and oxidative stress in the left ventricle in type 1 diabetic female rats and the effects of the combined treatment with insulin and pyridoxamine (AGEs inhibitor). This study was approved by the Ethical Committee for Animal Research Use (CEUA UNICAMP 4532/2017). Female Wistar rats (180–200g) were divided into four groups: control (CTR), type 1 DM (DM1, alloxan 170 mg/kg IP), DM1 treated with insulin (DM1+INS, 2U morning + 4U evening SC/day) and DM1 treated with insulin and pyridoxamine (DM1+INS+PDX, 180 mg/kg/day oral gavage). One week after DM1 induction the DM1+INS and DM1+INS+PDX groups initiated the respective treatment that lasted for three weeks. Concentration‐response curves to acetylcholine (ACh), sodium nitroprusside (SNP) and thromboxane A2 analog (U46619) were obtained in septal coronary artery. The generation of reactive oxygen species (ROS) were evaluated in left ventricle in basal condition and in the presence of superoxide dismutase mimetic (MnTMPyP). Biochemical parameters were measured. One‐way ANOVA followed by a Tukey's test was performed. As expected, the body weight was reduced and the blood glucose was increased in DM1 as compared with CTR group. In DM1+INS and DM1+INS+PDX groups the blood glucose was reduced and the body weight values were normalized. The maximal response (EMAX) to ACh was decreased in DM1 (72±6%) and DM1+INS (78±8%) groups compared with CTR (97±8%), the combined treatment in DM1+INS+PDX (99±5%) restored this alteration with no changes in potency (pEC50). Neither the EMAX nor pEC50 were modified for SNP and U46619 in all experimental groups. At basal condition, ROS measurement in the left ventricle was not modified in all groups. However, the reduction of ROS generation in the presence of MnTMPyP was impaired in DM1 group (approximately 50%) as compared with CTR group. Only the combined treatment with insulin and pyridoxamine was effective in preventing this alteration in DM1+INS+PDX group. In conclusion, our results show that insulin associated with pyridoxamine treatment prevented the coronary dysfunction and cardiac oxidative stress in type 1 diabetic female rats.