Aversa.2_EU Urological Review 15/03/2010 13:02 Page 81
Endothelial Function and Erectile Dysfunction
in men with or without ED, independently of the presence or absence (EPCs) from the bone marrow play a significant role in repair
of VRFs. By contrast, the augmentation index, which is an indirect mechanisms of the endothelium through regeneration of the
measurement of arterial stiffness, was higher in men with ED endothelial monolayer.
49
Studies have associated EPCs with ED,
50
compared with controls even when controlled for age and VRFs. In suggesting an additional pathophysiological link between erectile
that study, it was concluded that increased arterial stiffness, but not function and EDys. While the penile vasculature is the target of multiple
EDys, is present in men with vascular ED and may enable early potential insults, including oxidative stress, oxidised lipoproteins,
detection of vascular impairment that may precede endothelial infections and haemodynamic stressors, it is interesting to note that
dysfunction (see Figure 1) in populations at low risk of developing this organ may actively participate in the whole process by itself.
vascular ED.
39
Phosphodiesterase Type-5 Inhibitors
Erectile Dysfunction and Endothelium
The unique anatomy of the human penis is customised to produce a PDE5-i facilitate erection by increasing NO-determined relaxation
complex haemodynamic response to centrally and peripherally through the inhibition of cGMP breakdown in endothelial cells.
51,52
generated psychoneurogenic sexual stimuli. Central control of erectile However, since PDE5 is widely expressed in the vasculature
53
and
function resides in the hippocampus and the medial pre-optic area and PDE5-i enhance NO-mediated responses in other vascular beds, the
paraventricular nuclei of the hypothalamus.
40
The signalling of sexual efficacy of PDE5-i is reported to be lower in diabetic patients with ED
impulses is mediated via the dopaminergic, nitrergic and oxytocinergic compared with those without diabetes;
54
this is also true of the
pathways, and is enhanced by circulating bioavailable T.
41
effectiveness of other groups of drugs known to improve endothelial
function,
55
not only because of impaired NO production but also
An erection is a co-ordinated process involving psycho-neurogenic because of the decreased availability of precursors. It has been
stimulation, arterial and cavernosal vasodilatation, increased blood suggested that chronic sildenafil administration may regulate the
flow and venous occlusion. Peripheral control of erectile function transduction pathway leading to the activation of eNOS with no
centres on the interplay between relaxation and contraction of effect on NO bioavailability or on the cGMP pathway, thereby
smooth muscle in the walls of the cavernosal arterioles and the eliminating a possible concern for tachyphylaxis.
56
Another possible
trabeculae of the cavernosal sinuses. Vasodilatation caused by explanation as to why chronic sildenafil may induce endothelial
smooth-muscle relaxation results in increased blood flow, increased rehabilitation comes from a recent study by Ayala and co-workers
intracavernosal pressure and occlusion of the subtunical venous that demonstrated improvements in insulin action in a mouse model
plexus and emissary veins, leading to penile erection. Smooth-muscle of diet-induced obesity and insulin resistance.
57
In their experiment,
cell relaxation is achieved through the cGMP and cAMP pathways, these improvements occurred even in the absence of an exogenous
both of which are modulated by various chemomediators.
42
NO, the NO donor, suggesting that the endogenous supply of NO in the high-
principal chemomediator, activates guanylyl cyclase in penile smooth- fat-fed state did not limit the effect of sildenafil on insulin action.
muscle cells, thereby converting guanosine triphosphate (GTP) to Chronic PDE5 inhibition also resulted in increased energy
cGMP, with subsequent activation of protein kinase G and accelerated expenditure, suggesting that improved energy balance and weight
efflux of calcium and potassium from smooth-muscle cells, ultimately reduction might be partially responsible for the enhanced insulin
increasing penile blood flow. The synthesis and release of NO by action without any adverse effects on cardiac morphology or blood
neuronal NO synthase (nNOS) in the cavernosal non-adrenergic non- pressure measured in vivo, supporting human studies showing no
cholinergic (NANC) nerve terminals is calcium-dependent and is association between long-term use of sildenafil and risk of ischaemic
responsible for the initiation of penile erection following sexual events.
58
Furthermore, these data have been confirmed with
stimulation.
43
Penile engorgement and shear stress activate a adminstration of the the chronic long-acting PDE5-i tadalafil in men
phosphoinositide 3 kinase/Akt signalling pathway, leading to further with CRFs even in the absence of ED.
59
Most notably, these drugs are
NO release by endothelial NO synthase (eNOS), which maintains the largely used for obstructive sleep apnoea (OSA)-induced ED. Because
erection. Noradrenaline and other sympathomimetic agents, on the NO promotes upper airway congestion, muscle relaxation and
other hand, cause smooth-muscle contraction and vasoconstriction, pulmonary vasodilation, it has been demonstrated that a single 50mg
hence penile detumescence and flaccidity.
44
A defect in this system dose of sildenafil at bedtime worsens respiratory and desaturation
results in ED. events;
60
thus, caution is mandatory in this group of patients.
The vascular endothelium of the penis has an important role in An emerging role in the management of ED seems to be the chronic
modulating vascular tone and blood flow into the penis in response to use of PDE5-i with a three-fold purpose:
humoral, neural and mechanical stimuli.
45
Endothelial cells lining the
internal surface of penile arteries and sinusoids of the cavernosal transitioning non-responders to on-demand therapy;
tissue affect the tone of adjacent smooth-muscle cells through the rehabilitation of erectile function, and thus endothelial rehabilitation;
release of relaxing factors (such as nitric oxide, prostanglandin-E
2
and and
C-type natriuretic peptide [CNP]) and vasoconstrictor agents (such as modification of hormonal patterns.
endothelin-1 and angiotensin-II).
46
In vasculogenic ED, the regulatory
role of the endothelium is hindered, resulting in decreased A pilot study by McMahon evaluated improvements in response rates
bioavailability of and/or responsiveness to vasodilatory mediators; this once non-responders to on-demand tadalafil were shifted to daily
may also be combined with increased levels of and/or sensitivity to dosing; he concluded that up to 30% of non-responders may be
vasoconstricting agents.
47
Even a subtle alteration in the balance ‘salvaged’ by daily dosing.
61
Additional data on endothelial response
between the factors favouring corporal relaxation and contributing to to chronic tadalafil were obtained in another pilot study in men with
contraction may result in ED.
48
Circulating endothelial progenitor cells ED and co-morbidities.
62
Altogether, the results suggest a beneficial
EUROPEAN UROLOGICAL REVIEW 81
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100