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mise à jour du
11 mars 2004
Brain Res Bull
1995; 36; 6; 527-531
Nitroglycerin-induced penile erection and yawning in male rats: mechanism of action in the brain
MR Melis, R Stancampiano, C Lai, A Argiolas
Bernard B. Brodie Department of Neuroscience, Cagliari, ltaly


Introduction : Penile erection and yawning are two different behavioral patterns that often occur concomitantly in physiological and experimental conditions. Among substances that induce these behavioral responses the best known are dopamine agonists, adrenocorticotropin (ACTH) and related peptides and N-methyl-D-aspartic acid (NMDA). Several lines of evidence suggest that the paraventricular nucleus of the hypothalamus (PVN) plays a key role in the expression of these behavioral responses.
Accordingly, dopamine agonists, oxytocin and NMDA induce penile erection and yawning when injected in this hypothalamic nucleus. The ability of nitric oxide (NO) synthase inhibitors such as N-nitro-L-arginine methyl ester and N-monomethyl-L-arginine when injected in the PVN to prevent penile erection and yawning induced not only by apomorphine and oxytocin, but also by NMDA, raises the possibility that the novel discovered neurotransmitter/ neuromodulator NO plays a key role in the control ofthese behavioral responses at level ofthe PVN. In agreement with this hypothesis, we show here that nitroglycerin, a drug that contains NO used in humans in the treatment of angina pectoris for its potent vasodilator effect induces penile erection and yawning when injected into a lateral ventricle (ICV) or into the PVN of male rats. The effect of methylene blue or hemoglobin, that antagonize NO activity, d(CH,),5Tyr(Me)2 -Orn'-vasotocin, that blocks oxytocinergic receptors and haloperidol, a classical dopamine receptor antagonist, on nitroglycerin responses is also reported. [...]
Discussion : The present results show that the ICV administration of nitroglycerin, an organic nitrate well known for its potent and rapid vasodilator effect, clinically used for relieving anginal pain and as a hypotensive agent, induces penile erection and yawning in male rats.
One of the brain areas in which the drug acts to induce these behavioral responses is the PVN, which is involved in the control of these responses induced by other substances, such as NMDA, dopaminergic agonists and oxytocin. The mechanism by means of which nitroglycerin induces penile erection and yawning by acting in the PVN is unknown and only some speculation is possible at prescrit.
One possibility is that nitroglycerin acts after being internalized in target neurons where is biotransformed in S-nitroso-thiol compounds that produce NO thereby activating enzymes such as soluble guanylate cyclase, as already suggested for explaining its vasodilator properties in vascular beds. Accordingly, ICV methylene blue, an inhibitor of guanylate cyclase in several tissues, prevents nitroglycerin responses.
However, the involvement of guanylate cyclase in these nitroglycerininduced behavioral responses must be considered with caution, because both methylene blue, despite its ability to inhibit guanylate cyclase in several tissues, and hernoglobin, which would act as a NO scavenger are ineffective when injected in the PVN. Although the inability of hemoglobin to prevent nitroglycerin responses when injected directly in the PVN can be explained by the inability of this compound to cross cellular membranes these findings raise the possibility that nitroglycerin induces penile erection and yawning in this area by a mechanism not related to the stimulation of guanylate cyclase, that is, by a cyclic guanosine 3',5'-monophosphate-indepenilent mechanism.
Accordingly, if one assumes that nitroglycerin responses are mediated by NO produced in nitroglycerin target neurons, NO might interact with numerous other enzymes that, like guanylate cyclase, bind metal ions such as iron, as described for instance in fibroblasts. Whatever mechanism nitroglycerin-derived NO activates in the PVN to induce penile erection and yawning, the inability of hemoglobin to prevent nitroglycerin responses suggests that NO is not released out from the neurons where it is formed but is acting intracellularly. This implies a local second messengerrole of NO in the PVN. This hypothesis iscomplicated by the finding that ICV methylene blue prevents nitroglycerin responses, which favours a neurotransmitter role of NO in distant brain areas from the PVN rather than a local second messenger role.
A possible unifying explanation for such discrepancy is that NO activates those neurons where it is fonned, releasing in turn a neurotransmitter(s) that activates a methylene blue-sensitive guanylate cyclase in brain areas distant from the PVN. Although only the identification of the site(s) where methylene blue acts to prevent nitroglycerin-induced responses will clarify this point, this hypothesis is supported by the ability of the potent oxytocin receptor antagonist d(CH,)_5Tyr(Me )2 -Orn'-vasotocin, given ICV but not in the PVN, to prevent nitroglycerin-induced penile erection and yawning. In tact, this finding suggests that nitroglycerin induces these behavioral responses by activating central oxytocinergic transmission, as already suggested for apomorphine-, oxytocin- and NMDA-induced penile erection and yawning. The finding raises also the possibility that nitroglycerin-derived NO is produced in the cell bodies of oxytocinergic neurons originating in the PVN and projecting to extrahypothalamic brain areas, and provides further support to the hypothesis that PVN NO is involved in the control of penile erection and yawning.
Indeed, a) NO-synthase inhibitors prevent apomorphine-, oxytocin- and NMDA-induced penile erection and yawning by acting in the PVN; b) the PVN is one of the richest brain areas containing NO-synthase; and C) NO-synthase is localized in PVN oxytocinergic neurons.
Conversely, the inability of the dopamine receptor antagomist haloperidol to prevent nitroglycerin responses is in line with the hypothesis that dopamine acts in the PVN to induce penile erec- tion and yawning by activating oxytocinergic transmission, by acting therefore at sites located before oxytocin. The finding rules out also the possibility that nitroglycerin-induced penile erection and yawning are mediated by the activation of central dopaminergic transmission.
The interpretation given above of the present results is based on two main assumptions. The first is the existence of central oxytocinergic pathways originating in the PVN that are involved in the control of penile erection and yawning, whose activity can be modulated by several neurotransmitters, including oxytocin itself. However the possibility that nitroglycerin induces these behavioral responses by activating oxytocinergic transmission by a mechanism different from that postulated above cannot be rule out by the present results. Parallel or alternative neuronal pathways might be involved as well. For instance it was recently shown that the addition of the NO precursor L-arginine or a N - synthase inhibitor to the perfusion medium of a microdialysis probe modulates in an opposite manner dopamine and serotonin release in the medial preoptic area. This area is very close to the PVN and, most important, contains NO-synthase and plays a key role in the control of male sexual behavior, including penile erection and seminal emission.

The second assumption, that needs further experimental verification, is that nitroglycerin is acting in the central nervous system exclusively as a NO donor, as found in vascular smooth muscles, including the corpus cavernosum, since several reports on the use of nitroglycerin as an effective topical ointment for the treatment of erectile impotence have been published. Our results show that nitroglycerin can act also in the central nervous system to induce penile erection. This provides further evidence for a physiological role of NO in the control of this primary male sexual function not only in the corpus cavernosum, but also in the central nervous system.