Apomorphine, systèmes dopaminergiques centraux et contrôle de l’érection

Relaxation of penile erectile tissue and increased blood flow in the penile arteries are the two basic local mechanisms of erection. Relaxation is elicited by several agents released by the nerve terminals of sacral parasympathetic pathways (nitric oxide [NO] and vasoactive intestinal polypeptide [VIP]) and endothelial cells. The increased activity of sacral parasympathetic pathways leads to erection. Other molecules (e.g. noradrenaline) released by the nerve endings of sympathetic pathways contract the penile tissue and arteries. A decrease in sympathetic pathway activity can therefore lead to erection. A better understanding of the local mechanisms of penile erection has led to the production of compounds designed to treat erectile dysfunction via a peripheral target. Such compounds are recognised as initiators if they elicit erectionper se or as conditioners if they potentiate a mechanism already present. The central control of penile erection plays an important role in the optimal functioning of the erectile process. Sympathetic and parasympathetic nerves to the penis originate in the spinal cord. In a sexually relevant context, it is likely that a shift of the balance between sympathetic and parasympathetic activities causes erection. This shift is controlled at the spinal cord level by information from the periphery (reflex pathways) and from supraspinal nuclei. Recent experiments have focused on supraspinal nuclei present in the brainstem, pons, and hypothalamus that directly project onto the sacral spinal cord. Pharmacological approaches have revealed an important role for central dopamine in the control of sexual behavior and the genital tract in males. Central dopamine can therefore regulate both sympathetic and parasympathetic pathways. Levels of DA and its metabolites increase in several brain structures during sexual activity. DA agonists, e.g. the D₁/D₂ agonist apomorphine, affect the sexual behavior, erection and ejaculation in a variety of animal species and in humans. Recent clinical investigations have revealed the benefits of the use of apomorphine in patients suffering from erectile dysfunction. Compounds acting centrally, such as apomorphine, can contribute to reorganize the activity of sympathetic and parasympathetic outflows leading to an appropriate recruitment of the autonomic pathways to the genital tract.     

Commande nerveuse peripherique de l’erection

Local mechanisms causing penile erection and detumescence result from variation in tone of vascular and trabecular smooth muscles and in a lesser part of striated muscles around the crura penis. All these events are neurally mediated. We reviewed human and animal data concerning the functional peripheral neuroanatorny of erection. General organization of peripheral nervous system is recalled. Somatic efferents of the pudendal nerve, originating in the sacral spinal cord, innervate the striated musculature of the perineum. Somatic afferents of the penis are conveyed by the dorsal penile nerve, a branch of the pudendal nerve. Afferent terminations project into the spinal cord, their role is discussed. Parasympathetic pathways are involved in the reflexogenic erections. Sympathetic pathways destinated to the erectile structures are more complex. They are issued from thoracolumbar spinal cord and travel through the hypogastric nerve or the lumbosacral sympathetic chain. Sympathetic fibers originating in the sacral sympathetic chain are present in both pelvic and pudendal nerves. Inhibitory role on the erection of the sympathetic nervous system is well-known, it could be also responsible for psychogenic erections. Parasympathetic and sympathetic fibees are mixed in the pelvic plexus and the cavernous nerves which are described. Relations between the four sets of peripheral nerves (somatic efferents, penile afferents, thoracolumbar sympathetic sacral parasympathetic and sympathetic) are discussed.     

Cardiovascular risk factors, erection disorders and endothelium dysfunction

Upon sexual stimulation, penile erection, occurring in response to the activation of pro-erectile autonomic pathways, is greatly dependent on adequate inflow of blood to the erectile tissue and requires coordinated arterial endothelium-dependent vasodilatation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. Nitric oxide (NO) is the principal peripheral pro-erectile neurotransmitter which is released by both non-adrenergic, non-cholinergic neurons and the sinusoidal endothelium to relax corporal smooth muscle through the cGMP pathway. Any factors modifying the basal corporal tone, the arterial inflow of blood to the corpora, the synthesis/release of neurogenic or endothelial NO are prime suspects for being involved in the pathophysiology of erectile dysfunction (ED). In fact, conditions associated with altered endothelial function, such as ageing, hypertension, hypercholesterolemia and diabetes, may, by changing the balance between contractant and relaxant factors, cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defect in smooth muscle relaxation and thus, ED. There is increasing evidence to suggest that ED is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. Recent results illustrating the importance of endothelial dysfunction in the pathophysiology of different forms of experimental ED are discussed. These pathways may represent new potential treatment targets.     

Mecanismes des phases de l’erection

The erectile phenomenon is scientifically described since the early 19 th century. During the last 10 years, new methodologies in experimental and clinical approaches added further details to our knowledge on the erectile process. Postaganglionic parasympathetic neurotransmitters as Acetyl-Choline, Vasoactive-Intestinal-Polypeptide or Calcitonine — Gene — Related — Peptide are identified; their information reaches the cavernous smooth muscle cells indirectly via the endothelium, mediated by Endothelium Derived Relaxing Factor. Sympathetic neurotransmitters as Norepinephrine seem to influence the smooth muscle cell directly, but recent studies suggest a role for endothelin, an endothelium derived contracting substance. The neurogenic information reaches the cavernous bodies probably via pace maker-cells that are connected with the other smooth muscle cells by gap junction. The balance between parasympathetic and sympathetic influences determines the state of erection.     

Melanocortinergic control of penile erection

Melanocortin receptors in the forebrain and spinal cord can be activated by endogenous or synthetic ligands to induce penile erection in rats and human subjects. To better understand how melanocortin circuits play a role in sex behavior, we review the contribution of melanocortin receptors and/or neurons in the hypothalamus, hindbrain, spinal cord and peripheral nerves to erectile function. New information regarding neuropeptides that mediate penile erection has extended our understanding of the central control of sex behavior, and melanocortin agonists may provide alternatives to existing treatment for highly prevalent problems including erectile dysfunction.     

eNOS function and dysfunction in the penis

Endothelial nitric oxide (NO) synthase (eNOS) has an indispensable role in the erectile response. In the penis, eNOS activity and endothelial NO bioavailability are regulated by multiple post-translational molecular mechanisms, such as eNOS phosphorylation, eNOS interaction with regulatory proteins and contractile pathways, and actions of reactive oxygen species (ROS). These mechanisms regulate eNOS-mediated responses under physiologic circumstances and provide various mechanisms whereby endothelial NO availability may be altered in states of vasculogenic erectile dysfunction (ED). In view of the recent advances in the field of eNOS function in the penis and its role in penile erection, the emphasis in this review is placed on the mechanisms regulating eNOS activity and its interaction with the RhoA/Rho-kinase pathway in the physiology of penile erection and the pathophysiology of ED.     

Age-related changes of the GABA-B receptor in the lumbar spinal cord of male rats and penile erection

Dorsal horn neurons of lumbosacral spinal cord innervate penile vasculature and regulate penile erection. GABAergic system is involved in the regulation of male sexual behavior. Because aging is frequently accompanied by a progressive decline in erectile function, the aim of this work was to examine age-related changes of the GABA-B receptor in the lumbar spinal cord. Sprague-Dawley rats of 10 and 21 days old, 3, 9 and 20 months old were used. GABA-B receptors were evaluated by quantitative autoradiography using [3H]-Baclofen as ligand with or without GABA (10 microM) to determine the non-specific binding. Ten days after birth a homogeneous neuroanatomical distribution pattern was found in the gray matter, however at 20-day-old adult distribution emerged becoming heterogeneous with the highest binding values at layers II-III and X. In dorsal layers a significant decrease was observed in 9-month-old rats while layer X showed an earlier decrease (21-day-old). GABA-B receptor affinity showed significant age-dependent and regional increase. The GABA-B receptor decrease in aged rats seems not to be related to this receptor inhibitory function in penile erection. Moreover the changes found in GABA-B receptor binding anatomical distribution may indicate its role in the morphological development of the lumbar spinal cord rather than in the decline of the erectile function.     

Contrôle neurologique de l’éjaculation

The brain control of the genital tract and sexual behaviour remains poorly understood. Clinical results and basic research indicate that the neural control of ejaculation depends on three levels of organization. The first level consists of peripheral autonomic and somatic nerves. Leaving the spinal cord, these nerves control the motility, secretions and blood supply of the genital tract, and contractions of perineal striated muscles. Their path in the abdominal cavity and the effects of their neuro-transmitters on peripheral tissues have been established. These nerves also convey sensory information from the genital tract to the spinal cord. The second level is represented by the spinal cord. The thoracolumbar (sympathetic), and sacral (parasympathetic and pudendal) segments of the cord contain the somata of autonomic and somatic motoneurons, whose axons run in the above nerves. These motoneurons are part of a spinal network that likely organizes the activity of the whole genital tract in a given context such as copulation. The role of the different spinal cord segments in the control of ejaculation is mainly inferred from observations of the deleterious effects of spinal cord injury in human patients. A small population of galaninergic positive neurons has recently been identified in the lumbar segments of the rat spinal cord that plays a major role in ejaculation (Truitt and Coolen, 2003). Selective lesion of this population abolishes in copula ejaculations, but spares erection. Finally, the third level of organization is represented by supraspinal nervous structures. The spinal cord receives direct excitatory and inhibitory information from the brainstem, pons and hypothalamus. In turn, these structures receive sensory information from the genital tract. However, their role in the control of ejaculation remains poorly investigated. Again, it is mainly inferred from the observation of the deleterious effects of pharmacological treatments on brain neurotransmission. Positron emission tomography has recently been used to observe brain areas whose activity is enhanced during ejaculation in humans (Holstege et al., 2003). In this study, several areas of the right side of the cortex and the cerebellum were activated. The targets of future clinical and basic research include: the neural basis of the required coordination between spinal autonomic and somatic nuclei that innervate the genital tract, the role of sensory information from the genital tract in the recruitment and coordination of spinal and supraspinal nuclei, and finally the integration of descending excitatory and inhibitory influences onto the spinal cord. Both the organization during development and the activation at puberty of the spinal neural network that controls the genital tract are dependent on androgens. Future research should identify the regulatory factors that, in response to the action of androgens, provide neurons with the possibility of building their connexions and selecting their neurotransmitters and receptors.     

Vasopressinergic and oxytocinergic pathways in the central nervous system

Recent data obtained by immunohistochemical and other anatomical tracing methods indicate that oxytocin and vasopressin pathways are much more complex and extensive than previously recognized. In addition to the classic magnocellular neurons that project from the supraoptic and paraventricular (PVN) nuclei to the posterior pituitary gland, generally smaller neurons in various parts of the PVN send vasopressin fibers to the portal capillary bed in the median eminence, or send oxytocin or vasopressin projections to other brain and spinal cord sites. In addition, vasopressin neurons are also found in the suprachiasmatic nucleus and may contribute to extrahypothalamic projection areas. Many of these axonal projections appear to form synapses with other neurons in forebrain, hindbrain, and spinal cord regions, which suggests roles for these peptides in neuronal communication. In brain stem and spinal cord, terminal fields include both parasympathetic and sympathetic regulatory centers. Oxytocin terminals are also found on large intracerebral arteries where the peptide may regulate cerebral blood flow.     

Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase.

BACKGROUND: Nitric oxide (NO) has been implicated as a mediator of penile erection, because the neuronal isoform of NO synthase (NOS) is localized to the penile innervation and NOS inhibitors selectively block erections. NO can also be formed by two other NOS isoforms derived from distinct genes, inducible NOS (iNOS) and endothelial NOS (eNOS). To clarify the source of NO in penile function, we have examined mice with targeted deletion of the nNOS gene (nNOS- mice). MATERIALS AND METHODS: Mating behavior, electrophysiologically induced penile erection, isolated erectile tissue isometric tension, and eNOS localization by immunohistochemistry and Western blot were performed on nNOS- mice and wild-type controls. RESULTS: Both intact animal penile erections and isolated erectile tissue function are maintained in nNOS mice, in agreement with demonstrated normal sexual behaviors, but is stereospecifically blocked by the NOS inhibitor, L-nitroarginine methyl ester (L-NAME). eNOS is abundantly present in endothelium of penile vasculature and sinusoidal endothelium within the corpora cavemosa, with levels that are significantly higher in nNOS- mice than in wild-type controls. CONCLUSIONS: eNOS mediates NO-dependent penile erection in nNOS- animals and normal penile erection. These data clarify the role of nitric oxide in penile erection and may have implications for therapeutic agents with selective effects on NOS isoforms.     

Penile erection: possible role for vasoactive intestinal polypeptide as a neurotransmitter.

Concentrations of vasoactive intestinal polypeptide were measured in blood drawn from the cavernous spaces of corpus cavernosum of the human penis during tumescence and erection, and the effect of injecting the polypeptide into the cavernous spaces was studied. A significant release of the polypeptide was shown during tumescence and erection. Injection of exogenous vasoactive intestinal polypeptide induced erection. These findings support the concept of vasoactive intestinal polypeptide as a neurotransmitter in penile erection and suggest that it might have a clinical use in patients suffering from erectile dysfunction.     

Characterization of p-chloroamphetamine-induced penile erection and ejaculation in anesthetized rats

Methodological shortcomings present in elicitation of male sexual reflexes in anesthetized animals. The present study has demonstrated, however, that intraperitoneal (i.p.) injection of p-chloroamphetamine (PCA), an indirect serotonin (5-HT) agonist, elicited simultaneously both penile erection and ejaculation in anesthetized rats. PCA (2.5-10.0 mg/kg, i.p.) caused an intermittent cluster of genital responses consisting of penile erection, glans erections, and penile cups, which closely resembles the response observed during the ex copula tests in unanesthetized rats. Measurements of intracavernous penile pressure showed that rhythmic changes in penile pressure were produced by PCA, together with glans erections and penile cups. PCA also caused a frequent ejaculations and the weighing of ejaculate accumulated over 0.5 hr was increased in a bell-shaped pattern, and the maximum effect was observed at 5.0 mg/kg. Pretreatment with p-chlorophenylalanine, a serotonin (5-HT)-synthesis inhibitor, significantly inhibited the expression of PCA-induced penile erection and ejaculation, while acute spinal transection at thoracic level did not affect the sexual responses. These results indicate that PCA-induced penile erection and ejaculation in anesthetized rats are mainly produced by the release of 5-HT, which is limited to the lower spinal cord and/or the peripheral sites. Furthermore, the sexual responses can be easily and reliably elicited by administration of PCA, which may be useful for the study of the mechanisms underlying male sexual functions.     

Proerectile effects of apomorphine in mice

Dopaminergic pathways play a key role in the central control of sexual behavior. Stimulation of central dopaminergic receptors elicits penile erection in a variety of species and has been proposed as a treatment option for erectile dysfunction in humans. The present study investigated the proerectile effects of apomorphine in mice. In this species, subcutaneous injection of apomorphine (range: 0.11-110 microg/kg sc) elicited three different behavioral responses: erection, erection-like responses and genital grooming. Proerectile effects of apomorphine were dose-dependent. More than 50% of mice displayed erections after administration of 1.1-11 microg/kg of apomorphine sc. Proerectile effects of apomorphine were blocked by haloperidol, a central D2 antagonist, but not by domperidone, a peripherally active dopaminergic antagonist. We conclude that apomorphine elicits erection in mice. This effect is dose-dependent and due to activation of central D2 dopaminergic receptors. The mouse model may be useful for pharmacological approaches designed to provide a better understanding of the central mechanisms of penile erection and sexual behavior.     

Pharmacologic treatment of erectile dysfunction

Penile erection occurs in response to cavernous smooth muscle relaxation, increased blood flow to the penis, and restriction of venous outflow. These events are regulated by a spinal reflex relying on visual, imaginative, and olfactory stimuli generated within the central nervous system (CNS) and on tactile stimuli to the penis. Drugs can have a facilitatory or inhibitory effect either on the nerves regulating this reflex or on the cavernous smooth muscle. A balance between contractile and relaxant factors governs flaccidity/rigidity within the penis. Drugs that raise cytosolic calcium either prevent or abort erection. Conversely, drugs that lower cytosolic calcium relax smooth muscle and can initiate penile erection. Efficacy in treating erectile dysfunction (ED) with phosphodiesterase inhibitors, especially type 5; alpha-adrenergic-receptor antagonists; and dopamine agonists exploit these mechanisms within the penis or CNS. Recent advances in our understanding of the pharmacology of penile erection are being translated into effective therapies for ED.     

DA-8159 has erectile potentials much longer than the plasma half-life in a conscious rabbit model

DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.     

Physiopathologie des troubles de l’érection chez l’homme paraplégique

Peripheral mechanisms responsible for penile erection are dependant upon a complex control by the nervous system, including peripheral nervous pathways, spinally mediated reflex loops and supraspinal nervous structures. Spinal cord injury is accompanied by a partial or a complete modification of these controls. In relation to the reflexogenic or psychogenic origin of penile erection, spinal cord injury does not cause the same effects. Reflexogenic erections sitll occur after spinal cord injury at a suprasacral level. After lesions at a level lower than the thoracolumbar spinal cord, tumescence following psychogenic stimulation has been observed. The hypotheses resulting from clinical and experimental observations and explaining the differences at the origin of these response are detailed. The recent developments in the neurophysiology of penile erection and the role of neurotransmitters allow a more analytical approach of the phenomenous and also bring new insights into possible compensatory pathways following spinal cord injury.     

The role of prostaglandins in the aetiology and treatment of erectile dysfunction.

Both animal and human penile tissue synthesize prostaglandins (PGs). Furthermore, intracavernous injection of certain PGs elicits erection in men with erectile dysfunction (ED). It is also well established that PGs are involved in the pathophysiology of atherosclerosis and diabetes mellitus (DM). Since atherosclerosis and DM are major risk factors for ED, it has been suggested that the disruption of PG synthesis in penile tissues and related vasculature may play a role in the pathogenesis of ED. In this review, we discuss the role of PGs in normal penile erection as well as on the pathophysiology and treatment.     

Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection

The objective of the present study was to evaluate whether vascular endothelial growth factor (VEGF)-induced penile erection is mediated by activation of endothelial nitric oxide synthase (eNOS) through its phosphorylation. We assessed the role of constitutively activated eNOS in VEGF-induced penile erection using wild-type (WT) and eNOS-knockout (eNOS(-/-)) mice with and without vasculogenic erectile dysfunction. Adult WT and eNOS(-/-) mice were subjected to sham operation or bilateral castration to induce vasculogenic erectile dysfunction. At the time of surgery, animals were injected intracavernosally with a replication-deficient adenovirus expressing human VEGF145 (10(9) particle units) or with empty virus (Ad.Null). After 7 days, erectile function was assessed in response to cavernous nerve electrical stimulation. Total and phosphorylated protein kinase B (Akt) as well as total and phosphorylated eNOS were quantitatively assessed in mice penes using Western immunoblot and immunohistochemistry. In intact WT mice, VEGF145 significantly increased erectile responses, and in WT mice after castration, it completely recovered penile erection. However, VEGF145 failed to increase erectile responses in intact eNOS(-/-) mice and only partially recovered erectile function in castrated eNOS(-/-) mice. In addition, VEGF145 significantly increased phosphorylation of eNOS at Serine 1177 by approximately 2-fold in penes of both intact and castrated WT mice. The data provide a molecular explanation for VEGF stimulatory effect on penile erection, which involves phosphorylated eNOS (Serine 1177) mediation.     

A biomechanical model of Peyronie's disease

Peyronie's disease is a pathological condition of the penis which is characterized by localized ossification of the tunica albuginea. A common symptom of the chronic stage is penile deformity during erection, which is frequently associated with pain and erectile dysfunction. A two-dimensional biomechanical model of the penis was applied to study the development of Peyronie’s disease by simulating the mechanical stress distribution which would result from the interaction of the ossified tunical tissue with other penile soft tissues. The model was solved by using commercial finite element software for a characteristic erectile pressure. The results demonstrate that Peyronie’s plaques may induce intensified stresses around the penile nerves and blood vessels, up to double those in the normal penis. These elevated stresses may cause a painful sensation of neural origin or ischemia in regions of compressed vascular tissue. Severe penile deformities have been shown to develop if Peyronie’s plaques develop only around one of the corpora cavernosa due to the non-homogeneous resistance of the tunica to expansion during erection. The present model can be clinically applied as an aid in the planning process of reconstructive surgery or insertion of a prosthesis.     

Androgenic maintenance of the erectile response in the rat.

Ongoing studies in this laboratory have used the castrated rat, with and without testosterone replacement, to investigate how androgens maintain the erectile response. The high intracavernosal pressures during erection depend on both an increase in the rate at which blood flows into the sinuses of the corpus cavernosum and a decrease in the rate at which blood flows out (veno-occlusion). Accordingly, our studies investigated androgenic regulation of the arterioles that regulate inflow and of the intracavernosal muscle that regulates the veno-occlusive mechanism controlling outflow. The results of these studies show that castration causes a decline in the rate of inflow and that androgen replacement reverses this decline. The decline in inflow in the castrated rats is also reversed by the administration of a nitric oxide donor drug, suggesting that the androgen may regulate inflow by increasing the synthesis of nitric oxide. Testosterone also appears to regulate outflow by controlling the sensitivity of the erectile mechanisms to norepinephrine, considered to be the principle vaso-constrictor neurotransmitter in the erectile response. Taken together, the results of these studies suggest that androgens control the erectile response by altering the synthesis and action of the neurotransmitters that normally alter the state of contraction and relaxation of smooth muscle in the erectile tissue.