Mitidieri, Emma (2009) New pharmacological prospectives in erectile function. [Tesi di dottorato] (Unpublished)

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Abstract Erectile dysfunction (ED), defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity ), can be caused by a number of different pathophysiological process. For these reasons, the present study can be divided into three steps in which we have analyzed various aspects of physiology and physiopathology of erectile function to give a contribution in the development of novel therapeutic approaches for treatment of ED and sexual arousal disorders. We have first analyzed man dysfunctions that develop into ED, and in particular Peyroeni’s disease (PD), a connective tissue disorder involving the growth of fibrous plaques in the tunica albuginea of the penis. PD consists in a molecular and physiopathological disorder that is poorly understood mainly because of to the lack of an appropriate animal model. We were looking for a spontaneous animal model that may mirror the natural history of human PD and we showed that tight skin mice (Tsk) could reproduce the natural development of human PD with age. Indeed in Tsk mice was observed: i) a gradual increase in synthesis and deposition of collagen of type I, ii) an high level of TGFβ especially in the earlier stage of the disease, iii) an increase of iNOS mRNA level during the development of the pathology. PD represent a particular case of ED. Indeed, it is now widely accepted that ED is predominantly a vascular disease. In particular the erectile function is regulated by a balance between vasorelaxant and vasoconstrictor factors. The breaking of this balance can be cause of ED. To identify new pathways involved in penile erection, that could be target for new therapies, our attention has been placed on urotensin II (UII), an endogenous peptide previously described as an important vasoactive peptide. Interestingly, our data suggest that i) UII receptor is expressed in rat corpus cavernosum and in anesthetized rats, intracavernous administration of UII causes an increase of intracavernous pressure; ii) UII receptor is expressed on HCC and it is localized on endothelial cell; iii) the receptor is functional and mediates an endothelium-dependent relaxation that involves the L-arginine/NO pathway.; iiii) UII effect was inhibited by both geldanamicin and wortmannin. Finally we have analyzed various methods for ED diagnosis. ED and its grade and the efficacy of ED treatment, are actually evaluated by medical questionnaire scores, a non-objective method. The most used therapy in ED treatment is actually represented by PDE5 inhibitors which, inhibiting PDE5, increase the action of cGMP and thereby enhance penile cavernosum and vascular smooth muscle relaxation and erection. The target of these drugs, PDE5, has been founded in other tissues than the penis, such as vascular smooth muscle, smooth muscle of the gastrointestinal tract and in platelets. For these reasons we have assessed if platelet cGMP could act as a biomarker of PDE5 activity in ED clinical studies. In conclusion at first we have showed that: i) the Tsk mouse, as it replicates similar condition to the human disease, may represents a new animal model of PD naturally occurring; ii) UII could represent a novel target in physiology and physiopathology of penile erection; iii) Platelet cGMP is a relative simple assay and can provide information on the activity and duration of PDE5 inhibition within and over plasma levels.

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