Department of Pharmacy, University of Naples, Federico II, Via D. Montesano, 49, Naples, 80131, Italy.
Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via Sergio Pansini 5, Naples, 80131, Italy; Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples, Federico II, Naples, 80131 Italy.
Pharmacol Res. 2017 Oct;124:100-104. doi: 10.1016/j.phrs.2017.07.025. Epub 2017 Jul 29.
Erectile function is a widely accepted indicator of systemic endothelial activity since from a clinical standpoint erectile dysfunction (ED) often precedes cardiovascular events. Recently it has been described a potential role for β adrenoceptor in cardiovascular diseases emphasizing a possible development of new drugs. β adrenoceptor stimulation relaxes human corpus cavernosum (HCC) strips in cyclic guanosine monophosphate (cGMP)-dependent and endothelium/nitric oxide (NO)-independent manner. Hydrogen sulfide (HS), along with NO, is another gaseous molecule involved in cardiovascular system and as a consequence also in penile erection. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), the enzymes mainly responsible for HS biosynthesis, are constitutively expressed in HCC. CSE rather than CBS is more abundant in human penile tissue. Herein we investigated the involvement of HS pathway in β adrenoceptor-induced relaxation in HCC and penile artery. Penile artery expresses both CSE and β adrenoceptor. BRL37344, a β selective agonist, relaxed HCC strips and penile artery rings and this effect was significantly reduced by CSE inhibition. Incubation of HCC and penile artery homogenate with BRL37344 significantly increased HS production. This effect was significantly reduced by the inhibition of either CSE or β adrenoceptor. Finally, the BRL37344-induced increase in cGMP was reduced by CSE inhibition in both tissues. Thus, BRL37344-induced relaxation in HCC and penile artery occurs in a HS/cGMP-dependent manner. In conclusion, β/HS/cGMP pathway can act as an alternative to NO. Since about 15% of patients do not respond to phosphodiesterase-5 inhibitors, β agonists could represent a therapeutic alternative or a useful adjuvant therapy to treat these patients.
勃起功能是全身内皮细胞活动的广泛认可的指标，因为从临床角度来看，勃起功能障碍（ED）通常先于心血管事件发生。最近，有人描述了β肾上腺素能受体在心血管疾病中的潜在作用，强调了开发新药的可能性。β肾上腺素能受体刺激以环鸟苷酸（cGMP）依赖性和内皮/一氧化氮（NO）非依赖性方式松弛人海绵体（HCC）条带。硫化氢（HS）与 NO 一起是参与心血管系统的另一种气体分子，因此也参与阴茎勃起。半胱氨酸-β-合酶（CBS）和半胱氨酸-γ-裂解酶（CSE）是 HS 生物合成的主要酶，在 HCC 中组成型表达。CSE 比 CBS 在人阴茎组织中更为丰富。在此，我们研究了 HS 途径在 HCC 和阴茎动脉中β肾上腺素能受体诱导松弛中的作用。阴茎动脉表达 CSE 和β肾上腺素能受体。BRL37344，一种β选择性激动剂，松弛 HCC 条带和阴茎动脉环，这种作用被 CSE 抑制显著降低。将 HCC 和阴茎动脉匀浆与 BRL37344 孵育可显著增加 HS 的产生。这种作用被 CSE 或β肾上腺素能受体的抑制显著降低。最后，BRL37344 在两种组织中诱导的 cGMP 增加被 CSE 抑制所减少。因此，BRL37344 在 HCC 和阴茎动脉中的诱导松弛以 HS/cGMP 依赖性方式发生。总之，β/HS/cGMP 途径可以作为 NO 的替代物。由于大约 15%的患者对磷酸二酯酶-5 抑制剂没有反应，β激动剂可以代表一种治疗选择或治疗这些患者的有用辅助治疗。
