Pii: s0165-6147(00)01587-x

Pharmacotherapy for erectile dysfunction
Trinity J. Bivalacqua, Hunter C. Champion, Wayne J.G. Hellstrom and Philip J. Kadowitz

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. An estimated 20–30 million men suffer from some degree of sexual dysfunction. The past 20 years of research on erectile physiology have increased our understanding of the biochemical factors and intracellular mechanisms responsible for corpus cavernosal smooth muscle contraction and relaxation, and revealed that ED is predominantly a disease of vascular origin. Since the advent of sildenafil (Viagra®), there has been a resurgence of interest in ED, and an increase in patients presenting with this disease. A thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED.
Male erectile dysfunction (ED) is a condition defined by the of the cavernosal arteries). In the flaccid state, the smooth inability to attain or maintain penile erection sufficient for muscle trabeculae, which support the vascular sinuses, are satisfactory sexual intercourse. Data from the Massachusetts tonically contracted and permit only a small amount of Male Aging Study have indicated that the prevalence of ED arterial inflow6. The release of neurotransmitters from cav- is 39% in 40-year-old men and 67% in those aged 70 years1,2.
ernous nerve terminals and smooth muscle endothelium in In the past, ED was believed to be primarily a result of non- response to sexual stimulation results in cavernosal smooth specific psychological causes; more recently, an organic eti- muscle relaxation and ultimately penile erection.
ology can be identified in the majority of men with ED.
The penis is innervated by both autonomic and somatic Although patients can have several medical conditions, or- nerve fibers7. Sympathetic and parasympathetic nerves from ganic ED is usually associated with vascular risk factors, such the pelvis merge to form the cavernous nerves, which enter as atherosclerosis, hypertension, diabetes mellitus, Peyronie’s the corpus cavernosum to regulate blood flow to the penis disease and cigarette smoking3–5. Pelvic trauma and pelvic during penile erection8. The somatic pudendal nerve provides surgery (radical prostatectomy or radical cystectomy) resulting sensation to the penis. Cholinergic nerves, nonadrenergic, in either vascular or nervous injury can cause ED. In addition, noncholinergic nerves (NANC), nitric oxide (NO) and other specific pharmacological medications, such as antihypertensive factors such as vasoactive intestinal peptide (VIP) and calci- agents (␤-blockers), diuretics, cardiac medications, hormones tonin gene-related peptide (CGRP) mediate corpus caver- and antidepressants can induce ED (Ref. 4).
nosum smooth muscle relaxation7 (Fig. 1). In addition, shear Basic scientific research on ED has focused mainly on the stress and muscarinic acetylcholine receptors on trabecular H.C. Champion,
mechanisms of corpus cavernosum smooth muscle relax- endothelium stimulate the production of NO (Fig. 1). NO ation. Current pharmacotherapy for ED uses biochemical released from both NANC nerves and the trabecular endo- and physiological mechanisms that relax erectile tissue to thelium diffuses into smooth muscle cells where it directly achieve erectile function that is sufficient for normal sexual interacts with the soluble form of guanylate cyclase to in- crease intracellular concentrations of cGMP (Refs 9,10).
The increase in cGMP influences several cellular processes T.J. Bivalacqua,
Physiology of normal penile erection
that result in smooth muscle relaxation: (1) activation of The process of penile erection is dependent on an intact cGMP-dependent protein kinase G (PKG); (2) activation of central and peripheral nervous system. To understand the cGMP-dependent ion channels that reduce intracellular etiologies of ED, it is essential to understand the neural and Ca2+ via Ca2+ sequestration and/or extrusion; (3) opening vascular pathways that function during penile erection. Nor- of K+ channels causing hyperpolarization of corpus caver- mal erectile function involves three synergistic and simul- nosum smooth muscle cells; and (4) activation of myosin W.J.G. Hellstrom,
taneous processes: (1) a neurologically mediated increase in light chain phosphatases11–13. Similar to the more familiar penile arterial inflow; (2) relaxation of cavernosal smooth cAMP pathway, cGMP activity is terminated by hydrolysis muscle; and (3) restriction of venous outflow from the penis.
Ј5Ј bond by the type-5 phosphodiesterase (PDE)12.
ED occurs as a result of the failure of any of these processes, Moreover, VIP, CGRP and prostaglandin-mediated path- either alone or in conjunction with each other.
ways, which produce an increase in the concentration of The penis is composed of three bodies of tissue separated intracellular cAMP, might contribute to smooth muscle P.J. Kadowitz,
by connective tissue septae. The singular corpus spongiosum relaxation in the penis7 (Fig. 1). The increased corporal ar- supports and protects the urethra along the ventral surface of terial inflow results in an increase in intracavernosal pressure the penis. The paired corpora cavernosa, which lie dorsally and volume. As the penis expands in length and girth, the and adjacent to each other, function as blood-filling reser- intracavernosal pressure eventually exceeds that of the sub- voirs and provide structure to the penis in the erect state.
tunical venular plexus, thereby compressing it between the The cavernosal bodies comprise a network of vascular tunica albuginea and the peripheral sinusoids. This process sinuses supplied by the helicine arteries (terminal branches of veno-occlusion results in tumescence.
0165-6147/00/$ – see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01587-X Sildenafil
Fig. 1. Mechanisms and pharmacological therapies involved in regulation of corpora cavernosa smooth muscle tone and penile erection. All pharmacological
agents are shown in bold. Prostaglandin E (PGE ) and vasoactive intestinal peptide (VIP) activate adenylyl cyclase and increase intracellular levels of cAMP,
resulting in cavernosal smooth muscle relaxation and penile erection. Type-3 and -4 phosphodiesterase (PDE) inhibitors prevent the breakdown of cAMP to AMP.
Papaverine, a nonselective PDE inhibitor, prevents the breakdown of both cAMP and cGMP cyclic nucleotides, which leads to enhanced smooth muscle relax-ation and penile erection. Forskolin activates adenylyl cyclase directly, thus increasing intracellular cAMP levels. Nitric oxide (NO), synthesized by nonadrenergic,noncholinerigc (NANC) nerves and endothelial cells, diffuses into the smooth muscle cell activating guanylate cyclase and increasing intracellular cGMP syn-thesis, which results in cavernosal smooth muscle relaxation and penile erection. Sildenafil, the orally active type-5 PDE inhibitor, inhibits the breakdown of cGMPto GMP. Phentolamine, a nonselective ␤-adrenoceptor blocker, blocks the increase in intracellular Ca2+ by inhibiting the activation of protein kinase C (PKC) andinositol triphosphate, thus resulting in decreased intracellular Ca2+ and cavernosal smooth muscle relaxation. Abbreviations: ACh, acetylcholine; EP, prostaglandinreceptor; NOS, nitric oxide synthase.
Sexual behavior and erectile function are influenced by channels known as gap junctions in the membranes of the emotional and cognitive factors. At the level of the CNS, cavernosal smooth muscle cells16. Communication among the hypothalamic and limbic systems are responsible for the smooth muscle cells of the corpora cavernosa allows the pas- psychological components of penile erection. Within these sage and movement of physiologically relevant ions (K+, areas, central erectogenic signals facilitate spinal cord path- Ca2+) and second messengers (cGMP, cAMP), which gov- ways, which leads to tumescence of the penis via peripheral ern syncytial relaxation and contraction of the corpora cav- autonomic nerves. At the peripheral cellular level, trabecu- ernosal smooth musculature necessary for unified penile lar smooth muscle tone determines if the penis is in the flac- erection and detumescence16. Pharmacotherapy for the treat- cid or erect state. The balance between contractile systems ment of ED aims to develop new drug targets that inhibit (i.e. ␣-adrenoceptor, endothelin, angiotensin and throm- the contractile systems (␣-adrenoceptor antagonists) and stimu- boxane A ) and vasodilatory second messenger systems (i.e.
late [e.g. prostaglandin E (PGE ), NO-donors and forskolin] adenylyl-cyclase–cAMP and guanylate-cyclase–cGMP) de- or enhance (e.g. PDE inhibitors and gene therapy) the vaso- termines the state of the penis and tone of corpora cavernosa dilatory systems to promote increased trabecular smooth smooth muscle9,14,15. One important factor that should be con- muscle relaxation of the corpora cavernosa. Here, we discuss sidered in the erectile process and that contributes to the over- various pharmacotherapies and their mechanisms of action all vascular tone of the penis is the presence of intercellular Vasoactive intracavernous and transurethral injection
from the urethra and transported throughout the erectile tis- sue by communicating vessels between the corpus spongio- In the early 1980s, Virag and Brindley were the first to sum of the urethra and the corpora cavernosa. The main report on the clinical efficacy of intracavernosal injections of side-effect is penile pain in approximately 11% of the pharmacological agents to induce penile erection17,18. Since that time, intracavernosal injections of vasoactive agents The neuropeptide VIP has long been thought to be have been the most reliable and effective therapy for male involved in penile erection. Specific VIP receptors are pres- ED. However, intracavernosal injection can cause pain, ent on cavernosal smooth muscle cells and mediate smooth hypotension and a local fibrotic reaction in the penis19.
muscle relaxation through a G-protein-coupled interaction Direct injection of vasoactive agents into corpora cavernosa with adenylyl cyclase24. Although VIP plays a role in tu- bypasses the initial psychoneurological stimuli necessary to mescence, when injected alone it does not induce erections initiate penile erection and directly causes corpora cavernosa sufficient for vaginal entry25. However, when combined smooth muscle relaxation by activating specific receptors with phentolamine, it has moderate efficacy compared with and second messenger systems at the peripheral level. It is intracavernous PGE and has a recognized benefit of not well known that cavernosal cellular responses and the tone of the smooth muscle in the penis are regulated by cAMP The 37-amino-acid peptide CGRP is a potent vasodila- and cGMP (Refs 7,14,15). The cellular levels of cAMP and tor that relaxes the smooth muscle cells of the corpora cav- cGMP are determined by the relative synthetic activities of ernosa by hyperpolarization via K+ channel opening, and adenylyl and guanylate cyclase and the degradative activities activation of adenylyl cyclase with subsequent increases in of the cyclic nucleotide PDEs. Therefore, intracavernous intracellular cAMP (Ref. 27). When CGRP is administered vasoactive therapeutic agents use these cyclic nucleotides to intracavernosally in patients suffering from ED, there is a mediate smooth muscle relaxation, which leads to penile dose-related increase in penile arterial inflow27. The com- bination of PGE and CGRP has been used as an intra- cavernous combination therapy with moderate success but cAMP second messenger system and penile erection further studies are needed to determine the potential of this There have been many therapeutic agents used for the treat- combination for the pharmacological treatment of ED. ment of ED that elevate cAMP in the corpora cavernosa.
Forskolin is a plant alkaloid that has been shown to acti- Agents that increase intracellular levels of cAMP activate vate adenylyl cyclase directly and increase intracellular con- either specific cell-surface receptors that are coupled to centrations of cAMP (Ref. 28). Unlike PGE , forskolin does adenylyl cyclase, or adenylyl cyclase directly (Fig. 1). PGE not depend on activation of G proteins but activates the cat- binds to specific PGE receptors on corpora cavernosa alytic subunit of adenylyl cyclase directly. This agent has smooth muscle cells, which leads to elevation of intracellular been used in combination with other intracavernosal agents cAMP via a G-protein-coupled mechanism, and activation (e.g. PGE , phentolamine and papaverine) for the treatment of adenylyl cyclase14,20. Increases in cAMP result in phos- of severe vasculogenic ED but has not been used as a first- phorylation and dephosphorylation of the actin–smooth- line therapy for ED (Ref. 28). Forskolin has not been muscle–myosin cascade, which causes smooth muscle relax- approved for use in the USA because of the toxicity that ation14,20,21. In addition to its direct relaxant action on occurs with repeated use of this agent.
smooth muscle, PGE reduces adrenoceptor-mediated vaso-constrictor tone by inhibiting the release of noradrenaline cGMP second messenger system and penile erection through prejunctional receptors on noradrenaline-containing The principal mediator of corpora cavernosal smooth mus- cle relaxation and erectile function is NO (Refs 9,10,29). In Alprostadil, a natural prostanoid synthesized from the lipid the penis, NO is released from both nerve terminals and the precursor dihomo-␣-linoleic acid, is the synthetic form of endothelium that lines the cavernosal cisternae and blood PGE . Intracavernous PGE is the most efficacious intra- vessels, and subsequently diffuses into the smooth muscle cavernosal drug therapy used to date for the treatment cells where it activates guanylate cyclase to increase intra-of organic ED and was the first intracavernosal agent to cellular levels of cGMP (Ref. 29; Fig. 1). This process obtain FDA (US Food and Drug Administration) appro- reduces Ca2+ concentration, resulting in cavernosal smooth val (Caverject, Pharmacia, Kalamazoo, MI). When PGE muscle relaxation and, ultimately, in penile erection. cGMP is administered intracavernosally, it is metabolized largely activity is terminated by the breakdown of cGMP to GTP within the corpus cavernosum and has a half-life of 5–10 by the cGMP-specific type-5 PDE. In addition, NO acti- min (Ref. 22). The most significant adverse factors asso- vates the membrane-bound Na+–K+ ATPase, which in- ciated with the use of intracavernous PGE are painful erec- creases the membrane potential of the smooth muscle cells tions (7–50% of patients), high cost and fear of self-injection and further leads to smooth muscle relaxation30,31. The with a needle19,22. In 1997, transurethral PGE using a discovery of NO as the major neurotransmitter responsible novel delivery system [medicated urethral system for erec- for penile erection has led to the development of two classes tion (MUSE)] was introduced for the treatment of male ED; of pharmacological agents that are used for the treatment of this method of drug delivery into the penis is less invasive ED: NO-donors and -agents that increase or potentiate and does not use a needle23. Intraurethral PGE is absorbed (PDE inhibitors) cavernosal cGMP levels.
Linsidominer (SIN-1) is the active metabolite of the anti- anginal agent molsidomine. When SIN-1 is injected into the The PDEs are a class of intracellular enzymes involved in penis, it releases NO non-enzymatically, which in turn binds the breakdown of cAMP and cGMP. At least nine families to guanylate cyclase, leading to increases in intracellular cav- of PDE enzymes have been characterized in the human ernosal cGMP. SIN-1 hyperpolarizes the cell membrane by body, which suggests that each organ or tissue has its own influencing the Na+–K+ ATPase, thus making the caver- specific pattern of PDE enzymes35. Four PDE enzymes have nosal smooth muscle cells less responsive to ␣-adrenoceptor- been characterized in human cavernosal smooth muscle: mediated contraction27. SIN-1 induces tumescence in the cGMP-stimulated PDE (PDE2); cAMP-specific, GMP- majority of patients and a full erection in Ͼ50% of ED inhibitable PDE (PDE3); cAMP-specific PDE (PDE4); patients32. No local or systemic side-effects have been and cGMP-specific PDE (PDE5)36,37. PDE5 constitutes reported. However, SIN-1 is less efficient at inducing the majority of the cGMP hydrolytic activity in corporapenile erection satisfactory for sexual intercourse than is cavernosa smooth muscle cells. The oral type-5 PDE in- PGE (Ref. 33). SIN-1 has not been approved for use in the hibitor sildenafil citrate (Viagra®, Pfizer, New York, NY) USA; further clinical trials with SIN-1 or other NO-releas- is a safe and effective oral agent for the treatment of ED ing agents are necessary to evaluate their potential as thera- (Ref. 38; Fig. 1) The mechanism of action of sildenafil peutic alternatives for ED patients entering pharmacological requires intact NO-relaxing nerve fibers and intact cor- pus cavernosum endothelium. Sildenafil inhibits the break- Papaverine was the first effective intracavernosal agent down of cGMP induced by NO from neuronal and endo- used for the treatment of ED. Papaverine is a nonspecific thelial sources during sexual stimulation, and the increased PDE inhibitor that increases both intracellular cAMP and cGMP levels enhance cavernosal smooth muscle relax- cGMP levels, attenuates the ␣ -adrenoceptor-mediated con- ation12. Importantly, sildenafil will not be effective in the traction and, ultimately, leads to corporal smooth muscle absence of sexual stimulation or in patients with vascular relaxation11,24. Long-standing use of intracavernous papaverine disease, such as diabetes or radical prostatectomy, where might induce corporal fibrosis19. Moreover, when papaverine NO production is impaired. Moreover, sildenafil is con- is used as a monotherapy, 15–18% patients develop priapism, traindicated in cardiac patients taking nitrates because of most commonly men with neurogenic or psychogenic ED the potential of severe hypotension12. Headache, flush- etiologies34. Therefore, papaverine is used in combination ing, transient visual disturbances and dyspepsia are the most with phentolamine and PGE to reduce toxicity and priapism.
common adverse side-effects with sildenafil. Interestingly, Future pharmacological therapies might target cAMP- and there are three new second-generation oral type-5 PDE cGMP-specific PDE inhibitors in combination with other inhibitors for the treatment of ED that are in Phase III clini- agents as alternatives to the currently used intracavernous cal trials in the USA. These oral agents hope to offer patients agents because of fewer adverse side-effects.
less adverse side-effects. Currently, there are no cAMP PDEinhibitors available for the treatment of ED. However, both type-3 and type-4 PDE enzymes are present in the corpus Phentolamine, a nonselective ␣ - and ␣ -adrenoceptor cavernosum and thus, in the future, specific cAMP PDE antagonist, has been used for several years as an intracav- inhibitors might be targets for the pharmacological treat- ernous therapy agent. However, when used alone, this agent is weak in its ability to induce penile erection. Therefore, itis used in combination with papaverine and alprostadil21. The most common adverse side-effect is systemic hypotension Activation of the ␣-adrenoceptor is postulated to be in- volved in the suppression of erectile activity and themediation of the contracted corpus cavernosal tone of the Oral pharmacological therapies
penis in the flaccid state. An increased ␣-adrenoceptor- There has been a profound change in the current strategies mediated tone in the trabecular smooth muscle of the for the pharmacological treatment of ED with the advent of corpus cavernosum has been associated with ED in older effective oral erectogenic drugs. In the past, the first-line patients40. This ␣-adrenoceptor-mediated activity is regu- therapies for men suffering from ED were intracavernous lated by ␣ -adrenoceptors and prejunctional ␣ -adrenocep- and intraurethral pharmacological regimens. However, these tors in the adrenergic nerve terminals and the postjunctional agents have now become second-line therapies behind the receptors found on corpus cavernosum smooth muscle oral agents. In the past, fear of injections and concern about cells40. Blockade of these ␣-adrenoceptors might decrease other adverse effects from intracavernous therapy prevented the contractile function of the corpus cavernosum smooth several patients from seeking treatment. However, with the muscle cells and facilitate erection, as well as allow en- introduction of oral medications, public awareness of ED dogenous vasoactive mediators, such as NO and prosta- has increased and it has become easier to treat. Therefore, glandins, to demonstrate their vasodilatory properties in an new oral agents, which involve central stimulation and peripheral facilitation of erection by using the NO–cGMP Yohimbine, an ␣ -adrenoceptor antagonist with central pathway, represent the future targets of non-invasive alter- and peripheral effects, has been used for many decades as an oral agent in the treatment of male sexual dysfunction.
However, it has limited benefits in placebo-controlled Concluding remarks
studies41. Recently, oral phentolamine, a nonselective ␣- The increased public awareness of male sexual dysfunction adrenoceptor antagonist, has been proposed to improve will undoubtedly advance our understanding of the physio- erections in patients with psychogenic and mild arteriogenic logical mechanisms of erectile function and promote the ED (Refs 42,43; Fig. 1). In the future, it is likely that development of new, more effective oral and local agents for pharmacological management of patients with ED using oral the treatment of ED. The recent use of effective oral agents ␣-adrenoceptor antagonists will be in combination with as first-line therapy in most ED patients has been established.
agents that enhance or facilitate corpus cavernosal smooth Although sildenafil can cause serious adverse reactions in some individuals, such as patients with coronary disease takingnitrates, it has proved to be safe in combination with other antihypertensives. The future pharmacotherapy for male ED Dopamine receptors, especially dopamine D2 receptors, will focus on drugs that are non-invasive, efficacious and are located in the paraventricular nucleus and medial preop- demonstrate limited adverse side-effects.
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osteoporosis, cancer or both?

Mira Susva, Martin Missbach and Jonathan Green
Src was one of the first proto-oncogenes to be identified and is a prototype of non-receptor type tyrosine kinases.
The role of Src in bone metabolism first became apparent in Src-deficient mice and has been confirmed using low- molecular-weight Src inhibitors in animal models of osteoporosis. At the cellular level, it is well established that Src M. Susva,
plays an important role in proliferation, and adhesion and motility. In addition, recent data indicate an involvement of Src in cell survival and intracellular trafficking in various specialized cell types. These new findings suggest that Src inhibitors might have therapeutic value in the suppression of tumor growth, tumor angiogenesis and bone resorption.
M. Missbach,
Head of Bone
The protein tyrosine kinase Src is the prototype of a kinase The structure of Src and its regulation are well understood as family that comprises eight members in vertebrates, namely: a result of both mutational studies and structural models de- Src, Fyn, Yes, Fgr, Hck, Lyn, Lck and Blk. In contrast to rived from X-ray crystallography data2. The N-terminus has a receptor tyrosine kinases, which are integral plasma mem- unique sequence but its three-dimensional structure and func- brane proteins, Src belongs to the non-receptor class of tyro- tion are poorly defined. Two globular domains, Src homology J. Green,
sine kinases1. Src associates with various intracellular mem- domains 2 and 3 (SH2 and SH3), are adjacent to the N-termi- branes, where it catalyzes the transfer of phosphate from ATP nus, and are involved in protein–protein interactions. The SH1 to a tyrosine residue within proteins. Src, the first tyrosine domain has tyrosine kinase functionality within a two-lobe kinase to be characterized, was initially identified in the late structure (corresponding to an ATP- and substrate-binding site) 1970s in its viral form (v-Src) as a protein encoded by that is common to other protein kinases. Within the catalytic chicken Rous sarcoma virus. The cellular counterpart of SH1 domain, Tyr416 (in chicken c-Src) must be autophospho- v-Src, c-Src, is widely expressed in mammalian cells, with rylated for maximal activity, whereas the C-terminus (tail) can particularly high concentrations in brain, platelets and bone- be phosphorylated (Tyr527 in chicken c-Src) and folded back onto the SH2 domain to produce an inactive conformation.
0165-6147/00/$ – see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01567-4

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