Mechanism Of Erection Research Articles

Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction

Advances in molecular biology and protein chemistry, along with increasing understanding of the mechanisms of penile erection, have spurred development of pharmacologic approaches to the treatment of erectile dysfunction (ED). The next generation of oral agents includes tadalafil, a potent, highly selective phosphodiesterase 5 inhibitor. In vitro studies have shown that tadalafil enhances relaxation of trabecular smooth muscle, and clinical trials have supported its efficacy and tolerability in a broad population of men with ED. The effect of tadalafil in enhancing the erectile response to sexual stimulation is relatively rapid in onset and lasts for ≥24 hours. The ability of patients with ED treated with tadalafil to achieve improved erectile function is demonstrated by significantly increased subjective measures of penetration ability, successful intercourse, and sexual satisfaction. Partners have expressed similar or higher levels of satisfaction with the results of treatment. Men with ED of psychogenic, organic, or mixed etiology and in a range from mild to severe have experienced significant improvment with tadalafil treatment. Response to treatment in men with diabetes has been robust and not affected by disease severity. Tadalafil has been well tolerated. Adverse events have generally been mild or moderate and have abated with continued treatment. Headache and dyspepsia have been most frequently reported. Changes in color vision have been rare (<0.1%) with tadalafil across all clinical trials. Tadalafil appears to be a safe and effective treatment for men with ED.

Overview of phosphodiesterase 5 inhibition in erectile dysfunction

Since the early 1980s, research on the mechanisms of penile erection has done much to clarify erectile physiology and pathophysiology. More recent studies have identified the importance of neurochemical mediators in erection. These include the nitric oxide–cyclic guanosine monophosphate (cGMP) cell-signaling system—a complex molecular pathway that mediates smooth muscle relaxation in the corpus cavernosum. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates nitric oxide—cGMP–mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science. The prototype of this new therapeutic class of PDE5 inhibitors is sildenafil, which was approved for treatment of erectile dysfunction in 1998. Tadalafil and vardenafil are new agents in this class. These agents have demonstrated improvement in erectile function and have been shown to be well tolerated in diverse populations comprising thousands of men worldwide. Profiles of these 3 PDE5 inhibitors are reviewed herein.

Erectile dysfunctions.

Erectile dysfunction is one of the prime challenges confronting the treating physician. Its prevalence is directly proportional to aging. It is imperative to comprehend the intricate mechanism of erection in order to individualize the approach to management. Thus, it is appropriate to evaluate the etiology of erectile dysfunction. Normal aging, as well as psychogenic, vascular, neurogenic, and endocrinologic causes and/or those due to structural abnormalities of the penis should be considered when evaluating details to determine its probable cause. An increasing use of drugs, a legacy of civilization, has considerably compounded the problem. Therapy for erectile dysfunction, apart from psychosexual counseling, includes medical treatment by alpha adrenoceptor antagonists, dopamine agonists, phosphodiesterase type 5 inhibitors, sublingual apomorphine hydrochloride, or hormone therapy. Transdermal or transurethral corporeal drug delivery are other possible treatment modalities. Vacuum devices and surgical approaches are considered relevant only in refractory cases.

Is there an inhibitory role of cortisol in the mechanism of male sexual arousal and penile erection?

It has been speculated for more than 2 decades whether there is a significance of adrenal corticosteroids, such as cortisol, in the process of normal male sexual function, especially in the control of sexual arousal and the penile erectile tissue. However, only few in vivo studies have been carried out up until now on the effects of cortisol on human male sexual performance and penile erection. In order to evaluate further the role of cortisol in male sexual activity, the present study was conducted to detect serum levels of cortisol in the systemic and cavernous blood taken during different penile conditions from healthy males. The effects of cortisol derivative prednisolone, catecholamine norepinephrine (NE) and the peptide endothelin-1 (ET-1) on isolated human corpus cavernosum (HCC) were investigated using the organ bath technique. Fifty-four healthy adult male subjects were exposed to erotic stimuli in order to elicit penile tumescence and rigidity. Whole blood was simultaneously aspirated from the corpus cavernosum and the cubital vein during different penile conditions. Serum levels of cortisol (microg/dl) were determined by means of a radioimmunoassay (ELISA). In the healthy volunteers, cortisol serum levels significantly decreased in the systemic circulation and the cavernous blood with increasing sexual arousal, when the flaccid penis became rigid. During detumescence, the mean cortisol level remained unaltered in the systemic circulation, whereas in the cavernous compartment, it was found to decrease further. Under all penile conditions, no significant differences were registered between cortisol levels in the systemic circulation and in the cavernous blood. Cumulative addition of NE and ET-1 (0.001-10 microM) induced contraction of isolated HCC strips, whereas the contractile response to prednisolone was negligible. Our results strongly suggest an inhibitory role for cortisol in the mechanism of male sexual response and behaviour. These properties are mediated rather via an effect on central structures than on the penile erectile tissue. Future studies to include patients suffering from erectile dysfunction may reveal whether or not there are differences in the cortisol serum profiles of healthy subjects and patients under different stages of sexual arousal.

Identification of Communicating Branches Among Dorsal, Perineal and Cavernous Nerves of Penis

The mechanism of human erection requires the coordination of an intact neuronal system that includes the cavernous, perineal, and dorsal nerves of the penis. We defined the communication of these 3 nerves that travel under the pubic arch using specific neuronal immunohistochemical staining and 3-dimensional reconstruction imaging technique. A total of 18 normal human fetal penile specimens at 17.5 to 32 weeks of gestation were studied by immunohistochemical techniques. Serial sections were stained with antibodies raised against the neuronal markers S-100, and neuronal nitric oxide synthase (nNOS), vesicular acetylcholine transporter (VAChT), calcitonin gene-related peptide and substance P. The continuation of the dorsal neurovascular bundle of the prostate was documented under the pubic arch. Two distinct nerve bundles were identified superior to the urethra and medial to the origin of the crural bodies. Nerve bundles were observed to join the corporeal bodies at the penile hilum. Proximal to the penile hilum the dorsal nerves stained only for S-100 and VAChT. From the junction of the crural bodies at the hilum to the glans penis dorsal nerve fibers stained positive for S-100, VAChT and nNOS. Calcitonin gene-related peptide and substance P demonstrated positive staining at the distal nerves, particularly at the glans. In contrast, the whole course of the cavernous nerve stained for S-100 and nNOS. Under the pubic arch at the penile hilum the cavernous nerves were found to convey nNOS positive branches to the dorsal nerve to transform its immunoreactivity to nNOS positive. Proximal nNOS negative perineal nerves were shown to stain positive for nNOS distal on the penis. Interaction between nNOS positive dorsal nerve branches and perineal nerves was at the cavernous-spongiosal junction, where the bulbospongiosus muscle terminates. At penile hilum, where the corporeal bodies start to separate, the cavernous nerve sends nNOS positive fibers to join the dorsal nerve of the penis, thereby, changing the functional characteristics of the distal penile dorsal nerve. Similarly the nNOS negative, ventrally located perineal nerve originating from the pudendal nerve becomes nNOS reactive at the cavernous-spongiosal junction. These 2 examples of redundant neuronal wiring in the penis may impact erectile function, especially during reconstructive surgery.

New achievements and pharmacotherapeutic approaches to impotence in the elderly.

Erectile dysfunction (ED) has a negative impact on the quality of life of elderly men, but impotence is not an absolute concomitant of aging. Aging changes influencing sexual function in men consist of a decreased capacity to reach arousal by imagination or view, fragility of erection, and an increase in the refractory period. These events may be part of the andropause syndrome, which includes a decrease in intellectual activity, fatigue, depression, decreases in body hair, lean body mass and bone mineral density, accompanied by an increase in weight. As a consequence, the overlap of aging processes, concurrent diseases and social situations to which elderly men are subject, results in the great variability reported in epidemiological studies. In the same way, the complex physiology of erection depends on the social, environmental, or physical context in which it occurs. New achievements in research on intracellular mechanisms of erection and on the neuroendocrinology of aging contribute to better understanding the pathophysiology of ED in the elderly. For example, testosterone declines with age with great interindividual variability, since other hormonal changes are also involved. What currently can be easily identified is the alteration of LH-testosterone feedback alterations, although hormone levels fall in the normal range. Nevertheless, the extent to which age-dependent decline in hormones leads to health problems that may affect the quality of life remains to be clarified. Several concepts on aging-related processes have been challenged, and conditions that were once accepted as physiologically age-related are now thought to lead to medical problems, but until now erectile dysfunction remains underreported, underdiagnosed, and undertreated, especially in the elderly. Nowadays, we are witnessing a rapid growth in available pharmacotherapies, from intracavernous injections of vasoactive drugs, to powerful new oral agents, with differing pharmacological dynamic and kinetic properties. New options for treatment are therefore possible, taking into account both the possibility of changing ineffective drugs and augmenting efficacy by means of synergistic associations. This rich generation of progress is certainly contributing to a better medical approach to sexuality in aging people.

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 μg/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 μg/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.

Erection Mechanism of the Penis: A Model Based Analysis

We examined and elucidated the physical mechanism of penile erection in normal and pathological conditions of vascular origin. A nonlinear lumped parameter mathematical model of penile hemodynamics was developed based on physical structure and physiological function. The model was applied to simulate the normal erectile mechanism and the pathological conditions of arterial insufficiency and venous leakage. The model showed physiological behavior and suggested explanations for the relationships of corporeal pressure and venous flow limitation during erection. Other results related the reduction in rigidity and tumescence to the type and severity of vascular impairment. This model can be used in future studies of the diagnosis of erectile dysfunction.

Erection Mechanism of the Penis: A Model Based Analysis

Erection Mechanism of the Penis: A Model Based Analysis

Oxytocin plasma levels in the systemic and cavernous blood of healthy males during different penile conditions.

It is well established that transmitters of the nonadrenergic-noncholinergic (NANC) system are involved in the control of sexual arousal and penile erection in healthy males. The proerectile activity of dopamine D1/D2 receptor agonist apomorphine-HCl (IXENSE, UPRIMA) involves oxytocinergic pathways descending from the hypothalamus to the brain stem and spinal autonomic centers. Although it has been demonstrated that injection of oxytocin into the paraventricular nucleus and the hippocampus produces penile erection in rats, the significance of the peptide in the control of sexual arousal and penile erection in man has been, up until now, only poorly evaluated. The present study was undertaken to determine whether oxytocin (OT) plasma levels alter in the systemic and cavernous blood of healthy males under different penile conditions (flaccidity, tumescence, rigidity, detumescence). Twenty-five healthy adult males were exposed to visual and tactile erotic stimuli in order to elicit penile tumescence and rigid erection. Blood was taken from the corpus cavernosum (CC) and the cubital vein (CV) during penile flaccidity, tumescence, rigidity and detumescence. Following extraction from plasma aliqouts, oxytocin was measured by means of a radioimmunoassay. An increase was observed in the mean OT plasma levels in the systemic and cavernous blood when the flaccid penis became tumescent (CC: from 66.7+/-34 to 75+/-44 pg/ml; CV: from 71+/-41 to 79+/-49.5 pg/ml). From tumescence to rigidity, OT further rose in the cavernous blood (to 81+/-58 pg/ml), whereas it remained unaltered in the systemic circulation. During detumescence, oxytocin plasma levels dropped in the cavernous but again increased in the systemic blood (to 94+/-49 pg/ml). Our results support the hypothesis of a pivotal role of OT in the mechanism of male sexual arousal and penile erection and provide a rationale for the use of apomorphine in the treatment of erectile dysfunction.

Introduction

Introduction

Smooth muscle pathology and erectile dysfunction.

Penile erection is a vascular phenomenon that results from smooth muscle relaxation, arterial dilation and venous restriction. The atherosclerosis of the penis that occurs with aging causes a decrease in penile oxygen tension. A reduction of smooth muscle cells has been demonstrated in relation with this change in oxygen tension. Changes in the ratio of penile collagen have also been observed and could explain the decrease in penile elasticity and compliance. Chronic ischemia is, therefore, associated with fibrosis but also with nitric oxide (NO)-cyclic guanosine monophosphate. The sensitivity of the alpha-adrenoceptors on the smooth muscle cells increases with aging. All those modifications can explain the prevalence of erectile dysfunction with aging. Low oxygen tension in prostanoid production may also play a role in the mechanism of ischemia-induced cavernosal fibrosis; however, intracavernous injections of prostaglandin E(1) do not seem to modify the intracavernous structures by reducing muscular atrophy. The effects of androgen on libido and sexual behavior are well established, but their role in the human erectile mechanism remains unclear. Several studies performed on animals have demonstrated impacts directly on both the physiological function and the trabecular structure of the corpora cavernosa in rats, dogs and rabbits. However, in humans, no study seems to demonstrate a role of testosterone on muscular atrophy or penile neurologic control. Testosterone treatment alters the human behavior but not penile physiologic processes. Further studies are necessary to explain the real role of testosterone not only on the peripheral mechanism of erection but also on the central control.

Plasma levels of cyclic guanosine-3',5'-monophosphate in the cavernous and systemic blood of healthy males during different functional conditions of the penis.

The relaxation of cavernous arterial and trabecular smooth muscle is dependent upon the stimulation of guanylyl cyclase activity by nitric oxide (NO), which is released from nerve terminals and endothelial cells within the cavernous tissue, and the subsequent accumulation of cyclic guanosine-3',5'-monophosphate (cGMP) in the intracellular space. The present study was undertaken to determine whether or not plasma levels of cGMP in the systemic and cavernous blood of healthy male subjects change from penile flaccidity to tumescence, rigidity and detumescence. Fifteen adult healthy males were exposed to visual and tactile erotic stimuli to elicit penile tumescence and rigidity. Whole blood was simultaneously aspirated from the corpus cavernosum and the cubital vein in the respective penile stages, and cGMP was determined in plasma aliquots by means of a radioimmunoassay. Mean systemic and cavernous plasma levels of cGMP in the blood samples obtained from the healthy volunteers ranged from 1.2-1.7 pmol/ ml. cGMP levels in the systemic circulation and in the cavernous blood did not change during developing erection, rigidity and detumescence. No significant differences were found between cGMP plasma levels in the systemic and cavernous blood in the different penile stages. Our results may reflect the fact that the stimulation of NO production in healthy males during sexual arousal and developing penile erection either does not yield substantial quantities of cGMP or that the rate of cGMP-extrusion from cavernous smooth muscle cells into the extracellular space accounts only for a minor fraction of plasma cGMP. Moreover, basal levels of cGMP in the blood flushing the lacunar spaces of the cavernous body in the state of developing erection may conceal any local release of cGMP that may occur within the penile erectile tissue. Thus, we conclude that the quantification of cGMP is of no use in the evaluation of the physiologic mechanisms of penile erection in vivo.

Testosterone and penile erection

Male sexual function depends upon a complex inter-relationship between psychological, neurological, vascular and hormonal factors. Testosterone is responsible for the initiation, development and maintenance of primary and secondary sexual characteristics as well as having a role in male sexual behavior and potency. In adults, testosterone deficiency is associated with reduced libido and potency, infertility, lethargy and a number of behavioral modifications. This article reviews what is known about the role of testosterone on the mechanism of penile erection and describes the results of the experimental designs and animals models used in the study of erectile physiology. In animals, testosterone seems to have an action on some neurotransmitters of erectile mechanism, while in man, its role is mainly on the behavioral aspects.

Structural characteristics of the patagium of Ptychozoon kuhli (Reptilia: Gekkonidae) in relation to parachuting locomotion.

Ptychozoon kuhli is known for its parachuting/gliding capabilities. In this contribution, we document the allometric scaling properties of its patagium, accessory flaps and folds, and its total body surface area and compare them to similar attributes of the agamine lizard Draco volans. Ptychozoon kuhli has passive patagia that lack skeletal support and muscular control. Patagial area in P. kuhli is smaller than that in D. volans for individuals of identical snout-vent length, but the accessory folds and flaps compensate for this shortfall and overall P. kuhli has equivalent total body surface area to D. volans for equally sized individuals. The structure of the patagium of Ptychozoon kuhli was investigated in terms of its scalation patterns and structural integrity, its relationship to the body wall and its mechanism of erection, and the distribution of mechanoreceptive sensilla across its surface. Scalation patterns and the internal architecture of the patagium indicate how its shape and form are maintained as it erects and becomes exposed to air flow. Its cross-sectional shape, together with that of the entire body indicates how it is able to behave as an airfoil. The distribution of sensilla across the patagial surface reflect positioning indicative of the monitoring of scale-to-scale contact on the dorsal surface, and possibly air pressure and flow on the ventral surface.

Testosterone and penile erection

Male sexual function depends upon a complex inter-relationship between psychological, neurological, vascular and hormonal factors. Testosterone is responsible for the initiation, development and maintenanceof primary and secondary sexual characteristics as well as having a role in male sexual behavior and potency. In adults, testosterone deficiency is associated with reduced libido and potency, infertility,lethargy and a number of behavioral modifications. This article reviews what is known about the role of testosterone on the mechanism of penile erection and describes the results of the experimental designsand animals models used in the study of erectile physiology. In animals, testosterone seems to have an action on some neurotransmitters of erectile mechanism, while in man, its role is mainly on the behavioralaspects.

Peyronie's disease: advances in basic science and pathophysiology.

Peyronie's disease is an idiopathic, localized connective tissue disorder of the penis that involves the tunica albuginea of the corpus cavernosum and the adjacent areolar space. The tunica albuginea plays an important role in the mechanism of erection. Peyronie's disease is characterized by local changes in the collagen and elastic fiber composition of the tunica albuginea. The formation of fibrotic plaques alters penile anatomy and can cause different degrees of bending, narrowing, or shortening of the penis. Moreover, a significant number of men with Peyronie's disease develop erectile dysfunction. Penile blood flow studies in many patients with Peyronie's disease suggest a strong association with veno-occlusive dysfunction. Although long recognized as an important clinical entity of the male genitalia, the etiology of this disease has remained poorly understood. The following review focuses on recent research on the pathophysiology of Peyronie's disease.

Central control of erection and its pharmacological modification

Advances in our understanding of the local mechanisms of penile erection have paralleled the use of pharmacological treatments of erectile dysfunction. In contrast, the spinal and supraspinal mechanisms that control penile erection are less well understood. Although the role of hypothalamic areas (medial preoptic area, paraventricular nucleus) and brainstem nuclei (raphe nuclei) in penile erection has been evaluated, as has the role of an association between neuromediators and receptors (serotonin, dopamine, noradrenalin, glutamate, gamma-aminobutyric acid, nitric oxide), an integrative view of the central mechanisms of penile erection is lacking. New strategies to treat erectile dysfunction employ oral agents, some of which target central brain nuclei. The future of such treatments largely depends on a better understanding of the central mechanisms of penile erection.

Role of the Lateral Preoptic Area in Sleep-Related Erectile Mechanisms and Sleep Generation in the Rat

Penile erections are a characteristic phenomenon of paradoxical sleep (PS), or rapid eye movement sleep. Although the neural mechanisms of PS-related erections are unknown, the forebrain likely plays a critical role (Schmidt et al., 1999). The preoptic area is implicated in both sleep generation and copulatory mechanisms, suggesting it may be a primary candidate in PS erectile control. Continuous recordings of penile erections, body temperature, and sleep-wake states were performed before and up to 3 weeks after ibotenic acid lesions of the preoptic forebrain in three groups of rats. Neurotoxic lesions involving the medial preoptic area (MPOA) and anterior hypothalamus (n = 5) had no significant effects on either erectile activity or sleep-wake architecture. In contrast, bilateral lesions of the lateral preoptic region, with (n = 4) or without (n = 5) MPOA involvement, resulted in a significant decrease in the number of erections per hour of PS, number of PS-related erections, and PS phases exhibiting an erection. Lesion analysis revealed that the candidate structures for PS erectile control include both the lateral preoptic area (LPOA) and ventral division of the bed nucleus of the stria terminalis; however, lesions of the LPOA were the most effective in disrupting PS erectile activity. LPOA lesioning also resulted in a long-lasting insomnia, characterized by the significant increase in wakefulness and decrease in slow wave sleep (SWS). PS architecture and waking-state erections remained unchanged after lesion in all groups. These data identify an essential role of the LPOA in both PS-related erectile mechanisms and SWS generation. Moreover, higher erectile mechanisms appear to be context-specific because LPOA lesioning selectively disrupted PS-related erections while leaving waking-state erections intact.

Phytochemicals and the breakthrough of traditional herbs in the management of sexual dysfunctions

Traditional herbs have been a revolutionary breakthrough in the management of erectile dysfunction and have become known world-wide as an 'instant' treatment. The modern view of the management of erectile dysfunction subscribes to a single etiology, i.e. the mechanism of erection. A large number of pharmacological agents are orally consumed and vasoactive agents inserted intraurethrally or injected intrapenially to regain good erection. Modern phytochemicals have developed from traditional herbs. Phytochemicals focus their mechanism of healing action to the root cause, i.e. the inability to control the proper function of the whole body system. Hence phytochemicals manage erectile dysfunction in the frame of sexual dysfunction as a whole entity. Protodioscin is a phytochemical agent derived from Tribulus terrestris L plant, which has been clinically proven to improve sexual desire and enhance erection via the conversion of protodioscine to DHEA (De-Hydro-Epi-Androsterone). Preliminary observations suggest that Tribulus terrestris L grown on different soils does not consistently produce the active component Protodioscin. Further photochemical studies of many other herbal plants are needed to explain the inconsistent results found with other herbal plants, such as in diversities of Ginseng, Eurycoma longifolia, Pimpinella pruacen, Muara puama, Ginkgo biloba, Yohimbe etc.