Erectile Function

and modulators

Table10.1. Pro-andanti-erectileendogenousneurotransmitters

Erection

requires

relaxation of

penile

smooth

Central

Periphery

muscle to allow accumulation of blood within the

nervous

(penis)

system

corpora cavernosa and hence tumescence. The

smooth muscle relaxation is brought about by a

Pro-erectile transmitters and mediators

range of mediators, which is at least partly regu-

no

+

+

lated by the CNS. Some endogenous mediators

acetylcholine

Unclear

+

have complex effects on erectile function as

reviewed

comprehensively elsewhere.25

Never-

dopamine

+

−

theless, these mediators can roughly be divided

Excitatory amino acids

+

−

into proand anti-erectile agents as well as into

centrally

and

peripherally

acting

agents

oxytocin

+

−

(Table 10.1). The

most important pro-erectile

adrenocorticotropin

+

−

stimulus is NO, which has both central and, per-

haps more importantly, peripheral effects. Other

Prostaglandin E2

−

+

centrally acting pro-erectile stimuli include dop-

anti-erectile transmitters and mediators

amine, excitatory amino acids, oxytocin, adreno-

corticotropin,and related peptides,whereas other

noradrenaline

+

+

peripherally acting pro-erectile stimuli include

serotonin

+

−

acetylcholine and prostaglandin E . Of note the

pro-erectile effects of at least some2of these stim-

g-amino butyric acid

+

−

uli depend on the presence of androgens. The

opioid peptides

+

−

most relevant endogenous anti-erectile mediator

Endothelins

−

+

probably is noradrenaline, acting both centrally

and, perhaps even more importantly, peripherally

angiotensin ii

−

+

by stimulating a1-adrenoceptors. Other centrally

atP and adenosine

−

+

acting anti-erectile transmitters and mediators

include serotonin, g-amino butyric acid, and opi-

note that this table provides a rather simplified description and that

oid peptides, whereas peripherally acting anti-

some of the agents listed have complex effects

erectile mediators include the endothelins,

+ works at the indicated level;− does not work at the indicated level

angiotensin II,and ATP,the latter,possibly in part,

or insufficient evidence. for details see text or andersson.25

working via its metabolite adenosine.

While several neurotransmitters are involved

in the central promotion of erectile function,only

dopamine receptors have evolved into a potential

the formation of cyclic GMP (cGMP). This may

drug target. The pro-erectile mechanisms of dop-

lead to the opening of K+ channels, which cause

amine are largely mediated by D2-like receptors.

cellular hyperpolarization and hence smooth

Apomorphine, an agonist of all dopamine recep-

muscle relaxation. The action of cGMP is termi-

tor subtypes, has consistently shown pro-erectile

nated by phosphodiesterases (PDEs), specifi-

effects in animal models, although in some cases

cally PDE5. Accordingly, PDE5 inhibitors have

this was limited to low doses, whereas high doses

become the most effective form of medical treat-

had anti-erectile effects. Apomorphine has also

ment of erectile dysfunction.26 However, it has

shown some degree of efficacy in clinical studies

to be noted that PDE5 inhibition is a mechanism

in patients with ED ,but the extent of these effects

of amplifying endogenous signals of cGMP,

as well as apomorphine-induced nausea have

implying that it works only in the presence of

limited its clinical use.26,27

exogenous pro-erectile stimuli and an at least

NO, which is formed by NO synthases in

partly intact innervation of the penis still able to

nerves and in the endothelium of the penis, has

release at least some amount of NO.

pro-erectile effects both at the central and

An alternative mechanism to induce penile

peripheral level. At least in the periphery NO

smooth muscle relaxation is stimulation of

acts by diffusing into smooth muscle cells and

prostanoid receptors by prostaglandin E2 or its

activating a soluble guanylyl cyclase to promote

analogs such as alprostacil.26

This leads to