On the partner website doctordansfreedomforum.com given a complete description how to take these tablets. Be sure to check before use.

Je l'ai acheté le médicament cialis prix deux ou trois fois, l'effet est des pilules superbes, je ne ne nous a pas déçus même si je suis au dernier étage sur la pilule. Männer werden empfohlen, für mindestens 30 Minuten für den angeblichen Geschlechtsverkehr durchschnittliche Rendite von cialis 20mg zu verwenden.

Jch-decsuppl06.indd

The Role of Nitric Oxide in Erectile
Dysfunction: Implications for Medical Therapy
Arthur L. Burnett, MD Erectile dysfunction is a common, multifactorial ed high tolerability and success rates for improved disorder that is associated with aging and a range erectile function. The efficacy of the PDE-5 of organic and psychogenic conditions, includ- inhibitors also serves to illustrate the importance ing hypertension, hypercholesterolemia, diabetes of the NO–cGMP pathway in erectile function mellitus, cardiovascular disease, and depression. since these agents counteract the degradation of Penile erection is a complex process involving NO-generated cGMP. Because not all patients psychogenic and hormonal input, and a neurovas- respond to PDE-5 inhibitors, additional therapies cular nonadrenergic, noncholinergic mechanism. are being investigated, such as soluble guanylyl Nitric oxide (NO) is believed to be the main vaso- cyclase activators and NO donors, which act on active nonadrenergic, noncholinergic neurotrans- NO-independent and NO-dependent pathways, mitter and chemical mediator of penile erection. respectively. (J Clin Hypertens. 2006;8(12 suppl Released by nerve and endothelial cells in the cor- 4):53–62) 2006 Le Jacq pora cavernosa of the penis, NO activates soluble guanylyl cyclase, which increases 3',5'-cyclic gua-nosine monophosphate (cGMP) levels. Acting as Erectile dysfunction (ED) is a common and a second messenger molecule, cGMP regulates the complex disorder that significantly impacts activity of calcium channels as well as intracel- quality of life and is recognized as an important lular contractile proteins that affect the relaxation public health problem.1–3 Defined as an inabil- of corpus cavernosum smooth muscle. Impaired ity to achieve and maintain an erection sufficient NO bioactivity is a major pathogenic mechanism for satisfactory sexual intercourse, ED is associ- of erectile dysfunction. Treatment of erectile dys- ated with aging and an increasing number of function often requires combinations of psycho- common systemic diseases including hypertension, genic and medical therapies, many of which have cardiovascular disease (CVD), diabetes mellitus, been only moderately successful in the past. The hypercholesterolemia, and depression, as well as advent of oral phosphodiesterase type 5 (PDE-5) behaviors such as smoking, alcoholism, and drug inhibitors, however, has greatly enhanced erectile abuse.2,4 Evidence suggests that ED may serve as a dysfunction treatment; patients have demonstrat- general marker for occult CVD and as an indicator of general physical and emotional health.3,5,6 Estimates of the prevalence of chronic ED in From the Department of Urology, Johns Hopkins the United States have varied, partly because of Medical Institutions, Baltimore, MD differences in methodology and populations in Address for correspondence: epidemiologic studies.7 An international study8 Arthur L. Burnett, MD, Professor of Urology, Director, Basic Science Laboratory in Neurourology, Director, that included 9284 men aged 20–75 years in the Male Consultation Clinic, Department of Urology, United States found that the prevalence of ED in JHH-407 Marburg 21287, Johns Hopkins Medical this population was 22% in 2001, which would Institutions, 600 North Wolfe Street, translate to approximately 20 million men. The Baltimore, MD 21287 Massachusetts Male Aging Study,9 conducted from 1987–1989 in Boston, showed that the combined prevalence of minimal, moderate, and complete SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
ED in men aged 40–70 years was 52%, with com- area, including the paraventricular and supraop- plete impotence increasing from 5% to 15% from tic nuclei, of the hypothalamus of the brain.16,18 40–70 years. A larger study, however, of more than In response, the hypothalamus releases multiple 31,000 US health care professionals aged 53–90 amines and neuropeptides, including gonadotropin- years found that the age-standardized prevalence releasing hormone, oxytocin, α-melanocyte–stimu- of ED, using conservative criteria of poor to very lating hormone, and substance P, which stimulate poor function, was 33%, ranging from about the erectile response.16 These neurohormones then 25% among those younger than 59 years to 61% project to the thoracolumbar sympathetic nerve in individuals older than 70 years.7 Overall, the fibers at the T –L region and to sacral S –S prevalence of moderate ED in the United States parasympathetic nerve fibers, which inhibit and appears to be about 20% in the total adult male stimulate penile erection, respectively.16 population, 30%–50% in those aged 40–70 years, Stimulation of the sacral parasympathetic nerves and >60% in men older than 70. Reflecting the is carried through the pelvic plexus and subse- epidemiologic scope of this disorder, more than 23 quently the cavernous nerves of the corpora caver- million men have been prescribed sildenafil citrate nosa, which are the 2 parallel columns of erectile since its release in 1998.10 tissue of the penis.2,16 The cholinergic and NANC Increased study of the epidemiology of ED nerve fibers of the corpora cavernosa, in turn, has been accompanied by significant advances in trigger the release of vasoactive neurotransmitters, research in its pathogenesis and treatment.3,8 Once including acetylcholine and NO, which promote largely attributed to psychological causes and relaxation of cavernosal trabecular smooth muscle aging, ED is now understood to have a complex and cause a several-fold increase in blood flow to organic etiology in many patients.4,7,9,11 The con- the corpora cavernosa and expansion of their sinu- siderable evidence linking ED with CVD suggests soids.16,18 The resultant penile tumescence causes that both may share the pathogenic pathway of compression of the emissary veins, which run endothelial dysfunction, which is characterized through the tunica albuginea, a sheath-like tissue by impaired bioactivity of the nitric oxide (NO) around the corpora cavernosa; this compression signaling pathway.7,11 Research has identified NO, occludes venous drainage, which traps the blood a major component of endothelial function, as the and produces rigidity.2 In addition, sexual activity primary biochemical mediating erectile function triggers the bulbocavernosus reflex, causing the and impairment of NO release or actions as a ischiocavernous muscles to forcefully compress the major pathogenic mechanism of organic ED.12–14 base of the perfused corpora cavernosa, resulting This article will explore the role of NO in erection in further, or full, rigidity.2 physiology and pathophysiology and the potential A reflexogenic erection is triggered by direct therapeutic strategies that target NO as a treat- physical stimulation of the genital organs. While the ment for ED.
stimulation sends ascending messages to the brain, it also sends direct messages via a local neural loop PHYSIOLOGY OF ERECTILE FUNCTION
involving parasympathetic sacral nerve stimula- Penile erection is a remarkably complex process that tion from S –S to create the erectile response.16,18 relies primarily on a neurovascular, nonadrenergic, Nocturnal penile erection, which occurs during noncholinergic (NANC) mechanism peripherally, as rapid eye movement sleep, is poorly understood, well as the central nervous system.2,15 The erectile but appears to occur through central nervous sys- response is modulated by psychological factors and tem mechanisms and involves such neuromediators androgens and may proceed through psychogenic or as serotonin, dopamine, noradrenalin, glutamate, reflexogenic neuronal pathways.2,15 Detumescence γ-aminobutyric acid, and NO processed in the pon- is controlled by sympathetic responses through tine reticular formation and amygdalae.18,19 release of norepinephrine, which induces smooth muscle constriction, vasoconstriction, and penile NO in Erection Physiology
flaccidity.16,17 Therefore, a penile erection occurs NO is believed to be the main vasoactive NANC when both detumescence is inhibited and erectile neurotransmitter of erectile action in the corpora response stimulated and when penile blood inflow cavernosa.2,4,15 The enzyme NO synthase (NOS), exceeds outflow.16,17 which catalyzes NO from the conversion of L- A psychogenic erection is triggered by external arginine to L-citrulline, has been localized to neu- erotic input received through the 5 senses or mental ronal tissue, endothelium, and epithelium within fantasies that are processed in the medial preoptic pelvic and urogenital structures of humans and THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
various animal species.20,21 The erectile response NO is essential in facilitating the achievement and is triggered with the initial release of NO by the maintenance of full erection.22,30 In vivo studies autonomic NANC dilator nerve fibers supply- have shown that intracavernosal administration of ing the corpora cavernosa and the vascular and an adenovirus containing the eNOS gene to old or sinusoidal endothelium.2 Further NO release from diabetic rats with ED significantly improved erec- the endothelium results from blood flow shear tile function, as measured by intracavernous pres- forces.22 NO then diffuses across the smooth sure, in response to cavernous nerve stimulation, muscle membrane and activates soluble guanylate underscoring the physiologic effects of eNOS in cyclase (sGC), which catalyzes the production of erectile function.31,32 In addition, intracavernosal 3ʹ,5ʹ-cyclic guanosine monophosphate (cGMP).2 administration of vascular endothelial growth fac- The increased cGMP activates a protein kinase that tor, which promotes endothelial cell proliferation phosphorylates specific proteins and ion channels, and migration in vitro and angiogenesis in vivo, resulting in the opening of potassium channels and has been shown to restore erectile function and hyperpolarization of the muscle cell membrane.2,15 endothelium-dependent smooth muscle relaxation These actions lead to the sequestration of intracel- in rat and rabbit models of ED.33–36 lular calcium by the endoplasmic reticulum and to blockade of calcium channels and calcium influx, Modulators of NOS
which causes decreased cytosolic calcium levels, Findings from rat studies suggest that NO-mediated relaxation of vascular smooth muscle, and vasodi- cavernosal relaxation in erection physiology is in lation.2,15 Neuronal NO may also mediate the neu- part regulated by testosterone, of which the active rotransmission of erectile stimuli from the brain metabolite appears to be dihydrotestosterone.37,38 through the spinal cord, although these functions Castration in rats has been correlated with a 50% have not been well characterized.13 The erectile reduction in the erectile response to electrical field actions of NO have been demonstrated in human stimulation of the cavernous nerve.37 Conversely, penile tissue samples and in a range of experimen- administration of testosterone and dihydrotestos- tal in vitro and in vivo animal studies.23–26 terone to castrated rats has been shown to restore NO-mediated intracavernosal pressure and the erec- Role of NOS Isoforms
tile response.37,38 The association of androgens with Of the 3 known isoforms of NOS—neuronal cavernosal NOS activity in humans is less clear, NOS, endothelial NOS (eNOS), and inducible however.39 In addition, experimental studies suggest NOS—neuronal NOS and eNOS are constitutively that NO-mediated relaxation of the corpora caver- present in the corpora cavernosa, although to vary- nosa is also related to the physiologic levels of oxy- ing degrees and in different cell types.4 Neuronal gen, and can be inhibited in states of hypoxia.40,41 NOS is primarily localized to NANC cells of nerve fibers of the corpora cavernosa although it is also expressed in the paraventricular nucleus of the Consistent with the complex physiology of penile brain, where it may interact with erectile response erection, ED may be caused by 1 or more of a range neurohormones such as oxytocin, and in the spi- of psychologic, neurologic, vasculogenic, hormonal, nal cord, where the mechanisms of NO in erectile or pharmaceutical factors, and is broadly classified function are unclear.13 eNOS is chiefly found in as psychogenic, organic, or mixed (Table I)2,13; psy- the endothelium of the vasculature of the penis, chogenic and organic causes of ED are frequently although controversy exists over whether it may concomitant.4 Epidemiologic studies have shown also be found in cavernosal smooth muscle.4,13,15,27 that after adjustment for age, ED is significantly Inducible NOS has been detected in the corpora associated with CVD, hypertension, diabetes mel- cavernosa, most probably in smooth muscle cells, litus and associated medications, hypercholesterol- in association with inflammatory effects or other emia, metabolic syndrome, obesity, smoking, and pathologic changes of the penis.15,28 lower urinary tract symptoms, as well as anger, Neuronal NO has been assumed to play the depression, and fewer years of education.8,9,42–46 major role, compared with the other NOS iso- Neurologic diseases such as Parkinson's disease are forms, in facilitating relaxation of the corpora also recognized as a cause of ED (Table I).2 An anal- cavernosa and inducing increased blood flow to ysis of data from a managed-care claims database produce penile erection.15,29 Increasing evidence covering 51 health plans and 28 million lives in the suggests, however, that while neuronal NO pro- United States showed that 68% of all patients with motes initial cavernosal relaxation, endothelial ED (N=272,325) had 1 or more of the following 4 SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
Table I. Common Causes of Erectile Dysfunction
CATEGORY OF ERECTILE
CAUSES OF DYSFUNCTION Performance anxiety Loss of libido, overinhibition, or impaired nitric Relationship problems Stroke or Alzheimer's disease Dysfunction of initial nerve impulse or Spinal cord injury interrupted neural transmission Radical pelvic surgeryDiabetic neuropathyPelvic injury Loss of libido and inadequate nitric oxide Vasculogenic (arterial or Inadequate arterial flow or impaired Diabetes mellitusTraumaPeyronie's disease Antihypertensive and antidepressant drugs Central suppression Alcoholic neuropathy Cigarette smoking Vascular insufficiency Caused by other systemic Usually multifactorial resulting in neural and diseases and aging Diabetes mellitus vascular dysfunction Chronic renal failureCoronary heart disease comorbidities: hypertension, hyperlipidemia, diabe- had 1 or more risk factors for coronary heart dis- tes mellitus, or depression.47 ease (CHD).54 Furthermore, ED may be an early Among the most common organic risk factors, marker for the presence of CHD among asymp- diabetes mellitus is associated with a particularly tomatic individuals. Studies have found a signifi- high prevalence of ED, with estimates ranging cantly increased rate of ED among men without from 27%–75%, and with greater severity than in symptomatic ischemia but with established CHD nondiabetic men. This association may be related markers, such as elevated C-reactive protein, endo- to diabetic vasculopathy, neuropathy, or hypo- thelial dysfunction, and angiographic evidence of gonadism.6,48–50 A survey found that the rate of atherosclerosis.5,55,56 A study in 300 patients with hypertension in more than 285,000 men with ED symptomatic ischemic heart disease (mean age, in the United States was 41.2%, compared with 62.5 years) found that 49% had ED, of whom 19.2% in more than 1.5 million men without ED, 67% reported having experienced ED symptoms representing an odds ratio of 1.38 for hypertension before the onset of CHD symptoms.57 These and to be present with ED, after controlling for age and other data have led to an increased focus on the other variables (P<.0001).51 High plasma levels of neurovascular mechanisms of ED, with a particu- total and low-density lipoprotein cholesterol were lar emphasis on the role of endothelial dysfunction associated with odds ratios for ED of 1.74 (P=.04) and impaired NO bioactivity.58 and 1.97 (P=.02), respectively, in men with ED compared with those without ED.52 Impaired NO Bioactivity in ED
While the pathogenic links between each of Peripheral vascular mechanisms of ED may involve these risk factors and ED have been elucidated to failure of occlusion of the exit veins; inability of varying degrees, they are all strongly associated the cavernous smooth muscle to relax because of with CVD.53 Indeed, a study in 417 men with age-related fibrosis; degeneration or dysfunction ED (mean age, 59.1 years) showed that 92.1% of gap junctions; insufficient release of NO related THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
Table II. Specialized Tests for Men With Erectile Dysfunction (ED)
TEST
Intracavernous pharmacoerection test Suspected vasculogenic ED Pharmacopenile duplex ultrasonography Abnormal penile vasodilation test; suspected veno-occlusive dysfunction or Peyronie's disease Nocturnal penile tumescence and rigidity Abnormal PPDU; determine whether psychogenic or organic ED Abnormal NPTR; suspected congenital or traumatic venous leakage Pelvic arteriography Traumatic arterial insufficiency to a range of possible organic or psychogenic fac- including a thorough physical examination, labo- tors; or deficient vascular communication between ratory evaluation, and a complete medical, sexual, the corpora cavernosa and spongiosum or glans, and psychosocial history.2 In addition to laboratory which may be congenital or stem from trauma or tests recording endocrine and metabolic functions, penile surgery.16 Of these pathogenic mechanisms, urologic health, and CVD risk factors, specific tests impairment of NO bioactivity may be most impor- for erectile function may be appropriate (Table tant and offers a viable target for ED therapy.13 II).2,16 First-line treatment options for ED fall into Several animal models of ED have supported the 3 major categories: psychologic, medical, and hor- role of impaired endothelium-dependent vasodila- monal; a combination of these therapies is often tion and reduced NO bioavailability.59,60 indicated (Table III).2,68 Until recently, however, The role of NO in diabetic ED has been the most therapies for ED have been cumbersome, subject of several studies. An early in vitro study uncomfortable, and only moderately effective in found that relaxation of human cavernosal smooth some patients.4,18 muscle in response to electrical stimulation and to acetylcholine was significantly reduced in tis- Oral PDE-5 Inhibitors
sue samples from diabetic men, compared with Phosphodiesterase type 5 (PDE-5) inhibitors are the response in tissues from nondiabetic men the first effective oral therapies for ED. These (P=.001 for both), and that this relative impair- therapies have greatly enhanced ED treatment and ment increased with the duration of diabetes mel- are considered first-line therapies for ED regard- litus (P=.007).61 In animal studies, type 1 and type less of etiology.18 The 3 PDE-5 inhibitors that 2 diabetic rats with ED have been shown to have have been approved for use in the United States markedly reduced NOS activity and content, pos- between 1998 and 2003—sildenafil, vardenafil, sibly related to corresponding reductions in serum and tadalafil—have demonstrated similar effi- testosterone, compared with nondiabetic control cacy in a broad population, including men with rats.62 Other rat models have found that diabetes- CHD, hypertension, diabetes mellitus, or post- impaired NO bioactivity stemmed from lack of radical prostatectomy; psychogenic, organic, or NOS-stimulating cofactors or presence of inhibi- mixed causes of ED; and those with mild-to-severe tory factors associated with hyperglycemia, rather ED.18,69,70 Efficacy of PDE-5 inhibitor therapy than reduction in NOS protein content.63,64 ranges from 65%–75% for successful intercourse The role of impaired endothelium-dependent to 80%–85% for significantly improved erections, vasodilation and reduced NO bioavailability in ED based on measures of the International Index of has also been supported by various animal models Erectile Function, compared with placebo.18,71–73 of hypertension,65 hypercholesterolemia,66 and isch- These agents do not affect libido, however, which emia.66,67 Overall, studies have consistently demon- is usually a function of hormonal or psychologic strated the importance of impaired NO bioactivity status.18 Indeed, it is important to note that under- resulting in reduced cavernosal relaxation as a com- lying causes of ED such as depression, diabetes mon pathophysiologic basis for ED. Current studies mellitus, or hypogonadism should be investigated are underway to clarify the precise mechanisms of and treated in combination with initiation of PDE- impaired NO bioactivity for various disease states 5 inhibitor therapy.
and risk factors associated with ED.
The PDE-5 inhibitors are also generally well tolerated, with headache, facial or chest flushing, MEDICAL TREATMENT OF ED
dyspepsia, and sinusitis being the most commonly Based on the complexity of ED, optimal treatment reported adverse events, occurring in 5%–40% of of this disorder requires a multifactorial approach, patients.18,71–73 Dose-dependent visual disturbances SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
Table III. Treatment Options for Erectile Dysfunction (ED)
TREATMENT
GENERAL INDICATIONS Psychosexual therapy Counseling with sex therapist First-line treatment Testosterone replacement with intramuscular First-line treatment injection, dermal patches, gel Treatment of secondary causes: hyperthyroidism, hypothyroidism, diabetes Treatment and control of ED risk factors: First-line treatment hypertension, dyslipidemia, diabetes mellitus, smoking, cardiovascular disease, and neurologic diseases NONSPECIFICOral agents Phosphodiesterase type 5 inhibitors: sildenafil, First-line treatment vardenafil, tadalafil Vacuum constriction devices Second-line treatment Venous constriction rings Third-line treatment Inflatable cylinders Second-line treatment Papaverine, phentolaminePapavarine, phentolamine prostaglandin E1 Potassium channel openers Second-line treatment Vascular surgeries Penile microvascular arterial bypass Third-line treatment Penile venous ligation such as color distortion and light sensitivity have NO release.76,77 Thus, the interaction between been reported in up to 3% of men receiving PDE- PDE-5 inhibition and organic nitrates may not 5 inhibitor therapy, but these events appear to apply to the NO-stimulating action of nebivolol, be transient.2,71 Since the primary mechanism of and PDE-5 inhibitors appear to be safe to use with action of the PDE-5 inhibitors is arterial vasodila- tion, the most prevalent concerns regarding use of these agents involve the potential for hypotension PDE-5 Inhibition and NO
and cardiovascular events, particularly in elderly NO promotes penile vasodilation and blood flow patients and those with CVD.18 Safety and toler- by diffusing across the smooth muscle membrane ability data indicate that the risks of myocardial and activating sGC to produce cGMP, resulting in infarction and of mortality from stroke or myo- an enzymatic cascade that inhibits calcium influx, cardial infarction in men receiving these drugs are lowers cytosolic calcium concentrations, and thus low, with rates comparable to placebo and the induces relaxation of cavernosal smooth muscle.2 PDE-5 catalyzes the degradation of cGMP, facili- All of these agents are contraindicated in patients tating smooth muscle contraction.18,78 PDE-5 is the taking nitrates for angina pectoris; addition of a most important of the PDEs in the corpora caver- PDE-5 inhibitor greatly compounds the vasodila- nosa.79 By selectively blocking the PDE-5 enzyme, tory effect of nitrates, and this combination has PDE-5 inhibitors thus preserve and sustain the resulted in severe hypotension and deaths in the NO-triggered increase in cGMP that promotes cav- United States.2,18,70 This contraindication under- ernosal trabecular smooth muscle relaxation.18 lines the close correlation between the mechanisms Impaired NO bioactivity, as often occurs in of action of PDE-5 inhibitors and NO in erectile diabetes mellitus or advanced CHD or neuropathy, function.75 An in vitro study in isolated vessel may limit cGMP formation whereby the action of rings of rat aorta, however, found that sildenafil PDE-5 inhibition is inapplicable; this may account did not potentiate the vasodilatory action of the for nonresponse to oral ED therapy.80 In hyper- β-blocker nebivolol, which induces endothelium- cholesterolemic rabbits with reduced cavernosal dependent vasodilation through stimulation of relaxation in response to sodium nitroprusside, THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
sildenafil nitrate, an NO-donating derivative of sildenafil, improved erectile function to a greater NO is an essential mediator of erectile function, degree than regular sildenafil, suggesting that the and impaired NO bioactivity is associated with NO-donating component was important in com- ED. Treatment of ED often involves a combina- pensating for the impairment of NO bioactivity in tion of psychogenic and organic therapies. The hypercholesterolemia and the resulting reduction major first-line oral therapy for ED involves PDE-5 inhibitors, which block an enzyme that degrades Other data, however, suggest that sildenafil at cGMP; they have proven to be highly effective and tissue levels approaching millimolar concentra- well tolerated in most patients with ED, regardless tions may act at least in part independently of of etiology. These agents depend on sufficient NO- the NO–cGMP pathway.82,83 Several agents have stimulated production of cGMP, however, which also been shown in rat and rabbit models of ED is decreased by severe underlying disease, such as to activate sGC and thus stimulate cGMP produc- CHD or diabetes mellitus. Alternate therapies for tion and induce cavernosal tissue relaxation and ED may be necessary in some patients, possibly in penile erection independently of NO by binding to combination with a PDE-5 inhibitor. Speculative a novel allosteric site in the enzyme different from therapies include sGC activators, which act through the NO-binding site.84,85 These sGC activators are an NO-independent mechanism, and NO donors, under investigation as a possible new class of ED which promote NO-dependent relaxation of caver- therapies.84 Nonetheless, the central importance nosal smooth muscle.
of NO in erectile function was demonstrated in a study showing that the effect on erectile function of the sGC activator BAY 41–2272 alone in con- 1 NIH consensus conference. Impotence. NIH Consensus
scious rabbits was weak, but it was potentiated Development Panel on Impotence. JAMA. 1993;270:83–90.
by concomitant administration of the NO donor 2 Lue TF. Erectile dysfunction. N Engl J Med.
sodium nitroprusside.86 3 Laumann EO, Paik A, Rosen RC. Sexual dysfunction
in the United States: prevalence and predictors. JAMA. 4 Maggi M, Filippi S, Ledda F, et al. Erectile dysfunction:
Although there is a clear rationale for the direct from biochemical pharmacology to advances in medical targeting of penile NO in the treatment of ED, therapy. Eur J Endocrinol. 2000;143:143–154.
development of such therapies is still largely in the 5 Chiurlia E, D'Amico R, Ratti C, et al. Subclinical coronary
artery atherosclerosis in patients with erectile dysfunction. preliminary stages, in part owing to the complexity J Am Coll Cardiol. 2005;46:1503–1506.
of the multiple physiologic mechanisms of NO.13,87 6 Solomon H, Man JW, Jackson G. Erectile dysfunction and
Transdermal administration of nitroglycerin, an the cardiovascular patient: endothelial dysfunction is the common denominator. Heart. 2003;89:251–254.
organic nitrate, via ointment, patch, or plaster has 7 Bacon CG, Mittleman MA, Kawachi I, et al. Sexual func-
demonstrated only moderate and inconsistent effi- tion in men older than 50 years of age: results from the cacy in improving erectile function, and also has Health Professionals Follow up Study. Ann Intern Med. been observed to cause headaches.13,88 Similarly, 8 Rosen RC, Fisher WA, Eardley I, et al. The multinational
oral L-arginine supplements in men with ED have Men's Attitudes to Life Events and Sexuality (MALES) yielded inconclusive results and may only be effec- study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res tive in men with reduced exogenous NO produc- tion.89,90 The NO donor linsidomine chlorhydrate 9 Feldman HA, Goldstein I, Hatzichristou DG, et al.
has also been investigated for use in ED therapy, Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. but it has demonstrated only minimal-to-moderate efficacy in clinical trials.91,92 10 Jackson G, Gilles H, Osterloh I. Past, present, and future:
New classes of NO donors, including sildenafil a 7-year update of Viagra (sildenafil citrate). Int J Clin nitrate and S-nitrosothiols, have demonstrated 11 Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial
more promising results in experimental animal function and dysfunction. Part II: association with car- models of ED.93,94 A possible advantage of these diovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors new therapies is that they may have minimal of the European Society of Hypertension. J Hypertens. hemodynamic effects, resulting in less risk of adverse events.93 In addition, various combina- 12 Burnett AL. Nitric oxide in the penis: physiology and
pathology. J Urol. 1997;157:320–324.
tions of ED therapies, including those targeting 13 Andersson K-E. Pharmacology of penile erection.
NO, are being considered and tested in patients Pharmacol Rev. 2001;53:417–450.
nonresponsive to monotherapies.95 14 Toda N, Ayajiki K, Okamura T. Nitric oxide and penile
erectile function. Pharmacol Ther. 2005;106:233–266.
SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
15 Burnett AL. Role of nitric oxide in the physiology of erec-
relaxation in the hypercholesterolemic rabbit: a prelimi- tion. Biol Reprod. 1995;52:485–489.
nary study. Int J Impot Res. 2000;12:334–339.
16 Fabbri A, Aversa A, Isidori A. Erectile dysfunction: an
37 Lugg JA, Rajfer J. González-Cadavid. Dihydrotestosterone
overview. Hum Reprod Update. 1997;3:455–466.
is the active androgen in the maintenance of nitric 17 Burnett AL. Neurophysiology of erectile function and dys-
oxide-mediated penile erection in the rat. Endocrinology. function. In: Hellstrom WJG, ed. The Handbook of Sexual Dysfunction. New York, NY: The American Society of 38 Mills TM, Lewis RW, Stopper VS. Androgenic mainte-
nance of inflow and veno-occlusion during erection in the 18 Fazio L, Brock G. Erectile dysfunction: management
rat. Biol Reprod. 1998;59:1413–1418.
update. CMAJ. 2004;170:1429–1437.
39 Lewis RW, Mills TM. Effect of androgens on penile tissue.
19 Giuliano F, Rampin O. Central control of erection and
its pharmacological modification. Curr Opin Urol. 40 Kim N, Vardi Y, Padma-Nathan H, et al. Oxygen tension
regulates the nitric oxide pathway. Physiological role in 20 Burnett AL, Ricker DD, Chamness SL, et al. Localization
penile erection. J Clin Invest. 1993;91:437–442.
of nitric oxide synthase in the reproductive organs of the 41 Angulo J, Cuevas P, Fernandez A, et al. Activation and
male rat. Biol Reprod. 1995;52:1–7.
potentiation of the NO/cGMP pathway by NG-hydroxyl- 21 Gonzalez CM, Brannigan RE, Bervig T, et al. Protein and
L-arginine in rabbit corpus cavernosum under normoxic gene expression of nitric oxide synthase isoforms I and III and hypoxic conditions and ageing. Br J Pharmacol. in the rat penile shaft. J Androl. 2001;22:54–61.
22 Burnett AL. Novel nitric oxide signaling mechanisms regu-
42 Nicolosi A, Moreira ED Jr, Shirai M, et al. Epidemiology
late the erectile response. Int J Impot Res. 2004;16(suppl of erectile dysfunction in four countries: cross-national study of the prevalence and correlates of erectile dysfunc- 23 Ignarro LJ, Bush PA, Buga GM, et al. Nitric oxide and
tion. Urology. 2003;61:201–206.
cyclic GMP formation upon electrical field stimulation 43 Johannes CB, Araujo AB, Feldman HA, et al. Incidence
cause relaxation of corpus cavernosum smooth muscle. of erectile dysfunction in men 40 to 69 years old: longitu- Biochem Biophys Res Commun. 1990;170:843–850.
dinal results from the Massachusetts Male Aging Study. J 24 Burnett AL, Lowenstein CJ, Bredt DS, et al. Nitric
oxide: a physiologic mediator of penile erection. Science. 44 Kratzik CW, Schatzl G, Lunglmayr G, et al. The impact of
age, body mass index and testosterone on erectile dysfunc- 25 Wang R, Domer FR, Sikka SC, et al. Nitric oxide mediates
tion. J Urol. 2005;174:240–243.
penile erection in cats. J Urol. 1994;151:234–237.
45 Esposito K, Giugliano F, Martedi E, et al. High propor-
26 Rajfer J, Aronson WJ, Bush PA, et al. Nitric oxide as
tions of erectile dysfunction in men with the metabolic a mediator of relaxation of the corpus cavernosum in syndrome. Diabetes Care. 2005;28:1201–1203.
response to nonadrenergic, noncholinergic neurotransmis- 46 Ponholzer A, Temml C, Mock K, et al. Prevalence and
sion. N Engl J Med. 1992;326:90–94.
risk factors for erectile dysfunction in 2869 men using a 27 Stanarius A, Uckert S, Machtens SA, et al.
validated questionnaire. Eur Urol. 2005;47:80–85.
Immunocytochemical distribution of nitric oxide synthase 47 Seftel AD, Sun P, Swindle R. The prevalence of hyperten-
in the human corpus cavernosum: an electron microscopal sion, hyperlipidemia, diabetes mellitus and depression study using the tyramide signal amplification technique. in men with erectile dysfunction. J Urol. 2004;171(2 pt Urol Res. 2001;29:168–172.
28 Garban H, Vernet D, Freedman A, et al. Effect of aging on
48 Penson DF, Latini DM, Lubeck DP, et al. Do impotent men
nitric oxide-mediated penile erection in rats. Am J Physiol. with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impo- 29 Andersson K-E. Erectile physiological and pathophysi-
tent patients? Results from the Exploratory Comprehensive ological pathways involved in erectile dysfunction. J Urol. Evaluation of Erectile Dysfunction (ExCEED) database. Diabetes Care. 2003;26:1093–1099.
30 Hurt KJ, Musicki B, Palese MA, et al. Akt-depen-
49 Giuliano FA, Leriche A, Jaudinot EO, et al. Prevalence of
dent phosphorylation of endothelial nitric-oxide synthase erectile dysfunction among 7689 patients with diabetes or mediates penile erection. Proc Natl Acad Sci U S A. hypertension, or both. Urology. 2004;64:1196–1201.
50 Corona G, Mannucci E, Petrone L, et al. Association of
31 Bivalacqua TJ, Usta MF, Champion HC, et al. Gene trans-
hypogonadism and type II diabetes in men attending an fer of endothelial nitric oxide synthase partially restores outpatient erectile dysfunction clinic. Int J Impot Res. nitric oxide synthesis and erectile function in streptozoto- cin diabetic rats. J Urol. 2003;169:1911–1917.
51 Sun P, Swindle R. Are men with erectile dysfunction more
32 Champion HC, Bivalacqua TJ, Hyman AL, et al. Gene
likely to have hypertension than men without erectile transfer of endothelial nitric oxide synthase to the penis dysfunction? A naturalistic national cohort study. J Urol. augments erectile responses in the aged rat. Proc Natl Acad Sci U S A. 1999;96:11648–11652.
52 Nikoobakht M, Nasseh H, Pourkasmaee M. The relation-
33 Byrne RR, Henry GD, Rao DS, et al. Vascular endothelial
ship between lipid profile and erectile dysfunction. Int J growth factor restores corporeal smooth muscle function Impot Res. 2005;17:523–526.
in vitro. J Urol. 2001;165:1310–1315.
53 Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction
34 Lee MC, El-Sakka AI, Graziottin TM, et al. The effect of
in the cardiac patient: how common and should we treat? vascular endothelial growth factor on a rat model of trau- J Urol. 2003;170(suppl 2):S46–S50.
matic arteriogenic erectile dysfunction. J Urol. 2002;167(2 54 El-Sakka AI, Morsy AM, Fagih BI, et al. Coronary artery
pt 1):761–767.
risk factors in patients with erectile dysfunction. J Urol. 35 Rogers RS, Graziottin TM, Lin CS, et al. Intracavernosal
vascular endothelial growth factor (VEGF) injection and 55 Kaiser DR, Billups K, Mason C, et al. Impaired bra-
adeno-associated virus-mediated VEGF gene therapy pre- chial artery endothelium-dependent and -independent vent and reverse venogenic erectile dysfunction in rats. Int vasodilation in men with erectile dysfunction and no J Impot Res. 2003;15:26–37.
other clinical cardiovascular disease. J Am Coll Cardiol. 36 Henry GD, Byrne R, Hunyh TT, et al. Intracavernosal
injections of vascular endothelial growth factor protects 56 Gazzaruso C, Giordanetti S, De Amici E, et al. Relationship
endothelial dependent corpora cavernosal smooth muscle between erectile dysfunction and silent myocardial isch- THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
emia in apparently uncomplicated type 2 diabetic patients. events in users of sildenafil: results from first phase of prescription event monitoring in England. BMJ. 57 Montorsi F, Briganti A, Salonia A, et al. Erectile dysfunc-
tion prevalence, time of onset and association with risk 75 Webb DJ, Muirhead GJ, Wulff M, et al. Sildenafil citrate
factors in 300 consecutive patients with acute chest pain potentiates the hypotensive effects of nitric oxide donor and angiographically documented coronary artery disease. drugs in male patients with stable angina. J Am Coll Eur Urol. 2003;44:360–364.
58 Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunc-
76 Rosenkranz S, Brixius K, Halbach R, et al. Phosphodiesterase
tion and cardiac risk (the Second Princeton Consensus type 5 inhibitor sildenafil citrate does not potentiate the Conference). Am J Cardiol. 2005;96:313–321.
vasodilative properties of nebivolol in rat aorta. Life Sci. 59 Haas CA, Seftel AD, Razmjouei K, et al. Erectile dysfunc-
tion in aging: upregulation of endothelial nitric oxide 77 Tzemos N, Lim PO, MacDonald TM. Nebivolol revers-
synthase. Urology. 1998;51:516–522.
es endothelial dysfunction in essential hypertension: a 60 Musicki B, Kramer MF, Becker RE, et al. Age-related
randomized, double-blind, crossover study. Circulation. changes in phosphorylation of endothelial nitric oxide synthase in the rat penis. J Sex Med. 2005;2:347–355.
78 Friebe A, Koesling D. Regulation of nitric oxide-sensitive
61 Sáenz de Tejada I, Goldstein I, Azadzoi K, et al. Impaired
guanylyl cyclase. Circ Res. 2003;93:96–105.
neurogenic and endothelium-mediated relaxation of penile 79 Corbin JD, Francis SH, Webb DJ. Phosphodiesterase
smooth muscle from diabetic men with impotence. N Engl type 5 as a pharmacologic target in erectile dysfunction. J Med. 1989;320:1025–1030.
Urology. 2002;60(suppl 2):4–11.
62 Vernet D, Cal L, Garban H, et al. Reduction of penile
80 Sáenz de Tejada I. Therapeutic strategies for optimizing
nitric oxide synthase in diabetic BB/WORdp (type 1) PDE-5 inhibitor therapy in patients with erectile dysfunc- and BBZ/WORdp (type II) rats with erectile dysfunction. tion considered difficult or challenging to treat. Int J Impot Res. 2004;16(suppl 1):S40–S42.
63 Escrig A, Marin R, Abreu P, et al. Changes in mating
81 Shukla N, Jones R, Persad R, et al. Effect of sildenafil
behavior, erectile function, and nitric oxide levels in penile citrate and a nitric oxide donating sildenafil derivative, corpora cavernosa in streptozotocin-diabetic rats. Biol NCX 911, on cavernosal relaxation and superoxide for- mation in hypercholesterolaemic rabbits. Eur J Pharmacol. 64 Musicki B, Kramer MF, Becker RE, et al. Inactivation
of phosphorylated endothelial nitric oxide syn- 82 McAuley IW, Kim NN, Min K, et al. Intracavernosal silde-
thase (Ser-1177) by O-GlcNAc in diabetes-associ- nafil facilitates penile erection independent of the nitric ated erectile dysfunction. Proc Natl Acad Sci U S A. oxide pathway. J Androl. 2001;22:623–628.
83 Sharabi FM, Daabees TT, El-Metwally MA, et al.
65 Ushiyama M, Morita T, Kuramochi T, et al. Erectile dys-
Comparative effects of sildenafil, phentolamine, yohim- function in hypertensive rats results from impairment of bine and L-arginine on the rabbit corpus cavernosum. the relaxation evoked by neurogenic carbon monoxide Fundam Clin Pharmacol. 2004;18:187–194.
and nitric oxide. Hypertens Res. 2004;27:253–261.
84 Brioni JD, Nakane M, Hsieh GC, et al. Activators of
66 Azadzoi KM, Goldstein I, Siroky MB, et al. Mechanisms
soluble guanylate cyclase for the treatment of male erectile of ischemia-induced cavernosal smooth muscle relaxation dysfunction. Int J Impot Res. 2002;14:8–14.
impairment in a rabbit model of vasculogenic erectile dys- 85 Mizusawa H, Hedlund P, Brioni JD. Nitric oxide indepen-
function. J Urol. 1998;160:2216–2222.
dent activation of guanylate cyclase by YC-1 causes erec- 67 Masuda H, Tsujii T, Okuno T, et al. Accumulated
tile responses in the rat. J Urol. 2002;167:2276–2281.
endogenous NOS inhibitors, decreased NOS activity, 86 Bischoff E, Schramm M, Straub A, et al. BAY 41–
and impaired cavernosal relaxation with ischemia. 2272: a stimulator of soluble guanylyl cyclase induces Am J Physiol Regul Integr Comp Physiol. 2002;282: nitric oxide-dependent penile erection in vivo. Urology. 68 Guay AT, Spark RF, Bansal S, et al, for the American
87 Scatena R, Bottoni P, Martorana GE, et al. Nitric
Association of Clinical Endocrinologists Male Sexual oxide donor drugs: an update on pathophysiology Dysfunction Task Force. American Association of Clinical and therapeutic potential. Expert Opin Investig Drugs. Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunc- 88 Gramkow J, Lendorf A, Zhu J, et al. Transcutaneous
tion: a couple's problem—2003 update. Endocr Pract. nitroglycerine in the treatment of erectile dysfunction: a placebo controlled clinical trial. Int J Impot Res. 69 Kloner RA. Cardiovascular effects of the 3 phosphodies-
terase-5 inhibitors approved for the treatment of erectile 89 Chen J, Wollman Y, Chernichovsky T, et al. Effect of oral
administration of high-dose nitric oxide donor L-arginine 70 Cheitlin MD, Hutter AM, Brindis RG, et al. Use of silde-
in men with organic erectile dysfunction: results of a nafil (Viagra) in patients with cardiovascular disease. double-blind, randomized, placebo-controlled study. BJU 71 Goldstein I, Lue TF, Padma-Nathan H, et al, for
90 Klotz T, Mathers MJ, Braun M, et al. Effectiveness of oral
the Sildenafil Study Group. Oral sildenafil in the L-arginine in first-line treatment of erectile dysfunction in treatment of erectile dysfunction. N Engl J Med. a controlled crossover study. Urol Int. 1999;63:220–223.
91 Truss MC, Becker AJ, Djamilian MH, et al. Role of the
72 Hellstrom WJ, Gittelman M, Karlin G, et al, on behalf of
nitric oxide donor linsidomine chlorhydrate (SIN-1) in the the Vardenafil Study Group. Vardenafil for treatment of diagnosis and treatment of erectile dysfunction. Urology. men with erectile dysfunction: efficacy and safety in a ran- domized, double-blind, placebo-controlled trial. J Androl. 92 Wegner HE, Knispel HH, Meier T, et al. Nitric oxide
donor, linsidomine chlorhydrate (SIN-1), in the diag- 73 Brock GB, McMahon CG, Chen KK, et al. Efficacy
nosis and treatment of erectile dysfunction: critical and safety of tadalafil for the treatment of erectile appraisal and review of the literature. Int Urol Nephrol. dysfunction: results of integrated analyses. J Urol. 93 Seidler M, Uckert S, Waldkirch E, et al. In vitro
74 Shakir SA, Wilton LV, Boshier A, et al. Cardiovascular
effects of a novel class of nitric oxide (NO) donating SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 THE JOURNAL OF CLINICAL HYPERTENSION The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.
compounds on isolated human erectile tissue. Eur Urol. ernosum. Int J Androl. 2003;26:101–108.
95 Sommer F, Engelmann U. Future options for combination
94 Filippi S, Crescioli C, Vannelli GB, et al. Effects of NCX
therapy in the management of erectile dysfunction in older 4050, a new NO donor, in rabbit and human corpus cav- men. Drugs Aging. 2004;21:555–564.
THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 4 VOL. 8 NO. 12 DECEMBER 2006 The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, Three Parklands Drive, Darien, CT 06820-3652. Copyright 2006 by Le Jacq, All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at showell@lejacq.com or 203.656.1711 x106.

Source: http://bionhealth.co.kr/manager/pds_board/download.asp?file1=The+Role+of+Nitric+oxide+in+Erectile+dysfunction++Implications+for+Medical+therapy.pdf&f_folder=2015

hairdirect.com

Material Safety Data Sheet Spectral DNC Hair Loss Treatment * * * Section - Chemical Product And Company Information * * * Chemical Name: Spectral DNC Hair Loss Treatment Product Use: Hair Growth Stimulant * * * Section 2 - Composition / Information on Ingredients * * * Component Information. The ingredients are listed in descending orders of concentration in compliance with the FDA's "Over the counter" drug regulations. INGREDIENT 1 COMMON NAME: Water % BY WEIGHT: 60 % (approximately) CAS NUMBER: 7732-18-5 INGREDIENT 2 COMMON NAME: Minoxidil % BY WEIGHT: 5 % CAS NUMBER: 38304-91-5 INGREDIENT 3 COMMON NAME: Ethyl alcohol % BY WEIGHT: 3 % (approximately) CAS NUMBER: 64-17-5 This product is non-hazardous and is not transport regulated.

imagingonline.co.uk

Arch Dis Child 2007;92:251–256. doi: 10.1136/adc.2006.106120 bone exceeds the ability of the bone to box). It is easier to show ligamentous laxity in this absorb the force by deforming. Fractures in older group than in infants. children are common—approximately one third ofchildren will have a fracture by 16 years of age, PATHOPHYSIOLOGY OF BONE DISEASES with more boys experiencing fracture than girls.1