L-cysteine/hydrogen sulfide pathway induces cGMP-dependent relaxation of corpus cavernosum and penile arteries from patients with erectile dysfunction and improves arterial vasodilation induced by PDE5 inhibition

• Published in: European journal of pharmacology Vol. 863; p. 172675
• Main Authors: La Fuente, José M., Fernández, Argentina, Pepe-Cardoso, Augusto J., Martínez-Salamanca, Juan I., Louro, Nuno, Angulo, Javier
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-11-2019
• Subjects: Arteries - drug effects; Arteries - physiopathology; Cyclic GMP; Cyclic GMP - metabolism; Cysteine - metabolism; Erectile dysfunction; Erectile Dysfunction - physiopathology; Human corpus cavernosum; Human penile arteries; Humans; Hydrogen sulfide; Hydrogen Sulfide - metabolism; L-cysteine; Male; Middle Aged; Muscle Relaxation - drug effects; Penis - blood supply; Penis - drug effects; Penis - physiopathology; Phosphodiesterase 5 Inhibitors - pharmacology; Sildenafil Citrate - pharmacology; Vasodilation - drug effects; Hydrogen sulfide; Human penile arteries; L-cysteine; Erectile dysfunction; Human corpus cavernosum; Cyclic GMP
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.172675

The aim was to evaluate and characterize H2S-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. H2S-mediated relaxations were evaluated by exposing these tissues to the stable analogue, NaHS, and to the precursor of H2S, 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 Ca2+-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 H2S 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 H2S relaxes HCC and HPRA from ED patients through cGMP accumulation and potentiates vasodilatory capacity of PDE5 inhibition, supporting the therapeutic potential of modulating H2S pathway.