Sulfur dioxide (SO2) donors, a new gasotransmitter, improve erectile dysfunction after castration in a rat model

Abstract

Background: Androgen deprivation is associated with erectile dysfunction (ED). In different animal models, sulfur dioxide (SO2) donors Na2SO3 and NaHSO3 reduced oxidative stress, fibrosis, and inflammation which contribute to the pathogenesis of androgen deprivation-induced ED, however the effect of SO2 donors on ED in castrated rats were not known. Objective: To investigate the therapeutic effect of SO2 donors, Na2SO3/NaHSO3, on ED in castrated rat model. Materials and methods: Sprague-Dawley male rats (n = 30) were divided into four groups; control, control-treated with Na2SO3/NaHSO3, castrated, and castrated-treated with Na2SO3/NaHSO3. Castration was induced by bilateral scrotal incisions. Four weeks after castration, rats were treated with Na2SO3/NaHSO3 (0.54/0.18 mmol/kg) intraperitoneally (i.p.) for 4 weeks. Intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) and total ICP were measured to evaluate in vivo erectile responses in cavernosal tissue. In vitro relaxant and contractile responses were measured in all groups. Endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), PI3 kinase p85 alpha + gamma (PI3K), protein kinase B (AKT 1/2/3), cysteine dioxygenase-1 (CDO), and aspartate aminotransferase (AAT) expressions and localizations were evaluated by Western blotting and immunohistochemical staining. The smooth muscle/collagen ratio was evaluated by Masson's trichrome staining. Results: Prostate (p < 0.001) and penis weight (p < 0.001), total serum testosterone (T) level (p < 0.001), and in vivo erectile responses (p < 0.001 at 7.5 and 5 V, p < 0.05 at 2.5 V for ICP/MAP and total ICP) of castrated rats were decreased compared with control. SO2 donors improved reduced ICP/MAP ratio and total ICP (p < 0.01 at 7.5, 5, and 2.5 V for ICP/MAP and total ICP) nitrergic (p < 0.05 at 20 Hz), and endothelium-independent relaxation (p < 0.05 at 1 nM, p < 0.01 at 10 M and 100 mu M) in the castrated group. Decreased eNOS (p < 0.01) and AKT (p < 0.001) protein expressions in the castrated group were normalized by SO2. SO2 donors partially restored the reduced smooth muscle/collagen ratio in the castrated group (p < 0.001). The expressions and locations of nNOS, PI3K, CDO, and AAT proteins in penile tissue did not alter among all groups (p > 0.05). Discussion and conclusion: SO2 donors significantly improve erectile functions and relaxation responses in a castrated rats via ameliorating endothelial damage and fibrosis. Androgen deprivation inhibits the AKT/eNOS signaling while SO2 activates this pathway. SO2 donors may be promising for the treatment of ED in hypoandrogenic men.