Yetik-Anacak Gunay, Dereli Mehmet V, Sevin Gulnur, Ozzayım Ozge, Erac Yasemin, Ahmed Asif
Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey.
Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK.
J Sex Med. 2015 Oct;12(10):2004-12. doi: 10.1111/jsm.12993. Epub 2015 Oct 6.
Resveratrol (RVT) found in red wine protects against erectile dysfunction and relaxes penile tissue (corpus cavernosum) via a nitric oxide (NO) independent pathway. However, the mechanism remains to be elucidated. Hydrogen sulfide (H2 S) is a potent vasodilator and neuromodulator generated in corpus cavernosum.
We investigated whether RVT caused the relaxation of mice corpus cavernosum (MCC) through H2 S.
H2 S formation is measured by methylene blue assay and vascular reactivity experiments have been performed by DMT strip myograph in CD1 MCC strips.
Endothelial NO synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 0.1 mM) or H2 S inhibitor aminooxyacetic acid (AOAA, 2 mM) which inhibits both cystathionine-β-synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme or combination of AOAA with PAG (CSE inhibitor) has been used in the presence/absence of RVT (0.1 mM, 30 min) to elucidate the role of NO or H2 S pathways on the effects of RVT in MCC. Concentration-dependent relaxations to RVT, L-cysteine, sodium hydrogen sulfide (NaHS) and acetylcholine (ACh) were studied.
Exposure of murine corpus cavernosum to RVT increased both basal and L-cysteine-stimulated H2 S formation. Both of these effects were reversed by AOAA but not by L-NNA. RVT caused concentration-dependent relaxation of MCC and that RVT-induced relaxation was significantly inhibited by AOAA or AOAA + PAG but not by L-NNA. L-cysteine caused concentration-dependent relaxations, which are inhibited by AOAA or AOAA + PAG significantly. Incubation of MCC with RVT significantly increased L-cysteine-induced relaxation, and this effect was inhibited by AOAA + PAG. However, RVT did not alter the effect of exogenous H2 S (NaHS) or ACh-induced relaxations.
These results demonstrate that RVT-induced relaxation is at least partly dependent on H2 S formation and acts independent of eNOS pathway. In phosphodiesterase 5 inhibitor (PDE-5i) nonresponder population, combination therapy with RVT may reverse erectile dysfunction via stimulating endogenous H2 S formation.
红酒中含有的白藜芦醇（RVT）可预防勃起功能障碍，并通过一条不依赖一氧化氮（NO）的途径使阴茎组织（海绵体）松弛。然而，其机制仍有待阐明。硫化氢（H2S）是海绵体中产生的一种强效血管舒张剂和神经调节剂。
我们研究了RVT是否通过H2S导致小鼠海绵体（MCC）松弛。
通过亚甲蓝法测量H2S的生成，并使用DMT条带肌动描记器在CD1 MCC条带上进行血管反应性实验。
在存在/不存在RVT（0.1 mM，30分钟）的情况下，使用内皮型一氧化氮合酶（eNOS）抑制剂Nω-硝基-L-精氨酸（L-NNA，0.1 mM）或H2S抑制剂氨氧基乙酸（AOAA，2 mM），其可抑制胱硫醚-β-合酶（CBS）和胱硫醚-γ-裂合酶（CSE）这两种酶，或AOAA与PAG（CSE抑制剂）的组合，以阐明NO或H2S途径对RVT在MCC中的作用的影响。研究了RVT、L-半胱氨酸、硫化氢钠（NaHS）和乙酰胆碱（ACh）的浓度依赖性松弛作用。
将小鼠海绵体暴露于RVT可增加基础和L-半胱氨酸刺激的H2S生成。这两种作用均被AOAA逆转，但未被L-NNA逆转。RVT导致MCC出现浓度依赖性松弛，且RVT诱导的松弛被AOAA或AOAA + PAG显著抑制，但未被L-NNA抑制。L-半胱氨酸引起浓度依赖性松弛，并被AOAA或AOAA + PAG显著抑制。将MCC与RVT孵育可显著增加L-半胱氨酸诱导的松弛，且这种作用被AOAA + PAG抑制。然而，RVT并未改变外源性H2S（NaHS）或ACh诱导的松弛作用。
这些结果表明，RVT诱导的松弛至少部分依赖于H2S的生成，且独立于eNOS途径发挥作用。在磷酸二酯酶5抑制剂（PDE-5i）无反应人群中，RVT联合治疗可能通过刺激内源性H2S生成来逆转勃起功能障碍。
