Serviço de Urologia, Hospital Santo Antonio, Porto, Portugal.
Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (UFV-IRYCIS), Hospital Universitario Ramón y Cajal, Madrid, Spain.
Eur J Pharmacol. 2019 Nov 15;863:172675. doi: 10.1016/j.ejphar.2019.172675. Epub 2019 Sep 19.
The aim was to evaluate and characterize HS-induced relaxation of human corpus cavernosum (HCC) and penile resistance arteries (HPRA) from patients with erectile dysfunction (ED). HCC and HPRA were obtained from men with ED at the time of penile prosthesis insertion. HS-mediated relaxations were evaluated by exposing these tissues to the stable analogue, NaHS, and to the precursor of HS, L-cysteine (CYS). The effects of NaHS and CYS were also evaluated on cGMP accumulation in HCC and on acetylcholine- and sildenafil-mediated relaxations in HCC and HPRA. NaHS consistently relaxed HPRA and HCC and more potently than human prostate and bladder. NaHS-induced relaxations in HCC and HPRA were unaffected by the ATP-sensitive K-channel blocker, glibenclamide or the NO synthase inhibitor, L-NAME, slightly reduced by the Ca-activated K-channel blocker, tetraethylammonium, and markedly inhibited by the soluble guanylyl cyclase inhibitor, ODQ. NaHS caused a cGMP increase in HCC that was inhibited by ODQ. CYS produced relaxations of HCC and HPRA that were sensitive to ODQ and to inhibition of the HS synthesizing enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). CYS also increased cGMP in HCC. In contrast to NaHS, CYS-induced relaxations were prevented by endothelium removal in HPRA. Only in HPRA, treatment with CYS (30 μM) potentiated acetylcholine- and sildenafil-induced relaxations. This effect was prevented by CSE/CBS inhibition and by removing the endothelium. Exogenous and endogenous HS relaxes HCC and HPRA from ED patients through cGMP accumulation and potentiates vasodilatory capacity of PDE5 inhibition, supporting the therapeutic potential of modulating HS pathway.
目的是评估和描述 HS 诱导的勃起功能障碍（ED）患者的人海绵体（HCC）和阴茎阻力动脉（HPRA）松弛作用。在阴茎假体植入时，从 ED 男性中获得 HCC 和 HPRA。通过使这些组织暴露于稳定类似物 NaHS 和 HS 的前体 L-半胱氨酸（CYS）来评估 HS 介导的松弛作用。还评估了 NaHS 和 CYS 对 HCC 中环磷酸鸟苷（cGMP）积累的影响，以及对 HCC 和 HPRA 中乙酰胆碱和西地那非介导的松弛作用的影响。NaHS 一致地松弛了 HPRA 和 HCC，其作用比人前列腺和膀胱更强。NaHS 诱导的 HCC 和 HPRA 松弛不受三磷酸腺苷敏感性钾通道阻滞剂格列本脲或一氧化氮合酶抑制剂 L-NAME 的影响，被钙激活钾通道阻滞剂四乙铵轻度抑制，被可溶性鸟苷酸环化酶抑制剂 ODQ 显著抑制。NaHS 引起 HCC 中 cGMP 的增加，该增加被 ODQ 抑制。CYS 产生 HCC 和 HPRA 的松弛作用，对 ODQ 和 HS 合成酶胱硫醚 γ-裂合酶（CSE）和胱硫醚 β-合酶（CBS）的抑制作用敏感。CYS 还增加了 HCC 中的 cGMP。与 NaHS 相反，CYS 诱导的 HPRA 松弛作用被内皮去除所阻止。仅在 HPRA 中，用 CYS（30μM）处理可增强乙酰胆碱和西地那非诱导的松弛作用。该作用被 CSE/CBS 抑制和内皮去除所阻止。外源性和内源性 HS 通过 cGMP 积累松弛 ED 患者的 HCC 和 HPRA，并增强 PDE5 抑制的血管舒张能力，支持调节 HS 途径的治疗潜力。
