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Objective  Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism.    Methods  Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and  ex vivo  transferred to isolated rat aortas. The maximal relaxation (E max ) and half maximal effective concentration (EC 50 ) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection.    Results  Diabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group ( P <0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased E max  and increased EC 50  in diabetic rats compared to control rats ( P <0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration ( P <0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher E max  and lower EC 50  in PDTC-treated diabetic rats compared to untreated diabetic rats ( P <0.01). Similar restoration of E max , EC 50  and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection.    Conclusions  These results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications.

Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity