Penile Smooth Muscle Relaxation Research Articles

Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone

Erectile dysfunction (ED) after injury to peripheral cavernous nerve (CN) is partly a result of inflammation in pelvic ganglia, suggesting that ED may be prevented by inhibiting neuroinflammation. The aim of this study is to examine temporal changes of TNF-α, after bilateral CN injury (BCNI), to evaluate effect of exogenous TNF-α on neurite outgrowth from major pelvic ganglion (MPG), and to investigate effect of TNF-α signal inhibition to evaluate effects of TNF-α on penile tone with TNF-α receptor knockout mice (TNFRKO). Seventy Sprague-Dawley rats were randomized to undergo BCNI or sham surgery. Sham rats' MPGs were harvested after 48 hours, whereas BCNI groups' MPGs were at 6, 12, 24, 48 hours, 7, or 14 days after surgery. qPCR was used to evaluate gene expression of markers for neuroinflammation in MPGs. Western blot was performed to evaluate TNF-α protein amount in MPGs. MPGs were harvested from healthy rats and cultured in Matrigel with TNF-α. Neurite outgrowth from MPGs was measured after 3 days, and TH and nNOS immunofluorescence was assessed. Wild type (WT) and TNFRKO mice were used to examine effect of TNF-α inhibition on smooth muscle function after BCNI. MPGs were harvested 48 hours after sham or BCNI surgery to evaluate gene expression of nNOS and TH. Gene expression of TNF-α signaling pathway, Schwann cell and macrophage markers, protein expression of TNF-α in MPGs, and penile smooth muscle function to electrical field stimulation (EFS) were evaluated. BCNI increased gene and protein expression of TNF-α in MPGs. Exogenous TNF-α inhibited MPG neurite outgrowth. MPGs cultured with TNF-α had decreased gene expression of nNOS (P < .05). MPGs cultured with TNF-α had shorter nNOS+ neurites than TH+ neurites (P < .01). Gene expression of nNOS was enhanced in TNFRKO mice compared to WT mice (P < .01). WT mice showed enhanced smooth muscle contraction of penises of WT mice was enhanced to EFS, compared to TNFKO (P < .01). Penile smooth-muscle relaxation to EFS was greater in TNFKO mice compared to WT (P < .01). TNF-α inhibition may prevent ED after prostatectomy. TNF-α inhibition might prevent loss of nitrergic nerve apoptosis after BCNI and preserve corporal smooth muscle function but further investigation is required to evaluate protein expression of nNOS in MPGs of TNFKO mice. TNF-α inhibited neurite outgrowth from MPGs by downregulating gene expression of nNOS and TNFRKO mice showed enhanced gene expression of nNOS and enhanced penile smooth-muscle relaxation. Matsui H, Sopko NA, Campbell JD, etal. Increased Level of Tumor Necrosis Factor-Alpha (TNF-α) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and Modulates Penile Smooth Tone. J Sex Med 2021;18:1181-1190.

Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation.

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

The Use of Vasoactive Drugs in the Treatment of Male Erectile Dysfunction: Current Concepts.

It is widely accepted that disorders of the male (uro)genital tract, such as erectile dysfunction (ED) and benign diseases of the prostate (lower urinary tract symptomatology or benign prostatic hyperplasia), can be approached therapeutically by influencing the function of both the vascular and non-vascular smooth muscle of the penile erectile tissue or the transition zone/periurethral region of the prostate, respectively. As a result of the discovery of nitric oxide (NO) and cyclic guanosine monophosphate (GMP) as central mediators of penile smooth muscle relaxation, the use of drugs known to increase the local production of NO and/or elevate the intracellular level of the second messenger cyclic GMP have attracted broad attention in the treatment of ED of various etiologies. Specifically, the introduction of vasoactive drugs, including orally active inhibitors of the cyclic GMP-specific phosphodiesterase (PDE) 5, has offered great advantage in the pharmacotherapy of ED and other diseases of the genitourinary tract. These drugs have been proven efficacious with a fast on-set of action and an improved profile of side-effects. This review summarizes current strategies for the treatment of ED utilizing the application of vasoactive drugs via the oral, transurethral, topical, or self-injection route.

MP84-08 TUMOR NECROSIS FACTOR ALPHA IS INCREASED AFTER CAVERNOUS NERVE INJURY AND IMPAIRS REGENERATION OF NITRERGIC NEURONS AND MODULATES PENILE SMOOTH MUSCLE TONE

You have accessJournal of UrologySexual Function/Dysfunction: Basic Research & Pathophysiology (MP84)1 Apr 2020MP84-08 TUMOR NECROSIS FACTOR ALPHA IS INCREASED AFTER CAVERNOUS NERVE INJURY AND IMPAIRS REGENERATION OF NITRERGIC NEURONS AND MODULATES PENILE SMOOTH MUSCLE TONE Hotaka Matsui*, Nikolai A. Sopko, Jefferey D. Campbell, Xiaopu Liu, Emmanuel Weyne, Maarten Albersen, Fabio Castiglione, Johanna L. Hannan, and Bivalacqua Trinity J Hotaka Matsui*Hotaka Matsui* More articles by this author , Nikolai A. SopkoNikolai A. Sopko More articles by this author , Jefferey D. CampbellJefferey D. Campbell More articles by this author , Xiaopu LiuXiaopu Liu More articles by this author , Emmanuel WeyneEmmanuel Weyne More articles by this author , Maarten AlbersenMaarten Albersen More articles by this author , Fabio CastiglioneFabio Castiglione More articles by this author , Johanna L. HannanJohanna L. Hannan More articles by this author , and Bivalacqua Trinity JBivalacqua Trinity J More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000976.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Erectile dysfunction is induced after cavernous nerve (CN) injury by inflammation in pelvic ganglia. We examined levels of tumor necrosis factor alpha (TNFA), after bilateral CN injury (BCNI) in vivo, and effect of exogenous TNFA (eTNFA) on neurite outgrowth from major pelvic ganglion (MPG) ex vivo. Additionally, we evaluated effect of TNFA signal inhibition to penile smooth muscle tone with TNFA receptor knockout mice (TNFRKO). METHODS: 70 male rats underwent sham or BCNI. MPGs of sham rats were collected after 48 hours. BCNI groups had MPG harvested at 6 h, 12 h, 24 h, 48 h, 7 days, or 14 days after surgery. We performed qPCR to examine gene expression of TNFA and Western blot to examine protein amount of TNFA in MPGs. Immunofluorescence(IF) for TNFA was performed in MPG. For ex vivo study, MPGs were harvested from control rats and cultured in Matrigel with eTNFA (0, 10, 20, 30 ng/mL). Neurite lengths from MPGs were measured 72 h after culture. MPGs were processed for qPCR of Tyrosine hydroxylase (TH) and neuronal nitric oxidase (nNOS). IF was assessed for TH and nNOS in MPG. To examine effect of TNFA inhibition on MPG and penis after BCNI, wild type mice (WT) and TNFRKO were randomized to undergo sham or BCNI. MPGs were harvested 48 hours after surgery to examine gene expression of nNOS and TH by qPCR. Penises were used to examine smooth muscle tone to electrical field stimulation (EFS). RESULTS: TNFA’s gene/protein expression was increased in MPGs after BCNI, with peaks at 2 and 7 days, respectively. IF showed TNFA localized to perivascular areas at 48 h and neuronal cell body at 14 days after BCNI. eTNFA inhibited neurite outgrowth in a dose-dependent fashion, and impaired gene expression of nNOS in MPG (p<0.05). MPGs cultured with eTNFA showed significantly shorter neurite lengths of nNOS+ neurons than TH+ neurons (p<0.01), while this difference was not seen in controls. TNFRKO showed enhanced gene expression of nNOS compared to WT (p<0.01). Penises of WT showed enhanced smooth-muscle contraction to EFS, compared to TNFKO (p<0.01). TNFRKO had enhanced relaxation response to EFS after maximal contraction, compared to WT (p<0.01). CONCLUSIONS: TNFA was increased following BCNI and inhibited neurite outgrowth from MPGs in a dose-dependent fashion. eTNFA lowered gene and protein expression of nNOS. TNFRKO mice showed enhanced gene expression of nNOS and enhanced penile smooth muscle relaxation. These results suggest that TNFA may selectively inhibit nNOS+ neurons, and impairs penile smooth muscle tone. Source of Funding: NIH © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1267-e1267 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hotaka Matsui* More articles by this author Nikolai A. Sopko More articles by this author Jefferey D. Campbell More articles by this author Xiaopu Liu More articles by this author Emmanuel Weyne More articles by this author Maarten Albersen More articles by this author Fabio Castiglione More articles by this author Johanna L. Hannan More articles by this author Bivalacqua Trinity J More articles by this author Expand All Advertisement PDF downloadLoading ...

171 Increased Level of Tumor Necrosis Factor-alpha (TNFA) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and TNFA Inhibition Can Enhance Penile Smooth Muscle Relaxation by Upregulating Expression of Nitrergic Neurons

171 Increased Level of Tumor Necrosis Factor-alpha (TNFA) Leads to Downregulation of Nitrergic Neurons Following Bilateral Cavernous Nerve Injury and TNFA Inhibition Can Enhance Penile Smooth Muscle Relaxation by Upregulating Expression of Nitrergic Neurons

Effects of endopeptidase inhibition on the relaxation response of isolated human penile erectile tissue to vasoactive peptides.

Peptides, such as CNP, CGRP and VIP, are involved in the function of male penile erectile tissue. Tissue levels of said peptides are controlled by the endopeptidase enzymes. Theoretically, the inhibition of the degradation of CNP, CGRP and/or VIP should result in an enhancement in penile smooth muscle relaxation. The effects were investigated of CNP or VIP (0.1nm-1μm), without and following pre-exposure of the tissue to a threshold concentration of the endopeptidase inhibitor KC 12615 (10μm, for 20min), on the reversion of tension induced by means of electrical field stimulation. Drug effects on the production of cyclic AMP/GMP were also evaluated. Neither KC 12615, CNP and VIP nor the combination of CNP plus KC 12615 or VIP plus KC 12615 increased the response of the tissue to EFS. While no effects were observed of a pre-exposure of the tissue to KC 12615 on the production of cyclic AMP in the presence of VIP, an enhancement was registered in the accumulation of cyclic AMP in the presence of CNP plus KC 12615. Further studies are indicated to investigate whether endopeptidase inhibitors might tend to be more effective in tissues affected by a decreased local production of vasoactive peptides.

Estrogen mediates metabolic syndrome-induced erectile dysfunction: a study in the rabbit.

Estrogen receptor (ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood. To investigate the effect of estrogens on metabolic syndrome (MetS)-associated erectile dysfunction (ED). We employed a recently established animal model of high fat diet (HFD)-induced MetS. Subgroups of MetS rabbits were dosed with either testosterone (T) or tamoxifen. We evaluated penile responsiveness to acetylcholine (Ach) as well as the expression of genes related to penile smooth muscle relaxation and contractility. Associations between MetS-induced penile alterations and sex steroids were investigated in an animal model of HFD-induced MetS. To understand the role of either androgen deficiency or estrogen excess on ED, we treated subgroups of MetS rabbits with either T or tamoxifen, a classical ER antagonist. Feeding an HFD-induced MetS was associated to elevated estradiol (E2) and low T levels. E2, but not T, was independently and negatively associated with genes able to affect penile erection. Smooth muscle-related markers decreased as a function of E2 and were positively associated with all the variables investigated. Increasing concentrations of circulating E2 were negatively associated with Ach-induced relaxation. In HFD rabbits, in vivo T dosing significantly improved MetS and completely normalized circulating E2. Conversely, in vivo tamoxifen dosing reduced visceral adiposity and partially restored T level. Ach-induced relaxation was severely impaired by HFD and significantly restored, up to the control level, by both tamoxifen and T dosing. In rabbit smooth muscle cells cultures 17β-E2 (1 nM) significantly reduced the expression of α-smooth muscle actin, transgelin, and phosphodiesterase type 5. The effects of 17β-E2 were completely reverted by tamoxifen (100 nM). This study demonstrates, for the first time, that HFD-induced ED is more associated with a high E2, rather than to a low T, milieu. HFD-induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen.

Arctium lappa improve Penile Erection in Penile Smooth Muscle

The aim of the present study was to investigate whether an ethanol extract of Arctium lappa (EAL) augments penile erection in vitro. Isolated rabbit endothelium‐intact corpus cavernosum was preconstricted with phenylephrine (PE). EAL relaxed penile smooth muscle in a dose‐dependent manner, which was significantly inhibited by pretreatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME), a nitric oxide synthase inhibitor, and 1H‐[1,2,4]‐oxadiazole‐[4,3‐¥á]‐quinoxalin‐1‐one (ODQ), a soluble guanylyl cyclase (sGC) inhibitor. EAL‐induced relaxation was also significantly attenuated by pertreatment with verapamil and diltiazem, respectively. On the other hand, relaxation of penile smooth muscle induced by EAL was not blocked by several inhibitors including tetraethylammonium (TEA), glibenclamide, indomethacin, atropine and propranolol, respectively. In the perfusion model of penile tissue, EAL also relaxed PE‐precontracted penile tissue tension in a dose‐dependent manner. Moreover, perfusion of penile tissues with EAL significantly increased the levels of cGMP and cAMP. Taken together, these results suggest that EAL may be induced penile erection through the activation of penile tissue NO/cGMP system and/or Ca2+channels in corpus cavernosum.

810 SILODOSIN (KMD-3213) IS A LONG-ACTING α-1A ADRENOCEPTOR ANTAGONIST WITH ACTIVITY IN THE HUMAN CORPUS CAVERNOSUM

INTRODUCTION AND OBJECTIVES: Silodosin (KMD-3213, RapafloTM, Watson Pharmaceuticals, Inc. USA) is a new and highly selective 1A-adrenoreceptor (AR) antagonist for the treatment of lower urinary tract symptoms (LUTS) in men with BPH, a condition associated with erectile dysfunction (ED). Silodosin treats both irritative and obstructive symptoms. Silodosin induced responses on the human corpus cavernosum (HCC) needs further clarification. METHODS: HCC samples were obtained from patients (patient age: 50 66 yr) undergoing penile prosthesis surgery. Using the organ bath technique, drug effects were investigated with phenylephrine (PE, 10 M)-induced tension and electrically induced (0-40 Hz, 3 ms, 10 seconds, 60V) relaxation as well as on the acetylcholine (10 nM1000 nM) and sodium nitroprusside (SNP, 1 nM) induced relaxations of HCC strips (n 12). Direct EFS and KCl (100 mM) induced contractile responses were also generated in the presence of silodosin (0.01 M). RESULTS: Silodosin (0.01 M to 100 mM) induced relaxation (84.68 13.8 % and 37.62 10%) on PE and KCl precontracted strips. EFS-induced relaxant nitrergic responses (43.66 4.44% and 57.05 6.80%, p 0.1178) and contractile adrenergic (11.03 5.98%) neurogenic responses were not significantly affected by incubation with silodosin. ACh (40.01 1.41%, at 100 mM) and SNP (37.46 7.98, at 1 nM) induced relaxations were significantly enhanced (84.68 13.8%, 85.47 3.30%, p 0.0001, respectively) by silodosin. CONCLUSIONS: Inhibition of 1A-AR induces marked penile smooth muscle relaxation. The enhanced relaxation responses to ACh and SNP indicates the involvement of nitric oxide-cGMP pathways. However, silodosin does not target afferent nitrergic and adrenergic nerves in the HCC, and thereby does not act on the neurogenic erectile responses. Our results provide a rationale for the future use of silodosin as an oral treatment for ED. If approved for the human CC, silodosin may contribute to improved erectile function in patients treated for BPH-linked LUTS. Further clinical investigations of silodosin are necessary to evaluate the beneficial effect in ED patients who are not responding sufficiently to PDE5 inhibitors. It is still unknown whether the combination of silodosin and PDE-5 inhibitors is more effective than either mono-treatment.

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, both autonomic and somatic, and supraspinal influences from visual, olfactory, and imaginary stimuli. Several central transmitters are involved in the erectile control. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropin/α-melanocyte-stimulating hormone, have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. The balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa (CC) and determines the functional state of the penis. Noradrenaline contracts both CC and penile vessels via stimulation of α₁-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and CC. The role of other mediators, released from nerves or endothelium, has not been definitely established. Erectile dysfunction (ED), defined as the "inability to achieve or maintain an erection adequate for sexual satisfaction," may have multiple causes and can be classified as psychogenic, vasculogenic or organic, neurologic, and endocrinologic. Many patients with ED respond well to the pharmacological treatments that are currently available, but there are still groups of patients in whom the response is unsatisfactory. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including oral phosphodiesterase inhibitors and intracavernosal injections of prostaglandin E₁. Irrespective of the underlying cause, these drugs are effective in the majority of cases. Drugs with a central site of action have so far not been very successful. There is a need for therapeutic alternatives. This requires identification of new therapeutic targets and design of new approaches. Research in the field is expanding, and several promising new targets for future drugs have been identified.

Phosphodiesterase inhibitors and the eye

Phosphodiesterase type 5 (PDE5) inhibitors are effective oral treatments for erectile dysfunction and have become one of the most widely prescribed medications worldwide. The mechanism of action is to reduce the degradation of cyclic GMP (cGMP) potentiating the effect of nitric oxide in the corpus cavernosum and allowing erectile function to occur by consequent relaxation of penile smooth muscle. Because of the presence of PDE5 in choroidal and retinal vessels these medications increase choroidal blood flow and cause vasodilation of the retinal vasculature. The most common symptoms are a blue tinge to vision and an increased sensitivity to light. There have been reports of non-arteritic anterior ischaemic optic neuropathy and serous macular detachment in users of PDE5 inhibitors, although a causal relationship has not been conclusively shown. Despite the role of cGMP in the production and drainage of aqueous humour these medications do not appear to alter intraocular pressure and are safe in patients with glaucoma. All PDE5 inhibitors weakly inhibit PDE6 located in rod and cone photoreceptors resulting in mild and transient visual symptoms that correlate with plasma concentrations. Psychophysical tests reveal no effect on visual acuity, visual fields or contrast sensitivity; however, some studies show a mild and reversible impairment of blue-green colour discrimination. PDE5 inhibitors transiently alter retinal function on electroretinogram testing but do not appear to be retinotoxic. Despite the role of cyclic nucleotides in tear production there is no detrimental effect on tear film quality. Based on the available evidence PDE5 inhibitors have a good ocular safety profile.

Effect of a methanol extract of Arctium lappa on penile erection in penile smooth muscle

The aim of the present study was to investigate whether a methanol extract of Arctium lappa (EAL) augments penile erection. In isolated endothelium‐intact rabbit corpus cavernosum preconstricted with phenylephrine, EAL relaxed penile smooth muscle in a dose‐dependent manner, which was inhibited by pretreatment with a nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine methyl ester (L‐NAME), and a soluble guanylyl cyclase inhibitor, 1H‐[1,2,4]‐oxadiazole‐[4,3‐α]‐quinoxalin‐1‐one (ODQ), L‐type Ca2+ channel blockers, verapamil, and diltiazem, respectively. On the other hand, penile smooth muscle relaxation induced by EAL was not blocked by several inhibitors including indomethacin, atropine, propranolol, tetraethylammonium (TEA), and glibenclamide, respectively. In addition, incubation of endothelium intact rabbit corpus cavernosum tissues with EAL increased cGMP production in a dose‐dependent manner. Taken together, these results suggest that EAL may be induce penile erection through the activation of penile tissue NO/cGMP system and/or Ca2+channels in rat corpus cavernosum.

Run training ameliorates the established erectile dysfunction in rats under long-term nitric oxide (NO) blockade

Introduction Stimulation of nitrergic neurons and endothelial cells in the erectile tissue results in release of NO that diffuse to surrounding smooth muscle cells where it activates the soluble guanylate cyclase (sGC), facilitating the conversion of GTP to cGMP. This second messenger diminishes the intracellular levels of calcium thereby causing penile smooth muscle relaxation and penile erection [1]. Epidemiological studies have shown a strong association between erectile dysfunction (ED) and arterial hypertension [2], where the deficiency of the NO-cGMP pathway seems to greatly contribute to such association [3]. Regular physical exercise has been shown to increase the NO production thus ameliorating cardiovascular diseases [2,4]. Recently, we have shown that prior physical conditioning improves the erectile function in normotensive rats [5] and prevents the impaired corpus cavernosum relaxation secondary to chronic NO blockade in rats [2].

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

The discovery that inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cGMP, allowing erectile function to occur by relaxation of penile smooth muscle, represents a revolutionary approach or the treatment of erectile dysfunction (ED). Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) are clinically available at this time, and extensive drug design efforts are registered for finding agents with a better activity, enhanced selectivity and reduced side effects. Many classes of such compounds have been reported, belonging to diverse chemical entities. The drug design has been very much facilitated after the report of the X-ray crystal structure of the PDE5 catalytic domain in complex with the three clinically used derivatives. PDE5 inhibitor therapy, has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. The duration of action of sildenafil and vardenafil is of about 4 hours, whereas that of tadalafil is of about 36 hours, and the overall safety of the treatments is good. There is a risk of hypotension if nitrates are given concurrently with the PDE5 inhibitors. Common side-effects include headache, facial flushing, nasal congestion, dyspepsia and transient visual impairment. There are pharmacological interactions between these drugs and other medications metabolized by the cytochrome P450 (P3A4 isoform), such as the azole antifungals, erythromycin and the HIV protease inhibitors.

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.

Current and future standards in evaluation of erectile dysfunction

Sexual dysfunction and more specifically erectile dysfunction (ED) can be a harbinger of serious occult medical conditions. ED can be considered a clinical manifestation of generalized vascular disease and therefore shares similar risk factors: aging, hypertension, diabetes mellitus, hypercholesterolemia and smoking. The initial evaluation of men with ED should be thorough. Studies of normal and abnormal penile tumescence have led to the discovery of many important pathways. The greatest medical advance in the management of male sexual dysfunction since the identification of androgens have been the discoveries that nitric oxide (NO) is the primary neuro-modulator of penile smooth muscle relaxation and that oral phosphodiesterase type 5 inhibitors enhance erection quality through the NO mechanism. As a consequence of oral pharmacotherapies, the role of invasive diagnostics has diminished. Most guidelines recommend only history, physical exam and limited laboratory testing prior to instituting oral therapies for ED. In 2006 we still have unanswered questions about ED and these will frame the role of future diagnosis and therapy: can lifestyle changes alone improve erectile function; is ED a marker for the development of atherosclerotic heart disease, do lower urinary tract symptoms of benign prostatic hypertrophy and ED share a common pathway?

The evolution of vascular testing in erectile dysfunction

Over the past 20 years, many contributions have been made to our understanding of the mechanisms of erection as a result of penile vascular testing. The greatest medical advances in the management of male sexual dysfunction since the identification of androgens have been two discoveries: 1) that nitric oxide is the primary neuromodulator of penile smooth muscle relaxation, and 2) that oral phosphodiesterase type 5 inhibitors enhance erection quality through the nitric oxide mechanism. As a consequence of oral pharmacotherapies, the role of invasive diagnostics has diminished. Most guidelines recommend only history, physical examination, and limited laboratory testing before instituting oral therapies for erectile dysfunction (ED). We still have unanswered questions about ED. Can lifestyle changes alone improve erectile function? Is ED a marker for the development of atherosclerotic heart disease? What are the specific effects of known cardiovascular morbidities on penile vascular integrity? These questions will frame the role of future penile vascular diagnostics.

The efficacy and safety of PDE5 inhibitors

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat.

Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using alpha-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species.

Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology

Modern drugs used to treat erectile dysfunction act locally to facilitate penile smooth muscle relaxation, but a new generation of centrally acting agents is in clinical trials. One of these, apomorphine, a dopamine receptor agonist, was recommended in 2000 by a committee of specialists at the US Food and Drug Administration (FDA) as a treatment for impotence.1 We describe here evidence that the treatment of erectile dysfunction with apomorphine is not new: the Mayans and ancient Egyptians were well acquainted with the clinical effects of an apomorphine-containing plant, and they probably used that plant as an aid to sexual activity. Nymphaea caerulea (blue lotus) and N. ampla, which has a white flower but a similar alkaloid content, grow along lakes and rivers, thrive in wet soil, and bloom in the spring.2 They belong to the water-lily family. Another variety is N. lotos, sometimes called the 'white lotus' though not a true lotus. The isolation of the psychoactive apomorphine from Nymphaea species3 has offered chemical support to speculation that Nymphaea species may have been employed as hallucinogens in both the Old and the New World.4,5 The use of N. caerulea and of N. lotos in rites and rituals is depicted in the frescoes within the tombs, and in very early papyrus scrolls. The most important of these was the scroll of Ani (Book of the Dead). Nymphaea is mentioned and represented in several chapters of the book, always tied to magical-religious rites. Depictions of Papaver somniferum and mandragora, also known as mandrake, a hallucinogenic plant with anticholinergic properties, often appear alongside those of Nymphaea.6 Tutankhamon's tomb contained a gold-plated shrine decorated with a bas-relief of a pharoah holding a huge Nymphaea and two mandragoras in his left hand. Nymphaea flowers were also depicted in frescoes from the tomb of Nebaum (XVIII Dynasty, 1370-1318 bc) found in Luxor, and now located in the British Museum. The frescoes illustrate a ritualistic funeral dance with two male dancers accompanied by three women, garlanded with petals of N. caerulea. The women are offering vases, from which golden emanations flow as if they contained a magical fluid. Nymphaea species also feature in erotic cartoons (Figure 1). Figure 1 Detail from erotic cartoon (Turin papyrus 55001), showing 'lotus' over the head of woman, possibly symbolizing her powers of arousal. Reproduced by permission from Manniche L, Sexual Life in Ancient Egypt (London, New York, Bahrain; Kegan Paul, 2002) Similar motifs are seen in Mayan art, and Dobkin de Rios,7 Diaz,8 and Emboden9,10 hypothesize that the plants were used as hallucinogens during religious rites or as 'entheogenes', symbolic of a union between man and the divine. In a vase found in the Classic period Mayan site of Bonampak, the headpiece of the central figure depicts a character adorned with a Nymphaea, performing a ritual dance. In the Mayan ruins of Palenque, also in Chiapas, Mexico, a bas-relief in the tomb of Pacal, in the Temple of Inscriptions, contains a representation of two Mayan priests standing on either side of 'jaguar god'. One of the priests has a Nymphaea bud emerging from his head, and the other has the same bud emerging from his headpiece. Such striking similarities in such distant cultures lead to the conclusion that the plants had a common use. Studies from several different laboratories have identified apomorphine and aporphine in the bulbs and roots of N. ampla.11 The emetic effect of apomorphine (and aporphine, which is hydroxylated in the body to form apomorphine) is well known. Mescal beans, ritually used by shamans to induce an ecstatic states are likewise emetic; it has been hypothesized that Nymphaea was used by both Egyptian and Mayan cultures as a purifying ritual emetic.11 However, it has only recently become clear that apomorphine can be utilized, with excellent results, to treat erectile dysfunction. It is a centrally acting, selective D1/D2 dopamine agonist, and activation of dopaminergic receptors in the paraventricular nucleus of the hypothalamus initiates a cascade of events, ultimately resulting in smooth muscle relaxation and vasodilatation within the corpora cavernosa, leading to penile erection.12,13 This discovery provides a likely explanation for the appearance of Nymphaea in the Luxor frescoe and in erotic cartoons such as that reproduced in Figure 1. The fact that temple drawings only depict use by the higher castes, such as priests and royalty, suggests that the masses did not benefit from this discovery. The Nymphaea story serves as a further illustration of how the effects of substances of plant origin were known even though the discoverers lacked the technology to explain them.14,15