Introduction

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Male erectile dysfunction (MED) is defined as the "inability to achieve or maintain an (penile) erection adequate for sexual satisfaction" (National Institutes of Health Consensus Statement, 1993). Erectile dysfunction occurs in varying degrees in an estimated 20 to 30 million U.S. men and is associated with adverse effects on quality of life, particularly personal well being, family, and social interrelationships (Laumann et al., 1999; Johannes et al., 2000). The worldwide prevalence of MED has been estimated at over 152 million men, and the projections for 2025 suggest a prevalence of approximately 322 million with MED. Recent reports of quality of life data suggest that the importance of MED in contributing to other chronic health conditions such as depression has been largely underestimated (Laumann et al., 1999).

The treatment of MED has been revolutionized over the last decade from only surgical options (penile prostheses or revascularization) to intracavernosal and intraurethral administered agents [e.g., prostaglandin E₁ (PGE₁)_, papaverine, phentolamine] that paved the way to an effective oral therapy such as sildenafil. The clinical efficacy of oral agents such as sildenafil, apomorphine, phentolamine, IC351, and vardenafil represent the beginnings of noninvasive pharmacological treatment for MED.

Over the past 25 years, research on MED has focused on the mechanisms of corpus cavernosum smooth muscle relaxation, and this work has provided the basis for our current knowledge of the physiology of erection. On the other hand, the fields of experimental psychology and neuroscience have also unraveled critical information on the brain areas and the neuroanatomical connections regulating sexual behavior. In view of the latest developments in the clinical arena and the potential utility of several novel molecular targets for the pharmacological treatment of MED (Moreland et al., 2000), this review will summarize biochemical and neural mechanisms that affect corpus cavernosum smooth muscle tone and penile erection.

	Epidemiology

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Erectile dysfunction or impotence throughout most of the 20th century was considered predominantly as a psychological condition. The National Institutes of Health Consensus Development Panel on Impotence recognized that although it is difficult to separate psychogenic effects from organic disease, vasculogenic impotence accounts for about 75% of MED patients (National Institutes of Health Consensus Statement, 1993). In the literature before 1993, the term impotence is used and encompasses all forms of MED. Epidemiological studies suggest an association between impotence and increasing age and/or peripheral vascular disease (Laumann et al., 1999; Johannes et al., 2000). One recent study examined a random population of 1709 noninstitutional men aged 40 to 70 in the Boston area (Feldman et al., 1994; Johannes et al., 2000). The overall probability of some degree of sexual dysfunction was 52%. After adjusting for age, impotence was correlated with heart disease (39%), diabetes (28%), and hypertension (15%) as well as other vascular risk factors such as cigarette smoking. Treated heart disease (vasodilating drugs 36%), use of cardiac drugs (28%), and use of antihypertensive agents were also strongly associated. Correlations were also found with untreated medical conditions such as ulcers (18%), arthritis (15%), and allergies (12%). The follow-up study almost 9 years later allowed estimation of a risk of MED of about 26 cases per 1000 men annually, with correlation with vascular risk factors (heart disease, diabetes, and hypertension), age, and lower education (Johannes et al., 2000).

	Physiology of Penile Erection

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The tone of the corpus cavernosum smooth muscle is controlled by complex biochemical events coordinated at the level of the peripheral and central nervous system (Figs. 1 and 2). Sympathetic, parasympathetic autonomic, and somatic nerves control the tone of the corpus cavernosum smooth muscle and its vascular system via neuroanatomical connections that are an integral part of the innervation of the lower urinary tract (de Groat and Booth, 1993; Andersson and Wagner, 1995).

View larger version (35K): [in this window] [in a new window]   Fig. 1.   Peripheral mechanisms involved in flaccidity and erection. A conceptual framework depicting mechanisms involved in regulating corpus cavernosum smooth muscle tone as well as the mechanisms of action of peripheral pharmaceutical treatments for MED. AC, adenylate cyclase; AA, arachidonic acid; eNOS, endothelial NOS; GC, guanylate cyclase; L-Arg, L-arginine; IP3, inositol trisphosphate; PLC, phospholipase C.

View larger version (31K): [in this window] [in a new window]   Fig. 2.   Neuroanatomical connections and putative neurotransmitters in the central nervous system involved in penile erection. MFB, medial forebrain bundle; OXYT, oxytocin; PAG, periaqueductal gray matter; ZI, zona incerta; MPOA, medial preoptic area; PVN, paraventricular nucleus; NO, nitric oxide.

Peripheral Control of Penile Erection. The penis is composed of three bodies of erectile tissue: the corpus spongiosum, encompassing the urethra and terminating in the glans penis, and the two corpora cavernosa, which function as blood-filled capacitors, providing structure to the erect organ (de Groat and Booth, 1993; Andersson and Wagner, 1995). The corpus cavernosum is a unique vascular bed consisting of sinuses (the trabeculae) whose arterial blood supply arises from the resistance helicine arterioles, which in turn are fed from the deep penile cavernosal artery. The trabeculae are drained by the emissary venules that in turn communicate with the cavernosal veins. The trabeculae, while arterially fed, have measured blood PO₂ of 20 to 40 mm Hg when the penis is in the flaccid state (Kim et al., 1993).

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Central Mechanisms Controlling Penile Erection. The neural pathways involved in penile erection are just beginning to be integrated into a unified body of knowledge as the role of specific CNS pathways is corroborated by experimental findings from independent laboratories. The different areas in the brain and the neuroanatomical connections presently known to regulate penile erection are shown diagrammatically in Fig. 2. External information can stimulate sexual activity via the different sensory (visual, olfactory, tactile, and auditory) pathways that, with the exception of the olfactory system, reach the corresponding cortical areas and then project to polymodal cortical association areas. The piriform and entorhinal cortexes have extensive neuronal connections with limbic structures like the amygdala (de Groat and Booth, 1993). Lesions of the medial amygdala significantly impaired copulatory behavior in rats, while bilateral lesions of the temporal lobes including the amygdala induced a syndrome of hypersexuality and frequent penile erections in monkeys known as the Kluver-Bucy syndrome (Kluver and Bucy, 1938). Similar behavioral changes in sexual behavior have also been observed in humans, suggesting that the amygdala plays an important role regulating male sexual activity besides its participation in learning, memory, and the control of emotional behavior (Brioni, 1993).

	Pathophysiology of Male Erectile Dysfunction

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MED can be classified into four types: 1) psychogenic, 2) vasculogenic or organic, 3) neurologic, and 4) endocrinologic. MED can also result as a side effect of pharmacological treatments such as antihypertensive medications (-adrenoceptor blockers), serotonin reuptake inhibitors, diuretics, and cardiac medications (Meinhardt et al., 1997).

There are currently two hypotheses of pathophysiology: one proposes a structural basis of MED, while the other focuses on metabolic imbalances in the corpus cavernosum. The penis is comprised of soft tissue and functions as a blood-filled capacitor of sufficient rigidity during erection for vaginal penetration (Nehra et al., 1999). The two bodies of erectile tissue, the corpora cavernosa, that are integral to this function are composed of a specialized vascular bed, which has a high content of connective tissue (48-55%). The corpus cavernosum smooth muscle cells also synthesize connective tissue that contributes to the structural integrity of the corpora, and a functional corpus cavernosum smooth muscle/connective tissue ratio is necessary for veno-occlusion (Moreland, 1998). The implications of this finding are that regardless of the amount of corpus cavernosum smooth muscle relaxation, veno-occlusion cannot occur in some patients due to higher content of connective tissue and an inability to occlude the draining venules.

One area of active research in MED is to identify vasoactive factors, cytokines, autacoids, and/or neurotransmitters that may play a role in maintaining the connective tissue/smooth muscle balance (Moreland, 1998). Among the potential candidates are transforming growth factor ₁ (TGF-₁) and prostaglandin E, both of which are synthesized by the corpus cavernosum smooth muscle cells. These vasoactive substances are regulated by oxygen tension; TGF-₁ is induced under lower oxygen tension conditions consistent with flaccidity, while PGE is synthesized under conditions consistent with oxygen tensions during erection. In human corpus cavernosum smooth muscle cells in culture, TGF-₁ can induce a 2.5- to 4-fold increase in collagen synthesis in these cells, and this synthesis can be repressed by a single dose of PGE₁. While these are in vitro observations, it is interesting to note that nocturnal penile tumescence may provide a daily oxygenation of the corpus cavernosum regardless of sexual activity that may help to maintain a functional corpus cavernosum smooth muscle/connective tissue balance (Moreland, 1998). While research has yet to supply an answer to a number of the questions involved, strategies to alter the corpus cavernosum structure could be a future means to treat MED.

An alternate hypothesis regarding the pathophysiology of MED is attributed to a metabolic imbalance between contractile and relaxatory factors in the corpus cavernosum (dysfunctional antagonism; Melman and Gingell, 1999). Under normal physiological conditions in the penis, contractile factors (norepinephrine, ET, and contractile prostanoids) are in balance with relaxatory factors (NO, VIP) such that when the contraction of the corpus cavernosum diminishes and relaxatory factors are present, erection ensues. In the case of dysfunctional antagonism, contractile factors predominate, are overexpressed or relaxatory factors are inhibited, such that the trabecular smooth muscle remains contracted and the penis remains flaccid. However, in most cases of vasculogenic MED, a decrease in NO production and release probably plays some role in the dysfunction. In actual practice, the pathophysiology of erectile dysfunction probably has both structural and metabolic components.

	Experimental Approaches to Study MED

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In Vitro Models. As penile erection involves relaxation of corporal vascular and smooth muscle during sexual stimulation, the application of in vitro models of isolated corpus cavernosal tissue has significantly enhanced our understanding of the biochemical events at the cellular level (Andersson and Wagner, 1995). From a scientific perspective, these models allow dissection of the various neurotransmitters and vasoactive factors involved in this process and the signal transduction pathways therein.

In Vivo Animal Models. Intracavernosal pressure (ICP) changes in animal models as an index of penile erection have greatly enhanced our understanding of basic erectogenic pathways and systems. As discussed above, ICP increases as the corpus cavernosum relaxes and fills with blood, and the plateau of ICP is indicative of successful veno-occlusion and functional erection. Some researchers prefer ICP models for studies of penile erection to in vitro organ bath chamber experiments. Both approaches have merit in dissecting various aspects of male erectile physiology. Advantages of the ICP model aside from an intact animal preparation include the ability to perform continuous monitoring of ICP, duration of erection, and concomitant measurement of arterial pressure. A combination of intracavernosal drug administration and selective nerve stimulation or ablation has greatly increased understanding of the neurophysiology of erection (Andersson and Wagner, 1995; Christ et al., 1998; Sato et al., 2000). Many physiological studies on penile erection are carried out in larger animals, including monkeys, dogs, and cats (Giuliano et al., 1999). The large volume of tissues and prominent peripheral nervous and blood vessel supplies to the penis in these animals provide convenient access for pharmacological, neurological, and hemodynamic evaluations. The rabbit model has also been used for studying the erectile response to the intracavernosal injection of vasoactive drugs. The important differences among species should be considered for every specific study.

	Advances in the Treatment of MED

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A variety of drug targets have been proposed for the potential treatment of MED. The large number and diversity of targets is indicative of the significant interest in the pharmaceutical arena to identify novel agents for MED, as it is still an unmet medical need for a substantial portion of patients. In view of the recent success of sildenafil, a major area of activity is in the development of PDE5 inhibitors. There is also interest in several other molecular targets at the smooth muscle level as well as in the CNS. Drugs used presently in clinical practice are shown in Table 1 and Fig. 1. Peripheral treatment of erectile dysfunction focuses on enhancing corpus cavernosum smooth muscle relaxation as described below.

Agents That Increase cAMP Synthesis. The finding that erection proceeds through mechanisms that increase intracellular levels of cyclic nucleotides (cAMP and cGMP) have allowed the development of several classes of therapeutic agents. The first class of agents that increases intracellular cAMP synthesis works either via specific cell surface receptors, which are then coupled to adenylate cyclase, or drugs that activate adenylate cyclase directly. Prostaglandin E₁ binds to specific EP receptors on the corpus cavernosum smooth muscle cells, elevating intracellular cAMP levels by coupling through G_s protein mechanism and activation of adenylate cyclase (Narumiya et al., 1999). This increase in cAMP activates a signal transduction cascade whose ultimate result is phosphorylation/dephosphorylation events with the actin-myosin system leading to smooth muscle relaxation (Fig. 1).

-Adrenoceptor Antagonists. Sympathetic -adrenoceptors are thought to maintain the flaccidity of the corpus cavernosum (Andersson and Wagner, 1995; Traish et al., 1999), and blockade of these receptors by ₁-, ₂-, or mixed -adrenoceptor antagonists have been used to treat MED. In contrast to the general view that -adrenoceptor antagonists act only at the level of the smooth muscle, these agents can act either in the CNS or peripherally pre- and postsynaptically.

Agents That Increase cGMP Synthesis. The discovery that NO is one of the major effectors in penile smooth muscle relaxation and erectile function has led to the development of two classes of agents: NO donors and agents that elevate and/or potentiate cGMP levels (PDE inhibitors). As discussed above, NO is synthesized by neural NOS in the NANC nerve terminals as well as by the corpus cavernosum endothelial cells (endothelial NOS) in response to shear stress, acetylcholine, or bradykinin (Andersson and Wagner, 1995). Examples of drugs that work as NO donors include nitroglycerin, minoxidil, and sodium nitroprusside. However, NO donors themselves can activate guanylate cyclase not only in corpus cavernosum but also in other tissues because of the ubiquitous distribution of guanylate cyclase. Recently, the use of NO donors attached by nitrosylation either to -receptor antagonists or to PDE inhibitors has been investigated. Attached NO was shown to significantly improve the therapeutic efficacy of both compound classes, increasing intracavernosal pressure and the duration of the erection. The development of these compounds, while promising, is still at the preclinical stage (Moreland et al., 2000).

PDE Inhibitors. PDEs are enzymes that hydrolyze cAMP and cGMP to their respective monophosphates to terminate signal transduction by these second messengers within the corpus cavernosum. To date, of the 11 known PDEs, types 2, 3, 4, and 5 have been identified in the corpus cavernosum (Stief et al., 1997; Corbin and Francis, 1999). PDE5 is the major cGMP hydrolytic activity in the corpus cavernosum smooth muscle cell (Corbin and Francis, 1999). Sildenafil is a selective PDE5 inhibitor that has been shown to be a safe and effective oral treatment for MED (Goldstein et al., 1998; Cheitlin et al., 1999). The mechanism of action of sildenafil requires an intact NO response as it blocks the hydrolysis of cGMP induced by NO as well as constitutive synthesis of cGMP in the cells. This may explain why sexual arousal is necessary for the effectiveness of sildenafil in men. Sildenafil is a potent competitive inhibitor of PDE5 (IC₅₀ = 3.5 nM) and is selective over PDE1 to -4 (80- to 19,000-fold) and retinal PDE6 (10-fold). Sildenafil enhanced cGMP accumulation driven with NO in the corpus cavernosum of rabbits without affecting cAMP accumulation. More importantly, in the absence of NO release, sildenafil had no functional effect on the human and rabbit isolated corpus cavernosum but potentiated the relaxant effects of NO on these tissues (Moreland et al., 2000). In the anesthetized dog, sildenafil enhanced the increase in intracavernosal pressure induced by electrical stimulation of the pelvic nerve or intracavernosal injection of sodium nitroprusside without effects on blood pressure. Consistent with its mode of action, sildenafil potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings (Corbin and Francis, 1999).

ET Receptor Antagonists. It has been recently reported that ET receptor antagonists may be used as effective treatment of MED. ET is a potent vasoconstrictor synthesized by the corpus cavernosum smooth muscle cells and endothelium (Andersson and Wagner, 1995). In addition to acting as a vasodilator of corpus cavernosum smooth muscle, NO regulates the expression of endogenously produced ETs (Nehra et al., 1999). The pharmacology of the interaction between nitric oxide and endothelin receptor systems is an area of research still to be resolved.

Dopamine Receptor Agonists. Apomorphine is a dopamine receptor agonist known to induce penile erection in men when administered orally (Morales et al., 1995). It has been tested in clinical trials in a sublingual formulation, which overcomes the major side effect of mild nausea. It is expected that it will be effective in a population of patients similar to that of sildenafil (psychogenic and mild-to-moderate vasculogenic MED patients) but without the cardiovascular side effects. A sublingual formulation of apomorphine (Uprima, TAP, Deerfield, IL) has recently been withdrawn from FDA review until the safety profile is further investigated. Although several dopaminergic agents like apomorphine, quinpirole, and 3-PPP can induce penile erections in animals, it is unclear which dopamine receptor subtype mediates the proerectile effect (Vallone et al., 2000).

	Future Prospects

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The development of noninvasive or minimally invasive routes of administration is a key issue in the drug discovery area for the treatment of MED. While a number of reports focus on the use of topical agents to treat erectile dysfunction, success using this route of administration has been limited. Topical PGE₁, papaverine, and nitroglycerin have been tested (Nehra et al., 1999). In most of these limited clinical trials, penile blood flow increased and most subjects reported tumescence, but the number of subjects responding with erections sufficient for vaginal penetration was low and in most instances indistinguishable from the placebo. These results are consistent with the problem of drug delivery through the tunica albuginea. Recently, iontophoresis has been tested using an intraurethral catheter. While this report is promising, further studies are necessary to determine whether this means of delivery is effective as a minimally invasive method of treatment.

Oral agents have the advantage of convenience but the disadvantages of systemic side effects. Since the penis is a vascular organ, many of these side effects center around vascular liabilities such as hypotension and incidence of myocardial infarction. There are three PDE5 inhibitors in late stages of clinical development (IC351, ICOS/Lilly; vardenafil, Bayer; E8010, Eisai Pharmaceuticals). Any cGMP-based therapy will have to contend with liabilities of nitrate-based heart disease medications.

Research defining the peripheral pathways of erectile physiology and investigating the pathogenesis of erectile dysfunction has led to the recognition of a predominant vascular basis for organic male sexual dysfunction, while the role of the central nervous system is just beginning to emerge. These scientific advances have laid the foundation for the advent of new treatments. Significant advances in the research of erectile dysfunction indicate that vascular disease appears to exacerbate the changes in corpus cavernosum structure seen with aging. The recent availability of new oral and minimally invasive medications offers the possibility of multiple pharmacological approaches for the treatment of MED. The new frontier of understanding the central control of erection is still in its infancy, and future research into CNS regulation of erection may lead to novel, safer, and efficacious pharmacotherapies.