MECHANISMS OF ERECTION - continuation

MECHANISMS OF ERECTION 7

REGULATION OF INTRACAVERNOSAL SMOOTH MUSCLE CONTRACTILITY

Two principal mechanisms control the tone of penile smooth muscle cells:

(1) Neurogenic control, in which adrenergic, cholinergic and NANC fibers
all play a role; and

(2) Endothelial control, by neurotransmitter substances released by the
endothelium lining the helicine arteries and lacunarspaces.

ADRENERGIC VASOCONSTRICTOR MECHANISMS

Catecholamine-containing adrenergic nerves have been demonstrated in the
cavernosal and helicine arteries as well as incavernosal smooth muscle of
humans. Norepinephrine is released from dense-core vesicles of sympathetic nerve
terminals tointeract with a-adrenoceptors located on cavernosal smooth
muscle membranes (Figure 18). The main mediator of penilesmooth muscle
contraction appears to be the a1-adrenoceptor, all three subtypes (a1A, a1B and
a1D) of which have beendetected in the human corpus cavernosum. There is
some evidence that the (a1A subtype is functionally predominant.
Theinteraction of norepinephrine with the a1-adrenoceptor results in an
increase in intracellular calcium via a guanidinenucleotide-binding protein
(G protein) mechanism amplified through inositol phosphate (IP3) and
diacylglycerol (DAG)pathways (Figure 19). Sympathetic nerve activity is
therefore involved in both inducing detumescence and active maintenanceof
intracavernosal smooth muscle tone when the penis is in its normal flaccid
state. This is the basis for the clinicaleffectiveness of drugs such as
phentolamine (Vasomax®).

CHOLINERGIC MECHANISMS

Erection is initiated by increased neural activity in the parasympathetic
nerves originating from the S2-S4 spinal segments.The preganglionic
neurotransmitter is acetylcholine, but the postganglionic nerve endings
mediating vasodilation are NANC.Acetylcholine may, however, modulate
noradrenergic vasoconstrictor tone by acting upon prejunctional muscarinic
receptorson adjacent sympathetic nerve endings.

NON-ADRENERGIC NON-CHOLINERGIC MECHANISMS

The principal neurotransmitter mediating trabecular smooth muscle relaxation
is NANC. Originally, the 28 amino-acidpeptide VIP was put forward as the
candidate molecule, but it is now recognized that nitric oxide (NO) is the most
importantmolecular mediator of erection. NO synthase is present in the
pelvic nerves (Figure 20) and in the peripheral autonomic nerveendings
innervating the corpora (Figures 21 and 22). Release of NO leads to the
accumulation of cGMP within trabecularsmooth muscle cells and
hyperpolarization of the cell membrane. The resultant reduction in intracellular
calcium leads tosmooth muscle cell relaxation which, as already mentioned,
spreads rapidly from cell to cell through so-called gap
junctions.Vasodilatory responses are terminated by degradation of cGMP,
mainly by the enzyme PDE5.

ENDOTHELIAL MECHANISMS

Endothelium-derived relaxation factors were first described in the rabbit
aorta by Furchgott in 1980. A similar mechanism inwhich lacunar endothelium
releases a substance that relaxes trabecular smooth muscle also occurs in the
corpora. Again, themain relaxing factor is NO, produced by NO synthase,
which exerts an effect by stimulating the activity of guanylate
cyclase,resulting in an accumulation of cGMP and a decrease in cytoplasmic
free calcium.

Other molecules play a part in tumescence and detumescence, including
endothelin-1, which has a powerfulvasoconstrictory effect. In contrast, the
action of PGE1 is to relax trabecular smooth muscle. Other prostaglandins, such
asPGI2, may also play a role in preventing intracorporeal coagulation by
their antiplatelet aggregation activity.

HEMODYNAMICS OF ERECTION

Penile erection is a hemodynamic response to a combination of humoral,
neurogenic and local signals. Vasodilatory signalingcoincides with reduced
vasoconstrictor activity. The result is increased flow through the dilating
cavernosal arteries. At thesame time, the smooth muscle helicine arteries
and lacunar spaces relax, thereby allowing blood to fill the
intracorporealspace (Figures 23 and 24). Cavernosal filling compresses the
obliquely running subtunical venules against the sturdy tunicaalbuginea,
resulting in a hundred-fold increase in resistance to venous outflow (Figure
25). Intracavernosal blood pressuresoon rises to approximate that of
systolic blood pressure, thereby producing penile erection (Figure 26).