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 µM and 100 µM) 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.