Tetrathiomolybdate Partially Alleviates Erectile Dysfunction of Type 1 Diabetic Rats Through Affecting Ceruloplasmin/eNOS and Inhibiting Corporal Fibrosis and Systemic Inflammation

Abstract

Introduction Patients with erectile dysfunction induced by diabetes mellitus (DMED) show a poor effect rate for oral phosphodiesterase type 5 inhibitors (PDE5is). Therefore, the new therapeutic strategy is necessary in patients with DMED. Aim To investigate whether Tetrathiomolybdate (TM) supplementation could ameliorate DMED by activation of eNOS. Methods Twenty-four diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ) and the other 6 normal rats constituted the control group. Eight weeks later, the erectile function of rats was assessed with an apomorphine test. Only some rats with DMED were treated with TM orally every day for 4 weeks; the other rats remained in the same condition for 4 weeks. After 1 week washout, the erectile function of rats in each group was evaluated. Then, the serum concentration of IL-6 and histologic changes of corpus cavernosum were measured. Main Outcome Measure Erectile function was measured after DMED rats treated with TM. The cavernosum level of Ceruloplasmin (Cp), eNOS, endothelial cell content, corporal fibrosis, apoptosis rate and the serum level of IL-6 were also assayed. Results Erectile function in the DMED group was significantly impaired compared with the control group and was partly, but significantly, improved in the DMED+TM group. The DMED group showed upregulation of Cp and inhibition of eNOS, but the inhibition was partly reversed in the DMED+TM group. The DMED group showed serious corporal fibrosis. However, TM supplementation partly increased the ratio of smooth muscle to collagen, decreased the ratio of apoptosis. What's more, gavage administration of TM profoundly decreased the serum level of IL-6 in DMED rats. Conclusion TM supplementation inhibits endothelial dysfunction, corporal fibrosis, and systemic inflammation, ultimately leading to partial improvement of DMED in rats.

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“…Intracavernous pressure (ICP) was measured by electrical stimulation, as previously reported ( 17 , 18 ). All rats were anesthetized by injection with pentobarbital (40 mg/kg).…”

“…The staining procedures were reported in our previous study ( 18 , 19 ). Slides containing tissue sections were deparaffinized using a dry oven at 60°C for 30 minutes and in 2 changes of xylene for 10 minutes, and then rehydrated in a series of decreasing concentrations of alcohol.…”

“…The staining procedures were reported in our previous study ( 18 ). Tissue sections of the middle part of the penis were stained according to Masson kit instructions (Solarbio, Beijing, China).…”

“…TUNEL staining was carried out according to previous studies ( 18 ). Apoptosis of the corpus cavernosum of each group was detected using a TUNEL apoptosis detection kit (KeyGEN BioTECH, Nanjing, China) following the manufacturer’s instructions.…”