Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression

Abstract

Abnormalities in vascular function are well recognized in diabetes. Hyperglycemia may be central to the pathogenesis of vascular dysfunction but is not certain whether improvements in glycaemic control will improve vascular function. The effects of metformin, an antidiabetic agent that improves insulin sensitivity and glycaemic control, on the microvascular reactivity have not been reported in neonatal streptozotocin-induced (n-STZ) diabetes. Diabetes was induced by STZ injection (160 mg/kg, ip) in neonates (2-day-old) Wistar rats. n-STZ diabetic rats were treated with metformin (300 mg/kg, 15 d, by gavage). Using intravital microscopy the changes in mesenteric arteriolar and venular diameters were determined in anesthetized control and n-STZ diabetic rats, before and after topical application of endothelium-dependent vasodilator agents, mediators or not of the inflammatory response, and endothelium-independent vasodilator agent. We also determined the total nitric oxide synthase (NOS) activity (conversion of L-arginine to citrulline) and endothelial(e), inducible(i), and neuronal(n) NOS expression (using polymerase chain reaction after reverse transcription of the mRNAs into cDNAs) in the mesentery of metformin-treated n-STZ diabetic and vehicle-treated n-STZ diabetic and control rats. Although metformin treatment did not correct the high glycaemic levels and the impaired glucose tolerance, the reduced vasodilator responses and total NOS activity in n-STZ diabetic rats were corrected by the treatment. Neither diabetes nor metformin treatment altered the expression of the three NOS isoforms. We concluded that metformin restores the reduced response to vasodilator agents, independently of the correction of the metabolic alterations. Improvement of total NOS activity might be in part responsible for the correction.