MOLECULAR AND FUNCTIONAL CHARACTERISATION OF THE ROLE OF HYDROGEN SULPHIDE IN SEXUAL MEDICINE

Abstract

Hydrogen sulphide (H2S) is an endogenously produced gasotransmitter with a similar role as nitric oxide (NO) which has long been recognised as an important mediator in erectile physiology. Several studies have investigated the role of H2S in erectile function and H2S was found to exert definitive pro-erectile effects. The aim of this thesis is to elucidate the contribution of H2S to erectile response and shed some light on the mechanism(s) involved, including any possible cross talk between H2S and NO.

It was observed that NaHS, a H2S-donor, significantly improved the magnitude of erectile response to cavernous nerve electrical stimulation in rats. This improvement was associated not only with an increase in the systemic H2S concentration and H2S biosynthesis in the corpus cavernosum (CC) of these rats but also with increased production of NO in both plasma and CC. The cross talk between H2S and NO was evident in this tissue. Further in vitro studies revealed that H2S increased endothelial nitric oxide synthase (eNOS) mRNA expression and cyclic guanosine monophosphate (cGMP) level. Moreover, H2S also exerted an effect on the NO pathway downstream of NOS, namely increasing the expression of both the active and inactive forms of soluble guanylyl cyclase (sGC) ß1 and stimulating the translocation of sGCa1 from the cytosol to the membrane. Overall, H2S seems to play a `supportive¿ role with respect to NO pathway in erectile physiology, amplifying NO signalling through dual action of increasing NO production and sensitizing the sGC towards NO. In addition, studies using castrated animals demonstrated that testosterone is not a requirement for the pro-erectile effect of H2S; however, testosterone is clearly implicated in this cross talk. High testosterone level seems to favour the cross talk, with H2S boosting NO production in this condition while low testosterone seems to cause H2S to `switch¿ to an NO-independent mechanism for its pro-erectile effect. Interestingly, H2S seems to act as a backup when the NO pathway is compromised. Under condition of high NO (observed in animals treated with sildenafil), normal H2S level and production were observed, while under condition of low NO (observed in animals treated with NO synthase inhibitor L-NAME), high H2S level was observed. Thus, shortage of NO can trigger the production of H2S, which can in turn stimulate the production of NO. The finding from this study that exogenous H2S seems to stimulate endogenous H2S production also shed some light on the possible auto-regulation of H2S through positive feedback.

The pro-erectile effect of H2S was also likely to result from its attenuating effect on the RhoA/Rho-Kinase contractile pathway. In this system, H2S was shown to downregulate the level of RhoA and Rho Kinase II (ROCK II) proteins which may have direct implication on corporal smooth muscle tone.

In summary, findings from this thesis work show that H2S plays an important physiological role in erectile function. It is likely to exert its pro-erectile effects through multiple mechanisms of action including a complex cross talk with NO as well as modulation of the contractile, anti-erectile pathway.