Local organ procurements are associated with fewer renal transplant complications.
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Analysis of Variance↗
Biomedical subjects
F Giuliano
Publications and source records attributed to F Giuliano.
Surgical injuries occurring during kidney procurement performed by a renal transplantation team.
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Female↗
alpha(2a) and alpha(2c) adrenoceptors on spinal neurons controlling penile erection.
The thoracolumbar and lumbosacral spinal cord contain respectively sympathetic and parasympathetic preganglionic neurons that supply the organs of the pelvis including the penis. These neurons are influenced by supraspinal information and receive aminergic projections from the brainstem. The presence of the alpha(1)- and alpha(2)-adrenoceptor subtypes has been demonstrated in the rat spinal cord. In this species, we looked for the presence of alpha(2a)- and alpha(2c)-adrenoceptor subtypes in the sympathetic and parasympathetic preganglionic neurons controlling erection. In adult male rats, transsynaptic axonal transport of pseudorabies virus injected into the penis was combined with immunohistochemistry against alpha(2a)- and alpha(2c)-adrenoceptor subtypes. At 4 days survival time, neurons infected with the pseudorabies virus were solely found in the intermediolateral cell column and dorsal gray commissure of segment T12-L2 and in the intermediolateral cell column of segment L6-S1. Neurons and fibers immunoreactive for alpha(2a)- and alpha(2c)-adrenoceptor subtypes were mainly present in the intermediolateral cell column, the dorsal gray commissure and the ventral horn of the T12-L2 and L5-S1 spinal cord, the dorsal horn displayed only immunoreactive fibers. Pseudorabies virus-infected neurons in the autonomic nuclei were both immunoreactive for alpha(2a)- and alpha(2c)-adrenoceptor subtypes and closely apposed by alpha(2a)- and alpha(2c)-immunoreactive fibers. The results suggest an intraspinal modulation of the noradrenergic and adrenergic control of the autonomic outflow to the penis by pre- and postsynaptic alpha(2) adrenoceptors.
Animals↗
Apomorphine SL (Uprima): preclinical and clinical experiences learned from the first central nervous system-acting ED drug.
An exclusive central site of action for the proerectile effect of apomorphine, including not only the brain but also the spinal cord, is supported by extensive experimental data. Assuming that the mechanisms of action of apomorphine are similar in humans and animal models, its use for the treatment of erectile dysfunction (ED) validates the emerging idea that erectile response could be enhanced by acting directly within the central nervous system (CNS). It also emphasized the key role of the dopaminergic system in the control of erection. As exemplified with the clinical development of apomorphine, targeting the CNS does not rule out the occurrence of undesirable side effects. Because the rare event of syncope induced by apomorphine is not well understood, further research should be conducted to explore its possible mechanisms. In clinical practice, however, approved doses of apomorphine SL are well tolerated. It is noteworthy that no modification of sexual desire was observed with apomorphine. Indeed, drugs acting within the CNS may more likely interact with sexual desire than peripherally acting drugs, and care should be taken to assess this point in the future. Although our knowledge of the control of penile erection by the CNS is restricted, there are many potential sites for CNS-acting ED drugs. New centrally acting therapy for ED should concentrate on receptor targets more specific to erectile command. Clinical efficacy of new centrally-acting compounds will assess the well-founded purpose of this rationalization.
Animals↗
Catecholaminergic projections onto spinal neurons destined to the pelvis including the penis in rat.
In rats, the spinal cord contains proerectile autonomic motoneurons destined to the penile tissue and its vasculature, and somatic motoneurons destined to the perineal striated muscles. It receives dense catecholaminergic projections issued from the medulla and pons. In adult male rats, we evidenced the catecholaminergic innervation of spinal neurons controlling lower urogenital tissues and regulating penile erection. We combined retrograde tracing techniques and immunohistochemistry against synthetic enzymes of noradrenaline and adrenaline. Both sympathetic and parasympathetic preganglionic neurons, labeled from the major pelvic ganglion or from the corpus cavernosum, were apposed by catecholaminergic immunoreactive fibers. Motoneurons, retrogradely labeled from the striated muscles, were also apposed by catecholaminergic immunoreactive fibers. Synapses between these motoneurons and fibers were suggested by confocal microscopy and confirmed by electron microscopy in some cases. The results reinforce the hypothesis of a catecholaminergic control of autonomic and somatic motoneurons regulating penile erection at the spinal level.
Animals↗
Selegiline enhances erectile activity induced by dopamine injection in the paraventricular nucleus of the hypothalamus in anesthetized rats.
Apomorphine delivered in the paraventricular nucleus of the hypothalamus (PVN) induces penile erection in rats, suggesting a role of dopaminergic projection to the PVN in the control of penile erection. We assessed whether the selective inhibitor of monoamine oxidase B, selegiline, could enhance the erectile activity induced by dopamine delivery in the PVN. Intracavernous and blood pressure (ICP and BP) were monitored in anesthetized rats to quantify ICP rises (number and percentage of ICP maximum/mean BP (ICPmax/BP x 100)) elicited by 10 micro g dopamine injection in the PVN after saline or 3 mg/kg i.v. selegiline (8 rats per group). The number of ICP rises (mean+/-s.d.: 4.5+/-2.9 vs 1.4+/-1.9; P=0.017) and their ICPmax/BP x 100 (49+/-8% vs 34+/-9%; P=0.015) were significantly greater upon dopamine injection in the PVN than upon vehicle. Compared to saline i.v., 3 mg/kg selegiline pretreatment significantly increased the number of ICP rises induced by dopamine injection in the PVN (9.4+/-2.6 vs 4.5+/-2.9; P<0.001), without affecting their amplitude. This suggests that drugs potentiating dopaminergic responses in the central nervous system might enhance proerectile commands of supraspinal origin.
Animals↗
Evidence for a direct projection from the paraventricular nucleus of the hypothalamus to putative serotoninergic neurons of the nucleus paragigantocellularis involved in the control of erection in rats.
In the male rat, serotoninergic neurons of the ventrolateral medulla send direct projections onto spinal preganglionic neurons that innervate the penis. The role of the paraventricular nucleus of the hypothalamus in the control of penile erection is well recognized. Our aim was to demonstrate anatomical relation between paraventricular neurons and medullary serotoninergic neurons innervating the penis. In adult male rats, stereotaxic iontophoretic injections of Phaseolus vulgaris leuco-agglutinin were performed in the paraventricular nucleus. Neurons in the ventrolateral medulla were retrogradely labelled using transneuronal retrograde transport of pseudorabies virus injected in the corpus cavernosum. Sections of the ventro-lateral medulla were processed for double immunofluorescence to reveal both Phaseolus vulgaris leuco-agglutinin and pseudorabies virus using specific antibodies. Sections were also processed for the simultaneous detection of pseudorabies virus and serotonin. Pseudorabies virus-infected neurons in the ventrolateral medulla were present in the nucleus paragigantocellularis, reticular formation of the medulla, raphe pallidus and raphe magnus. In the nucleus paragigantocellularis, all pseudorabies virus-infected-neurons were immunoreactive for serotonin. Some of them received Phaseolus vulgaris leuco-agglutinin-labelled varicose fibres that ran along the soma of pseudorabies virus-infected neurons. Confocal microscopy suggested the presence of several close appositions between them, which were demonstrated using three-dimensional reconstruction of serial optical sections. Our results show that paraventricular neurons send direct projections in the nucleus paragigantocellularis onto neurons that innervate the penis. They suggest a possible role of the paraventricular nucleus in penile erection through the control of descending serotoninergic raphe-spinal neurons. The neurotransmitter used in this pathway remains to be determined.
Animals↗
Cyclooxygenase selectivity of non-steroid anti-inflammatory drugs in humans: ex vivo evaluation.
We have recently described a novel assay to assess ex vivo the activity and selectivity on cyclooxygenase-1 and -2 (EC 1.14.99.1) of non-steroid anti-inflammatory drugs (NSAID) administered to rats [Br. J. Pharmacol. 126 (1999) 1824.]. Here, we have extended these studies to humans. Healthy male volunteers were given orally one of the following drugs (mg) for 5 days: etodolac (200 or 400 b.i.d.), meloxicam (7.5 or 15 q.d.), nimesulide (100 or 200 b.i.d.), nabumetone (500 or 1000 b.i.d.) or naproxen (500 b.i.d.). Blood samples were withdrawn from the volunteers before and up to 24 h after the last dose. Plasma obtained from the blood was tested for its ability to inhibit prostanoid formation in interleukin-1beta-treated A549 cells (cyclooxygenase-2 system) and human washed platelets (cyclooxygenase-1 system). Plasma from etodolac-treated subjects demonstrated a slight selectivity towards the inhibition of cyclooxygenase-2. This effect was more prominent in plasma from subjects receiving meloxicam or nimesulide. Plasma from nabumetone-treated subjects showed no or little selectivity towards cyclooxygenase-1 depending on the dose of drug administered, while plasma taken from subjects receiving naproxen was more active at inhibiting cyclooxygenase-1 than cyclooxygenase-2. In conclusion, we have demonstrated that this assay can be used to assess ex vivo the relative activity against cyclooxygenase-1 and cyclooxygenase-2 of NSAIDs consumed by human volunteers. It is to be hoped that data from such systems will aid in our understanding of the relationships between the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by NSAIDs and their reported efficacies and (gastrointestinal) toxicities.
Adolescent↗
Brain control of penile erection.
The spinal cord contains a network that controls erection. This network can be activated by information from the periphery and by supraspinal nuclei. Besides anatomical studies that have detailed central pathways putatively involved in the central process of proerectile information, functional approaches have focused on pharmacological manipulations of specific systems, e.g. central dopaminergic pathways, leading to clinical perspectives in the treatment of erectile dysfunction. The present review focuses on some aspects of the recent research in the field.
Brain↗
Central nervous system agents in the treatment of erectile dysfunction: how do they work?
Drugs acting within the central nervous system (CNS) that reduce the sympathetic antierectile flow and enhance the parasympathetic proerectile flow to the penis may restore penile erection in cases of erectile dysfunction of both psychogenic and organic origin. The best characterized of such drugs is the dopaminergic agonist apomorphine, which acts on the hypothalamus and, perhaps, the autonomic nuclei in the spinal cord. Other drugs that target the CNS and have been registered and tested are the a(2)-adrenoceptor antagonists yohimbine and delequamine, the alpha-melanocyte-stimulating hormone agonist melanotan II, and the serotonin reuptake inhibitor trazodone. Androgens also may influence sexual behavior by acting within the CNS, notably by modifying the neurotransmitter system targeted by these drugs. Our knowledge of the mode of action of CNS drugs comes mainly from experiments on rodents. Consequently, explanations regarding the way they work in humans are only speculative.
Animals↗
Oral drug therapy for erectile dysfunction.
Oral drugs are a well-established, first-line therapy for erectile dysfunction. As a result of the success of sildenafil, a plethora of new drugs for erectile dysfunction are on the horizon. Apomorphine and IC351 are in late phase III development. Vardenafil (Bayer, New Haven, CT), a PDE5 inhibitor, and the combination of yohimbine and L-arginine (NitroMed, Boston, MA) are in early phase III development. Early clinical and preclinical studies are investigating new phosphodiesterase inhibitors, cyclic AMP activators, alpha-adrenergic antagonists, dopamine agonists, melanocyte-stimulating hormone, potassium channel modulators, endothelin antagonists, and new nitric oxide donors. The future is bright for this infant field of sexual pharmacotherapy.
3',5'-Cyclic-GMP Phosphodiesterases↗
Efficacy results and quality-of-life measures in men receiving sildenafil citrate for the treatment of erectile dysfunction.
The aim of the present study was to evaluate the efficacy of sildenafil citrate and its effects on quality of life (QoL) in men with erectile dysfunction (ED) using data from three multicenter, double-blind, placebo-controlled clinical trials. Efficacy was evaluated using a global efficacy question (improvement of erections) and questions from the International Index of Erectile Function (IIEF) addressing the ability to achieve and maintain erections. QoL directly related to ED was evaluated using questions 13 and 14 of the IIEF, several psychometric instruments, and a questionnaire addressing men's concerns about their erection problems. Seventy-nine [corrected] percent of patients receiving sildenafil reported improved erections compared with 23% of patients receiving placebo (p < 0.0001); also reported were improvements in the ability to achieve and maintain erections with sildenafil but not with placebo (p < 0.0001). Improvements were also seen for other aspects of sexual function (overall satisfaction with sex life, sexual relationships with partners, concerns about erectile problems, p < 0.0001) and general mental health (well-being, self-control, satisfaction with relationship, health relative to 1 year ago, mental health; p < or = 0.05) following treatment with sildenafil. Thus, treatment of ED with sildenafil can significantly improve key QoL parameters related to sexual dysfunction and general mental health.
Adult↗
Spinal proerectile effect of apomorphine in the anesthetized rat.
Considering the presence of dopaminergic receptors in the lumbosacral spinal cord, we tested whether apomorphine could exert a proerectile effect by acting at the spinal level. Intracavernous (ICP) and blood pressures (BP) were measured in anesthetized rats. ICP rises were quantified (duration, percentage of ICPmaximum/meanBP (ICPmax/BPx100), area under ICP curve (AUC/BP) and sum of AUC/BP after intravenous (i.v.) and intrathecal (i.t.) injections of apomorphine alone or in presence of i.t. oxytocin (10 ng). Both 10 and 30 microg i.v. apomorphine dosings elicited erectile events evidenced by ICP rises. Upon the 30 microg i.v. injection, duration of ICP rises were increased from 25+/-10 to 69+/-18 s (P<0.001), ICPmax/BPx100 from 21+/-3 to 50+/-14% (P=0.001), AUC/BP from 3+/-1 to 14+/-6 s (P=0.002) and sum of AUC/BP from 5+/-7 to 34+/-35 s (P=0.021). Upon 30 microg i.t. injections of apomorphine at the lumbosacral level, the number of ICP rises was increased from 0.2+/-0.4 to 3.0+/-1.5, ICPmax/BPx100 from 16+/-9 to 43+/-12 and sum of AUC/BP from 1+/-3 to 31+/-15 s compared to vehicle injection (P<0.05 for all parameters). Injection of 30 microg i.v. or i.t. apomorphine non-significantly enhanced the number and amplitude of the ICP rises induced by 10 ng i.t. oxytocin. However, the enhancement of the amplitude of the ICP rises elicited by i.t. oxytocin was more pronounced with i.t. apomorphine than with i.v. apomorphine. These results suggest the existence of a spinal site of action for apomorphine which may (1) participate to generation of erection and (2) exerts a facilitator effect on erection of supraspinal origin.
Animals↗
The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial.
Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5, 10 and 20 mg of vardenafil. Primary endpoints were Q3 (vaginal penetration) and Q4 (maintenance of erection) of the International Index of Erectile Function (IIEF). In the intent-to-treat population (n=580), the changes from baseline for 5, 10 and 20 mg vardenafil (1.2, 1.3 and 1.5, respectively) were all improved (P<0.001) over placebo (0.2) for Q3 and were similarly improved for Q4 (1.4, 1.5 and 1.7) compared to placebo (0.5) (P<0.001). All vardenafil doses improved all IIEF domains compared to placebo (P<0.001). The percentage of successful intercourses was between 71 and 75% for the three vardenafil doses. For the 20 mg dose, 80% of the patients experienced improved erections (GAQ) compared to 30% for placebo. Most frequent treatment-emergent adverse events were headache (7-15%), flushing (10-11%) and up to 7% for dyspepsia or rhinitis. Vardenafil treatment resulted in a high efficacy and low adverse-event profile in a population with mixed ED etiologies.
Adult↗
Dopamine and sexual function.
The use of the D1/D2 dopamine receptor agonist apomorphine SL for the treatment of erectile dysfunction provides a strong support in favour of a participation of the dopaminergic system in the control of sexual function. However, the exact involvement of dopamine in sexual motivation and in the control of genital arousal in humans is unknown. In contrast, experimental data suggest an implication of dopamine at all these stages of the copulatory behaviour in rodents. The release of dopamine at the level of the nucleus accumbens, which is innervated by the mesolimbic dopaminergic pathway originating in the ventral tegmental area, is positively implicated in the pre-copulatory or appetitive phase in male rats. There is also a permissive role in the copulatory or consumatory phase for dopamine released at the level of the median pre-optic area, which receives projection from the dopaminergic incertohypothalamic pathway within the hypothalamus. It is noteworthy that these participations of the dopaminergic system are not specific to sexual behaviour but rather reflect the more general involvement of dopamine in the regulation of cognitive, integrative and reward processes. Due to its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behaviour. Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord. The counterpart of such regulation of the genital arousal by dopamine has not yet been established in females. In conclusion, the central dopaminergic system is a key element of the control of sexual function.
Animals↗
Spinal proerectile effect of oxytocin in anesthetized rats.
The spinal cord contains the neural network that controls penile erection. This network is activated by information from peripheral and supraspinal origin. We tested the hypothesis that oxytocin (OT), released at the lumbosacral spinal cord level by descending projections from the paraventricular nucleus, regulated penile erection. In anesthetized male rats, blood pressure and intracavernous pressure (ICP) were monitored. Intrathecal (it) injection of cumulative doses of OT and the selective OT agonist [Thr(4),Gly(7)]OT at the lumbosacral level elicited ICP rises whose number, amplitude, and area were dose dependent. Thirty nanograms of OT and one-hundred nanograms of the agonist displayed the greatest proerectile effects. Single injections of OT also elicited ICP rises. Preliminary injection of a specific OT-receptor antagonist, hexamethonium, or bilateral pelvic nerve section impaired the effects of OT injected it. NaCl and vasopressin injected it at the lumbosacral level and OT injected it at the thoracolumbar level or intravenously had no effect on ICP. The results demonstrate that OT, acting at the lumbosacral spinal cord, elicits ICP rises in anesthetized rats. They suggest that OT, released on physiological activation of the PVN in a sexually relevant context, is a potent activator of spinal proerectile neurons.
Animals↗
Vaginal physiological changes in a model of sexual arousal in anesthetized rats.
The understanding of the pathophysiology of female sexual dysfunction suffers from the lack of a convenient model for the study of female genital sexual response. In this study, systemic arterial blood pressure (BP) as well as partial oxygen tension, temperature, and blood engorgement of the vagina [using laser-Doppler flowmetry in arbitrary units (AU)] were measured in anesthetized, ovariectomized (1 wk before the start of the experiment) female rats. Vaginal sexual arousal was replicated by electrical stimulation of the pelvic nerve (PNS). PNS induced reproducible increases in the different vaginal parameters (from baseline value, respectively: 16 +/- 10 to 30 +/- 12 mmHg; 34.9 +/- 0.6 to 36 +/- 0.6 degrees C; 450 +/- 196 to 1,500 +/- 360 AU; P < 0.05, paired t-test) and BP (90 +/- 7 to 123 +/- 13 mmHg, P < 0.05, paired t-test). Vaginal vascular resistance was significantly decreased during PNS (from 0.23 +/- 0.15 to 0.08 +/- 0.02 mmHg/AU). Vaginal wall tension was also measured with a force transducer. PNS induced an increase in vaginal wall tension (1.0 +/- 0.2 g), followed by a decrease under the prestimulation value. Intravenous atropine sulfate (1 mg/kg) injection abolished the increase in vaginal wall tension without significantly affecting vaginal vascular resistance. Intravenous vercuronium bromide (2 mg/kg) injection abolished the decrease in vaginal wall tension. Concomitant electrical stimulation of the paravertebral sympathetic chain inhibited vaginal response induced by PNS. Electrical stimulation of the medial preoptic area of the hypothalamus induced a response qualitatively equivalent to PNS with a significant decrease of vaginal vascular resistance. These data support that vaginal contractions involve both smooth and striated muscles and indicate that neural control of vaginal sexual arousal have great similarities in male and female rats.
Anesthesia↗
Dopamine and male sexual function.
The use of the D1/D2 dopamine receptor agonist apomorphine for the treatment of erectile dysfunction provides strong support in favor of a participation of the dopaminergic system in the control of sexual function. However, the exact involvement of dopamine in the control of sexual motivation and genital arousal in males is unknown. Experimental data in male rats suggested an implication of dopamine in sexual motivation as well as in copulatory performance. Specific tests allowing assessment of sexual motivation showed that the release of dopamine at the level of the nucleus accumbens (innervated by the mesolimbic dopaminergic pathway) and the medial preoptic area of the hypothalamus (innervated by the dopaminergic incertohypothalamic pathway) positively regulated the anticipatory/motivational phase of copulatory behavior. A permissive role of dopamine released at the level of the median preoptic area of the hypothalamus in the display of copulatory behavior has also been demonstrated. It is noteworthy that these participations of the dopaminergic system are not specific for sexual behavior but rather reflect the involvement of dopamine in the regulation of cognitive, integrative and reward processes. Because of its role in the control of locomotor activity, the integrity of the nigrostriatal dopaminergic pathway is also essential for the display of copulatory behavior. Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus, and perhaps on the pro-erectile sacral parasympathetic nucleus within the spinal cord. In conclusion, central dopamine is a key neurotransmitter in the control of sexual function.
Animals↗