Descripción de la matriz DOFA para zoocriadero de avestruces

1.4.1 Cavernosal physiology and erectile dysfunction

Erectile dysfunction is defined as the persistent inability to attain and maintain an erection adequate to permit satisfactory sexual performance [NIH Consensus Conference 1993]. Although erectile dysfunction is not life threatening, this common problem can significantly affect the quality of life, as well as, psychological and social well-being [Hanson-Divers at al. 1998].

The Massachusetts male ageing study included a questionnaire on sexual function and activity for 1290 men [Feldman at al. 1994]. The combined

prevalence of erectile dysfunction was 52% (17.1% mild, 25.2% moderate, 9.6% complete). The prevalence of complete erectile dysfunction tripled from 5% to 15% between subject ages 40 and 70 years.

Extrapolation from historical data in the USA indicates that currently around 7 to 10 million men have erectile dysfunction [NIH Consensus Conference

1993; Furlow 1985]. However, because erectile dysfunction is a sensitive issue, it is likely that its prevalence is under-reported. Despite this, erectile dysfunction results in more than 400,000 outpatient visits and 30,000 hospital admissions in the USA per year [Shabsigh et al. 1988]. In the UK, an

estimated 17-19% of men are thought to suffer from erectile dysfunction [Goldmeier ef a/. 1997; Read etal. 1997].

The corpus cavernosum is a modified blood vessel. Penile erection requires the lacunar spaces to dilate and fill with blood. Relaxation of the smooth muscle surrounding the helicine arterioles allows an increase in arterial inflow whilst simultaneous relaxation of the trabecular smooth muscle results in lacunar dilatation and leads to tumescence. Ekhardt [1863] showed in his classic experiment that electrical stimulation of the sacral parasympathetic nerves in dogs produced penile erection. More recently it has been realised that these nerves are preganglionic and that NANC mechanisms are central to relaxing the cavernosal smooth muscle. Normal penile erectile function is dependent upon a delicate balance between contracting and relaxing factors in the corpus cavernosum smooth muscle, which are modulated by nerve signalling and endothelial cells [Andersson and Wagner 1995]. When this balance is disrupted erectile dysfunction can result. NO, in particular, plays a central role in mediating cavernosal smooth muscle relaxation [Burnett et al.

1992], but other neurotransmitters can modulate this action and may also play a role in erectile dysfunction. Endothelin-1, a neuropeptide with powerful vasoconstrictor properties may be involved in maintaining the balance of cavernosal smooth muscle tone, counteracting the effects of NO [Khan et al.

substance P (SP) are found in the human corpus cavernosum [Andersson and Wagner 1995]. NPY and AVP cause contraction in human cavernosal smooth muscle strips and VIP and SP cause relaxation in pre-contracted human cavernosal smooth muscle.

Other non-peptide neurotransmitters such as prostanoids, histamine and 5- hydroxytryptamine may have neuromodulatory effects on cavernosal smooth muscle tone [Andersson and Wagner 2000].

Due to the difficulty in obtaining human cavernosal tissue, the study of the pathophysiology of erectile dysfunction has been dependent upon the study of cavernosal tissue from animal models of conditions predisposing to erectile dysfunction. As already mentioned the corpus cavernosum is a modified blood vessel and, indeed, many conditions which predispose to vascular diseases also predispose to erectile dysfunction (e.g. diabetes mellitus, hypertension, hyperlipidaemia). Alterations in neurotransmitter distribution and function have been found in the corpora cavernosa of animal models of these conditions, implying a role in the pathogenesis of erectile dysfunction [Sullivan et al. 2001]. Knowledge of NANC neurotransmitters has

lead to the development of pharmacological treatments for erectile dysfunction. The most effective available treatments for erectile dysfunction are local administration of alprostadil (PGEi) and oral administration of sildenafil (a phosphodiesterase Type V inhibitor, which increases the availability of NO in the cavernosal smooth muscle). However, both of these treatments have significant failure rates [Khan at al. 2000b].

1.4.2 Purinergic signalling in the corpus cavernosum

ATP causes a dose-dependent relaxation of isolated precontracted rabbit cavernosal smooth muscle strips [Broderick et a/. 1991]. Intracavernosal

injection of ATP into anaesthetized dogs increased the intracavernosal pressure and induced erection [Takahashi at a/. 1992]. The order of potency

of different purine analogues suggests that a P2Y receptor may be involved [Filippi at al. 1999] and P2Yi mRNA has been identified in endothelial cells in

the corpus cavernosum [Obara at al. 1998]. Adenosine-5'-0-(2-

thiodiphosphate) (ADPpS, a relatively specific P2Yi-agonist) causes cavernosal smooth muscle relaxation which is inhibited by endothelial disruption or by the addition of the NO-synthase inhibitor L-NAME [Shalev at

al. 1999]. This may indicate that P2Yi-receptor activation on cavernosal

endothelial cell stimulates NO production which in turn relaxes cavernosal smooth muscle. Other investigators, however, have found that ATP-mediated cavernosal smooth muscle relaxation is not affected by endothelial disruption or L-NAME indicating that ATP might act through a different mechanism [Tong at al. 1992, Levin at al. 1995]. The first part of chapter 4 is a

pharmacological study of normal rabbit cavernosal smooth muscle which attempts to more precisely determine the receptor subtype mediating the ATP-induced cavernosal smooth muscle relaxation.

1.4.3 Purinergic signalling and erectile dysfunction

Alterations in purinergic signalling have been reported in a number of animal models of conditions which predispose to erectile dysfunction. Changes in

ATP-mediated cavernosal smooth muscle relaxation have been found in models of varying age [Ragazzi et al. 1996], chronic steroid abuse [Kaya at

ai. 1997], castration [Itoh etal. 1997] and diabetes mellitus in the rat [GCir and

Ôztürk 1999]. This provides evidence that purinergic signalling may be involved in the pathophysiology of erectile dysfunction. Much of the knowledge about purinergic signalling in the corpus cavernosum has been obtained from rabbit tissue. In Chapter 4 I then investigated whether the ATP-mediated cavernosal smooth muscle relaxation is altered in a rabbit model of diabetes mellitus. There is increasing evidence that benign prostatic obstruction is an independent risk factor for erectile dysfunction [Jing at ai.

2001 ; Richard at ai. 2000]. The final experiment in Chapter 4 was designed

to determine whether ATP-mediated cavernosal smooth muscle relaxation is altered in the rabbit model of bladder outflow obstruction.