Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis.This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice.Thirty-eight-week-old male C57BL/6J mice were divided into three groups:(1) nondiabetic control group,(2) diabetic mice + vehicle group,and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group.Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg-1 body weight for 5 consecutive days.Thirteen weeks later,diabetic mice were treated with MDL28170 or vehicle for 4 weeks.The erectile function was assessed by electrical stimulation of the cavernous nerve.Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway.Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis.Caspase-3 expression and activity were also measured to determine apoptosis.Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group.No differences in calpain-1 and calpain-2 expressions were observed among the three groups.However,calpain activity was increased in the diabetic group and reduced by MDL28170.The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice.Additionally,MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum.Inhibition of calpain could improve erectile function,probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.