There is a relative paucity of animal
pharmacological studies on sildenafil, which has
been recently introduced for the treatment of
human impotence. Apart from its ability to
improve erectile function in man, an effect that
has been attributed to a selective inhibition of
phosphodiesterase (PDE) type 5, little is known
about other activities of this compound.
Furthennore, its possible interference with
co-administered drugs has been almost excluvely
restricted to cardiovascular functions. However,
in view of the extremely potent sexual effects
which are elicited after oral administration, a
selectivity of action on the target organ and/or
on molecular mechanisms is improbable, for it
would represent an unique pharmacological
phenomenon.
Although sildenafil-induced sexual
stimulation has been ascribed to local action,
more recently it has been demonstrated that
intrathecal injection of the drug produces a
physiological profile that is qualitatively
similar to that observed clinically after
systemic administration. Sildenafil erectogenic
effect is mediated by a specific increase in
cyclic guanosilmonophosphate (cGMP)
accumulation, consistent with the known activity
of the drug as a potent inhibitor of cGMP PDE.
This effect may be linked to nitric oxide
(NO)-mediated relaxation pathways in the corpus
cavernosum, for numerous studies have documented
that NO released from peripheral nitrergic
nerves plays a prominent role in ensuring
corporal smooth muscle relaxation.
However, NO functions as a diffusible
messenger in the CNS as well, and recent data
indicate that central modulation of the NO/cGMP
pathway affects erectile capacity . Central
activity of sildenafil can also be inferred from
its ability to modify human memory tasks and
facilitate longterm retention of an inhibitory
avoidance response in mice.
The first aim of the present work was to
assess the behavioural response to sildenafil in
male rats, with particular attention to certain
aspects of sexuality. As it has been
demonstrated that central dopamine (DA) is the
main neurotransmitter of sexual behaviour, and
its release is modulated by NO, further
experiments were performed to investigate the
effects exerted by systemic sildenafil on the
typical signs centrally evoked by DA D2/D3
agonists, namely, penile erection (PE),
stretching-yawning (SY), sedation and
stereotyped behaviour (SB).
Discussion
The data obtained in Experiment 1 clearly
show that sildenafil exerts a stimulant effect
on the sexual behaviour of SE male rats, even in
the absence of the female. Surprisingly, the
phenomenon was not apparent in SI animals. A
plausible hypothesis for this intriguing result
concerns the experimental environment, i.e. the
observation cages where SE rats had previously
performed several mating tests, although a
considerable interval had elapsed between the
two events. It is well known that the specific
conditions, under which an animal is exposed to
a chug and/or a natural incentive, contribute to
the development of "sensitization" that results
in a subsequent greater response. The neural
processes underlying such envirenment-linked
"enhanced responsiveness" have been the subject
of intensive studies on psychostimulants and DA
agonists, leading to DA as the main candidate
for the mechanisms of sensitisation.
Therefore, sildenafil might exert a
facilitatory role on sexual responses further
augmenting the DA stimulation provoked by the
expectation of copulatory behaviour in SE rats.
The involvement of central DA in the effects of
sildenaiil was confirmed in Experiment 2, for
the drug, at 1 mg/kg, potentiated PE and SY,
typically induced by the two DA D2/D3 agonists.
B-HT 920 has been previously described as a
selective pre-synaptic DA D2 receptor agonist
and it is known to inhibit DA synthesis and
release.
More recently, its affinity for DA D3
receptors has been demonstrated. It potently
increases PE, SY and sedation over a large
dose-range and never elicits SB in normal
animals. 7-OH-DPAT has been shown to display
high affinity for the DA D3 receptors but,
despite this proposed selectivity, it does not
differ from a behavioural point of view from
other DA agonists previously reputed to be
specific for DA D2 receptors. As already stated,
7-OHDPAT, from 0.8 mg/kg upwards, induces SB of
low intensity, thus diminishing sedation.
This same effect was obtained when
sildenafil, at 10 mg/kg, was associated to
7-OH-DPAT at 0.1 mg/kg.The influence of the
manipulation of central DA transmission on human
and animal erectile responses is well
documented. It has been reported that sildenafil
increases and prolongs apomorphine-evoked
intracavernous pressure in the rat, thus
suggesting a possible combination of the two
drugs in the management of erectile
dysfunctions. While the enhancement of 7-OH-DPAT
and B-HT 920-induced PE might be attributed to
the concomitant peripheral and central
activities of sildenafil and the DA D2 agonists,
respectively, the unexpected increase or
decrease in SY, the reversal of sedation and the
appearance of SB strongly suggest a central
action of sildenafil, too. As previously stated,
sildenafil affects NO/ cGMP levels, and
modulation of a variety of CNS functions has
been ascribed to these pathways.
In particular, recent experimental evidence
has shown that NO plays a key role in the
expression of PE and SY. In fact, their
induction by DA agonists, oxytocin and
adrenocorticotropin hormone was found to be
associated with stimulation of the NO-synthase
activity in the cell bodies of the
paraventricular nucleus of the
hypothalamus.
Conclusion
Our data show that sildenafil modulates some
central DA-mediated behavioural effects, thus
suggesting that there may be a case for its use
in combination with DA agonists in the
management not only of erectile failure but also
of other pathologies linked to a dysfunction in
DA transmission.
