I. Introduction

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Penile erection is the end result of smooth muscle relaxation in the penis. It is basically mediated by a spinal reflex and involves central nervous processing and integration of tactile, olfactory, auditory, and mental stimuli (Fig. 1). Many central nervous transmitters and transmitter systems participate in the regulation. This is also the case peripherally, where both autonomic and somatic efferents are involved. The different steps of neurotransmission, impulse propagation, and intracellular transduction of neural signals in penile smooth muscles are still only partly known. However, it is well established that the balance between contractant and relaxant factors controls the degree of tone of the penile vasculature and of the smooth muscle of the corpora cavernosa and determines the functional state of the penis: detumescence and flaccidity, tumescence and erection.

View larger version (14K): [in this window] [in a new window]   Fig. 1.   Centrally evoked erections occur in response to various stimuli. Together with the input from tactile stimulation, these stimuli are processed and integrated supraspinally (e.g., medial preoptic area, paraventricular nucleus) as well as spinally. The integrated signal reaches the penile erectile tissues and starts the erection.

The field of erectile function and dysfunction has undergone a rapid development during the last decade, and several pharmacological, physiological, and clinical aspects have been reviewed previously (e.g., Andersson, 1993; de Groat and Booth, 1993; Andersson and Wagner, 1995; Giuliano et al., 1995, 1997; Rampin et al., 1997; McKenna, 1999; Giuliano and Rampin, 2000a,b; Heaton, 2000a,b; Levy et al., 2000; Lue, 2000; Lue et al., 2000; Maggi et al., 2000; Steers, 2000; Moreland et al., 2001). The present review is an attempt to update the rapidly expanding information on some of the transmitters/modulators believed to be involved in the control of erectile mechanisms centrally and peripherally, and that are the basis for the currently used treatments of erectile dysfunction (ED²). ED is defined as the "inability to achieve or maintain an erection adequate for sexual satisfaction" (National Institutes of Health Consensus Statement, 1993).

	II. Central Regulation

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The central nervous regulation of erectile function involves both spinal and supraspinal pathways and mechanisms. Not unexpectedly, the central neurotransmission of penile erection is complex and only partly known. However, progress continues to be made to identify effectors involved in this function. Much of the knowledge gained in this area relates to morphological and pharmacological studies in experimental animal models (e.g., rodents, primates). In these models, neurochemical perturbations can be performed and responses monitored in a reasonably meaningful way. Results of such investigations must be interpreted with caution, because they encompass a wide range of types and modes of elicitation of sexual function (Sachs, 2000). Species differences, drug-dependent effects, and multiple drug sites of action must also be considered (McKenna, 1999; Giuliano and Rampin, 2000a,b; Steers, 2000).

1. 5-Hydroxytryptamine. It is well established that 5-hydroxytryptamine (5-HT; serotonin) neurons participate in the control of sexual behavior, both in humans and in animals. The amine has been implicated in the supraspinal as well as the spinal pharmacology of erectile function and involves both sympathetic, parasympathetic, and somatic outflow mechanisms. 5-HT pathways are considered to exert a general inhibitory effect on male sexual behavior (Bitran and Hull, 1987). However, these pathways may be inhibitory or facilitatory depending upon the action of the amine at different subtypes of 5-HT receptors located at different sites in the central nervous system (de Groat and Booth, 1993). The effects also seem to be species specific (Paredes et al., 2000).

2. Dopamine. Central dopaminergic neurons comprise an incertohypothalamic system with projections to the medial preoptic area (MPOA) and paraventricular nucleus (PVN) (Bjorklund et al., 1975). Dopaminergic neurons have also been identified, traveling from the caudal hypothalamus within the diencephalospinal dopamine pathway to innervate the lumbosacral spinal cord (Skagerberg et al., 1982; Skagerberg and Lindvall, 1985). Thus, dopamine may be expected to participate in the central regulation of both the autonomic and somatic components of the penile reflexes. Supporting this view, the dopamine receptor agonist apomorphine, administered systemically to male rats, was found to induce penile erection (Benassi-Benelli et al., 1979), simultaneously producing yawning and seminal emission. The effect of apomorphine was biphasic in the freely moving rat, with low doses facilitating and high doses inhibiting erection (Pehek et al., 1988a). These observations were subsequently extended to investigations involving low dose systemic administration of other dopamine agonists such as piribedil, lisuride, and quinelorane to rats and other animals (for review, see Andersson and Wagner, 1995). The effects of these agonists were attenuated by centrally, but not peripherally, acting dopamine receptor antagonists. Dopamine-receptor agonist-induced erections were abolished by castration in rodents, and testosterone replacement restored erectile function (Scaletta and Hull, 1990; Heaton and Varrin, 1994; Melis et al., 1994; Szczypka et al., 1998; Brien et al., 2000). Interestingly, rhesus monkeys did not respond to apomorphine, suggesting that there are basic differences between rats and rhesus monkeys in the systems mediating sexual behavior (Chambers and Phoenix, 1989). Whether the proerectile effects of apomorphine in humans are dependent on the androgenic state has not been clarified.

3. Noradrenaline. Evidence for noradrenergic mechanisms involved in the supraspinal mediation of penile erection is sparse. Noradrenergic neurons from the A5 region and from the locus coeruleus project to the nuclei in the spinal cord involved in erection (Giuliano and Rampin, 2000b). Available data suggest that increased noradrenergic activity stimulates, whereas decreased noradrenergic activity inhibits, sexual function (Bitran and Hull, 1987). Insights have almost exclusively drawn from experimental work involving the administration of agents that interact through -adrenoceptor (AR) pathways. Furthermore, accurate conclusions can only be drawn from work that suggests that central adrenergic receptors have been selectively stimulated. In rats given the ₂-AR agonist, clonidine, by direct injection into the MPOA, male sexual behavior was suppressed (Clark, 1988). The suppression was inhibited by pretreatment with selective ₂-AR antagonists (Clark et al., 1985), consistent with established facilitatory effects of these agents on erectile responses in rats (Clark et al., 1985). However, although several ₂-AR antagonists, most notably yohimbine, have been shown to increase sexual responses in rats, the relatively poor therapeutic efficacy of yohimbine in clinical use among men with ED (see below), casts doubt on the significance of central noradrenergic mechanisms in erectile function.

4. Excitatory Amino Acids. Excitatory amino acids appear to exert a role in penile erection. Thus, microinjections of L-glutamate into the MPOA elicited an increase in intracavernous pressure (Giuliano et al., 1996). Behavioral studies have shown that N-methyl-D-aspartate (NMDA) increases the number of penile erections when injected in the PVN (Melis et al., 1994a-c). NMDA, amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid, or trans-1-amino-1,3-cyclo-pentadicarboxylic acid, increased intracavernous pressures when injected into the PVN (Zahran et al., 2000). The effect of NMDA was prevented by i.c.v. administration of an oxytocin antagonist (Melis et al., 1994a). The NO synthase signal transduction pathway is considered to mediate the effect of NMDA, since the administration of NOS inhibitors into the PVN and i.c.v. blocked the NMDA effect (Argiolas, 1994; Melis et al., 1994c). Further support was provided by findings that NMDA injected into the PVN also leads to an increased concentration of NO metabolites in this region (Melis et al., 1997c). The mechanism for NOS activation would conceivably involve increased calcium influx through previously described calcium channel-coupled NMDA receptors (Snyder, 1992). However, the ineffectiveness of -conotoxin injected into the PVN in blocking erections induced by NMDA injected in this nucleus indicates that -conotoxin-sensitive N-type calcium channels are not responsible for this mediation (Succu et al., 1998).

5. -Aminobutyric Acid. Cumulative data resulting from investigations on the role of -aminobutyric acid (GABA) in penile erection indicate that this neurotransmitter may function as an inhibitory modulator in the autonomic and somatic reflex pathways involved in penile erection (de Groat and Booth, 1993). In male rats, high concentrations of GABA have been measured in the MPOA (Elekes et al., 1986), and GABAergic fibers and receptor sites have been localized to the sacral parasympathetic nucleus and bulbocavernosus motor nucleus (Bowery et al., 1987; Magoul et al., 1987). The injection of GABA_A agonists into the MPOA decreases (Fernandez-Guasti et al., 1986), whereas the injection of GABA_A antagonists into this region increases copulatory behavior of male rats (Fernandez-Guasti et al., 1985). Systemic administration or i.t. injection at the lumbosacral level of the GABA_B receptor agonist, baclofen, decreased the frequency of erections in rats (Bitran and Hull, 1987). Recent investigations showed that activation of GABA_A receptors in the PVN reduced apomorphine-, NMDA-, and oxytocin-induced penile erection and yawning in male rats (Rosaria Melis et al., 2000).

6. Oxytocin. Experiments using retrograde labeling have shown that oxytocin-containing neurons in the PVN project to spinal autonomic nuclei (Swanson and Kuypers, 1980; Sawchenko and Swanson, 1982). This was confirmed by Tang et al. (1999) using retrograde transneuronal tracing with rabies virus. They found that oxytocinergic spinal projections from the PVN are more likely to influence the sacral autonomic rather than the somatic outflow. Plasma oxytocin concentrations are known to be elevated in humans following sexual stimulation (Carmichael et al., 1987; Murphy et al., 1987).

7. Adrenocorticotropin and Related Peptides. Proteolytic cleavage of the precursor, pro-opiomelanocortin, gives rise to several peptides including adrenocorticotropic (ACTH) and the -melanocyte-stimulating hormones (-MSH), which both have been associated with erectile responses. After i.c.v. or hypothalamic periventricular injection into various animal models, ACTH and -MSH induce penile erection and ejaculation, grooming, stretching and yawning (Ferrari et al., 1963; Bertolini et al., 1975; Mains et al., 1977; Poggioli et al., 1998; Argiolas et al., 2000). These effects were shown to be androgen-dependent, since they were abolished by castration and could be fully restored by treating castrated animals with testosterone (Bertolini et al., 1975). Interestingly, ACTH and the ACTH-like peptides do not enhance social interaction, since during periods of sexual stimulation the animals did not seek to copulate with partners (Bertolini and Gessa, 1981).

8. Opioid Peptides. Endogenous opioid peptides have long been assumed to be involved in the regulation of male sexual responses, since sexual dysfunction has been observed clinically in men chronically using opiates (Cushman, 1972; Crowley and Simpson, 1978). Copulatory behavior in male rats is depressed experimentally with the systemic administration of morphine or other opioids (McIntosh et al., 1980; Pfaus and Gorzalka, 1987). -Endorphin injection into the cerebral ventricles or MPOA of male rats attenuates copulatory behavior (McIntosh et al., 1980; Hughes et al., 1987). Morphine, injected systemically or into the PVN of male rats, prevents penile erection induced by i.c.v. administration of oxytocin or subcutaneous dopamine (Melis et al., 1992b) or NMDA injected into the PVN (Melis et al., 1997a). However, similar application of a selective agonist of the -opioid receptor does not alter apomorphine- or oxytocin-induced erectile responses (Melis et al., 1997b). This evidence and the demonstration that the opiate antagonist naloxone administered systemically abolishes the central morphine preventative effect on erections in rats, have supported the belief that µ receptors in the PVN account for the morphine effect (Melis et al., 1997b). NO metabolite concentrations that are increased in the PVN following apomorphine, oxytocin, or NMDA local administration, become reduced following morphine administration into the PVN, indicating that the morphine effect depresses an NO-mediated erection induction mechanism at this level (Melis et al., 1997a,b; 1999). Current data support the hypothesis that µ-opioid receptor stimulation centrally prevents penile erection by inhibiting mechanisms that converge upon central oxytocinergic neurotransmission.

9. Acetylcholine. The role of acetylcholine (ACh) at central levels in the regulation of penile erection is mostly inferred from limited neuropharmacologic studies involving systemically and/or intracerebrally administered muscarinic agonists and antagonists and lesioning studies in the brain (Hull et al., 1988a,b; Maeda et al., 1990, 1994a,b). These studies have suggested that cholinergic mechanisms operating seemingly at the hippocampus and MPOA may have a regulatory role in erectile function.

10. Nitric Oxide. The role of NO in the central neuromediation of penile erection followed observations that the injection of NOS inhibitors i.c.v. or into the PVN prevented penile erectile responses induced by dopamine agonists, oxytocin, ACTH, 5-HT_2C agonists, or NMDA in rats (Melis and Argiolas, 1993, 1995, 1997; Melis et al., 1994c, 1997d; Poggioli et al., 1995; Fig. 2). The inhibitory effect of NOS inhibitors was not observed when these compounds were injected concomitantly with L-arginine, the substrate for NO.

View larger version (12K): [in this window] [in a new window]   Fig. 2.   In the rat, erectile responses evoked by various centrally acting transmitters/agents appear to be dependent on nitric oxide as well as androgens.

View larger version (142K): [in this window] [in a new window]   Fig. 3.   Nitric-oxide synthase within the paraventricular nucleus of the rat. Bar = 100 µm.

	III. Peripheral Regulation

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The different structures of the penis receive sympathetic, parasympathetic, somatic, and sensory innervation (Dail, 1993). The nerves contain different transmitters, and the nerve populations have been categorized as adrenergic, cholinergic, and nonadrenergic, noncholinergic (NANC). The latter nerves may contain not only neuropeptides, but also transmitters and transmitter/modulator-generating enzymes, such as NOS and heme oxygenases (HO). NANC transmitters/modulators may be found in adrenergic and cholinergic nerves (Lundberg, 1996), which should make it more meaningful to define nerve populations based on their transmitter content. Thus, it seems that one important population of nerves in the corpora cavernosa contain not only ACh, but also NOS, VIP, and neuropeptide Y (Hedlund et al., 1999, 2000a,b).

The nerves and endothelium of sinusoids and vessels in the penis produce and release transmitters and modulators, which interact in their control of the contractile state of the penile smooth muscles. In addition, they may also have other important functions, some of which are discussed below.

A. Contraction-Mediating Transmitters/Modulators

1. Noradrenaline. Penile arteries and veins, and cavernosal smooth muscle receive a rich adrenergic innervation, and it is generally accepted that the penis is kept in the flaccid state mainly via a tonic activity in these nerves. Released noradrenaline (NA) stimulates -ARs in the penile vasculature, contracting the helicine vessels, and in the corpus cavernosum, contracting the trabecular smooth muscle (Andersson and Wagner, 1995). NA stimulates not only - but also -ARs. However, in the human corpus cavernosum, receptor binding studies have revealed that the density of -ARs is almost 10 times higher than that of -ARs (Levin and Wein, 1980); the number of -AR binding sites per cell was estimated to 650,000 (Costa et al., 1993).

2. Endothelins. On the basis of functional, autoradiographical, and immunohistochemical studies, endothelins (ETs) have been suggested to contribute to the maintenance of corporal smooth muscle tone (Andersson and Wagner, 1995). Cultured endothelial cells from the human corpus cavernosum, but not nonendothelial cells, were found to express ET-1 mRNA (Saenz de Tejada et al., 1991a). ET-like immunoreactivity was observed in the sinusoidal and also in cavernous smooth muscle (Saenz de Tejada et al., 1991a). Binding sites for ET-1 were demonstrated both in the vasculature and trabecular tissue of the human corpus cavernosum by autoradiography (Holmquist et al., 1990, 1992a).

3. Angiotensins. During detumescence, there is an increase in the level of angiotensin II in cavernous blood compared with the levels in the flaccid state (Becker et al., 2000a). Human corpus cavernosum was found to produce and secrete physiologically relevant amounts of angiotensin II (Kifor et al., 1997). In vitro, angiotensin II contracted human (Becker et al., 2000a) and canine (Comiter et al., 1997) corpus cavernosum smooth muscle. In canine corpus cavernosum, the effect was increased by NOS inhibition (Comiter et al., 1997). Intracavernosal injection of angiotensin II caused contraction and terminated spontaneous erections in anesthetized dogs, whereas administration of losartan, selectively blocking angiotensin II receptors (subtype AT1), resulted in smooth muscle relaxation and erection (Kifor et al., 1997). Also in the rabbit corpus cavernosum, results were obtained suggesting involvement of the renin-angiotensin system in the regulation of corpus cavernosum smooth muscle tone and that the angiotensin II receptor subtype AT1 is important for mediation of the response (Park et al., 1997).

B. Relaxation-Mediating Transmitters/Modulators

1. Acetylcholine. Penile tissues from animals and humans receive a rich cholinergic innervation as shown by histochemistry (ACh esterase staining) or immunohistochemistry (Dail, 1993; Hedlund et al., 1999, 2000a,b). ACh released from these nerves acts on muscarinic receptors located on cavernosal smooth muscle and endothelium. Four muscarinic receptor subtypes (M₁-M₄) were shown to be expressed in human corpus cavernosum tissue (Traish et al., 1995c); the receptor on smooth muscle was suggested to be of the M₂ subtype (Toselli et al., 1994; Traish et al., 1995c), whereas that on the endothelium was of the M₃ subtype (Traish et al., 1995c).

2. Nitric Oxide and the Guanylyl Cyclase/cGMP Pathway. Synthesis of NO and the consequences of NO binding to soluble guanylyl cyclase is essential for the erectile process. There are several steps in the pathway (Fig. 4) that may be interesting targets for pharmacological intervention.

View larger version (42K): [in this window] [in a new window]   Fig. 4.   The L-arginine/nitric oxide/guanylate cyclase/cGMP pathway.