The oral efficacy of vardenafil hydrochloride for inducing penile erection in a conscious rabbit model

PURPOSE: Inhibiting cyclic guanosine monophosphate metabolism may induce penile erection during concomitant nitric oxide production. Vardenafil hydrochloride is a new, highly selective, potent cyclic guanosine monophosphate phosphodiesterase 5 inhibitor. We determined the oral effectiveness of vardenafil in a simple and quantitative conscious rabbit model. MATERIALS AND METHODS: Vardenafil was given orally to conscious rabbits. Erection was assessed in a time dependent manner by measuring the length of the uncovered penile mucosa. Erection was evaluated in the absence and presence of intravenous sodium nitroprusside, a nitric oxide donor. RESULTS: Vardenafil induced dose dependent penile erection in conscious rabbits after the oral administration of 1 to 30 mg./kg. The efficacy of vardenafil was potentiated and effective doses were significantly reduced by the simultaneous administration of sodium nitroprusside. CONCLUSIONS: The effect of vardenafil on penile erection after oral administration was clearly demonstrated in the conscious rabbit model. The time course and early onset of activity indicate that it may be useful for treating erectile dysfunction. Potentiation of the effect by the nitric oxide donor sodium nitroprusside implies that it would have enhanced activity during sexual arousal, when nitric oxide is produced endogenously. The clinical development of this product for erectile dysfunction is proceeding.     

Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide–phosphodiesterase type 5–cyclic guanosine 3′,5′‐monophosphate pathway

It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5–cyclic guanosine 3′,5′‐monophosphate–nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho‐associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3′,5′‐monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3′,5′‐monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the phosphodiesterase type 5–nitric oxide–cyclic guanosine 3′,5′‐monophosphate pathway, vascular function and cardiovascular outcomes are examined.     

Pathophysiology of Erectile Dysfunction

Physiology of erection and pathophysiology erectile dysfunction is reviewed. Analysis is obtained from basic and clinical research including animals studies, anatomical studies, and molecular and cellular research on corporal tissue obtained during penile prosthesis implantation. Supraspinal influences and spinal influence on penile erection has been learned from spinal cord injury patient. Corporal smooth muscle relaxation of penile arteries and corpus cavernosum leads to penile erection, results from parasympathetic/nonadrenergic noncholinergic neural pathway activation and simultaneous inhibition of sympathetic outflow. Anatomical studies taught understanding of the mechanism for restriction of blood outflow from the corpora cavernosa. The change of smooth muscle tone has emerged as a key factor in erection and detumescence. Many independent factors converge on the modulation of corporal smooth muscle tone. Neuronal and local neurotransmitter effects via gap junction, potassium channels, and calcium channel. A nitric oxide/cyclic guanosine monophosphate mechanism as well as cyclic aminomonophosphate has an important role in mediating the corporal smooth muscle relaxation necessary for erectile function. Erectile dysfunction can be due to vasculogenic, neurogenic, hormonal, veno-occlusive, psychogenic and/or pharmacogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate (cGMP) or cyclic aminophosphate (cAMP) pathway or other regulatory mechanisms including gap junction or ionic channel resulting in an imbalance in corporal smooth muscle contraction and relaxation. Our present knowledge of the hemodynamics, functional anatomy, neurophysiology, and neuropharmacology of penile erection and dysfunction at the cellular and molecular level has led to better understanding of physiology and pathophysiology of erectile dysfunction.     

Indices of nitric oxide synthesis and outcome in critically ill patients

We measured the concentrations of serum nitrates/nitrites and plasma cyclic guanosine monophosphate as markers of nitric oxide synthesis in patients with or without septic shock for 5 days following admission to intensive care. We found that nitrate/nitrite concentrations, when corrected for the effect of renal failure, were significantly higher in patients with septic shock, both on admission and in the final samples drawn. In a logistic regression analysis, the rate of change of nitrate/nitrite concentration was associated with survival to day 28 (falling in survivors). The concentration of cyclic guanosine monophosphate when corrected for the confounding effects of renal function and platelet count, was only associated with the septic shock group on admission.     

【原创论文】他达拉非治疗有血管风险的ED男性对改善内皮细胞损伤和修复效果不明显

循环成血管细胞数（CACs）与来源于循环单核细胞的集落形成单位数（CFUs）在实验室检测中代表内皮细胞的修复能力。具有血管危险因素（VRF）的ED男性血清中内皮细胞损伤／功能障碍的标志物水平增加以及来源于健康男性的循环成血管细胞数和集落形成单位数减少。我们研究了选择性磷酸二酯酶5抑制剂他达拉非能否改善有VRF的ED男性内皮细胞的修复能力以及减少血清内皮细胞损伤／功能障碍标志物的水平。36例ED患者的20％血清培养健康男性的单核细胞以检测循环成血管细胞和集落形成单位。检测JED患者服用他达拉非（隔日20毫克）及安慰剂前及用药4周后的血清标志物。他达拉非治疗能改善勃起功能（P=0．0028）,但不能减轻ED患者的血清对健康男性的CACs和CFUs的抑制。与基线及安慰剂比较,治疗后内皮素．1的水平（P=0．011）和组织型纤溶酶原激活物（P=0．005）均减少,而E-选择素水平无变化。有血管危险因素的ED患者经他达拉非治疗后实验室检测内皮细胞损伤与修复能力显示只有轻微影响。PDE5抑制剂对血管稳态的可能益处尚需进一步研究。     

Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs

BACKGROUND: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. METHODS: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). RESULTS: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged. CONCLUSIONS: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.     

Effects of Icariside II on Improving Erectile Function in Rats With Streptozotocin-Induced Diabetes

Icariin and icariside II (ICA II), 2 active components isolated from herba epimedii, have a closely structural relationship. There is evidence that icariin may be useful in the treatment of erectile dysfunction (ED); however, the study on the therapeutic efficacy of ICA II on ED is currently scant. We investigated the effects of ICA II on improving erectile function of rats with streptozocin-induced diabetes. Fifty 8-week-old Sprague-Dawley rats were randomly distributed into normal control and diabetic groups. Diabetes was induced by a one-time intraperitoneal injection of streptozocin (60 mg/kg). Three days later, the diabetic rats were randomly divided into 4 groups including a saline-treated placebo arm and 3 ICA II-treated models (1, 5, and 10 mg/kg/d). After 3 months, penile hemodynamics was measured by cavernous nerve electrostimulation (CNE) with real time intracorporal pressure assessment. Penises were harvested with subsequent histological examination (picrosirius red stain, Hart elastin stain, and immunohistochemical stain) and Western blots to explore the expression of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) and transforming growth factor β1 (TGFβ1)/Smad2 signaling pathways. Diabetes significantly attenuated erectile responses to CNE. Diabetic rats had decreased corpus cavernosum smooth muscle/collagen ratio and endothelial cell content relative to the control group. The ratio of collagen I to III was significantly lower in the corpora of diabetic rats; furthermore, cavernous elastic fibers were fragmented in the diabetic animals. Neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase, and vascular endothelial growth factor were expressed at lower levels in the diabetic group; ICA II-treated diabetic rats had higher expression in the penis relative to placebo-treated diabetic animals. Both the TGFβ1/Smad2/connective tissue growth factor (CTGF) signaling pathway and apoptosis were down-regulated in the penis from ICA II-treated rats. ICA II treatment attenuates diabetes-related impairment of penile hemodynamics, likely by increasing smooth muscle, endothelial function, and nNOS expression. ICA II could alter corpus cavernosum fibrous-muscular pathological structure in diabetic rats, which could be regulated by the TGFβ1/Smad2/CTGF and NO-cGMP signaling pathways.     

Pathophysiology and treatment of diabetic erectile dysfunction

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront.The proposed mecha-nisms of erectile dysfunction(ED)in diabetic patients includes elevated advanced glycation end-products(AGEs)andincreased levels of oxygen free radicals,impaired nitric oxide(NO)synthesis,increased endothelin B receptor bindingsites and ultrastructural changes,upregulated RhoA/Rho-kinase pathway,NO-dependent selective nitrergic nervedegeneration and impaired cyclic guanosine monophosphate(cGMP)-dependent kinase-1(PKG-1).The treatment ofdiabetic ED is multimodal.Treatment of the underlying hyperglycemia and comorbidities is of utmost importance toprevent or halt the progression of the disease.The peripherally acting oral phosphodiesterase type 5(PDE5)inhibitorsare the mainstay of oral medical treatment of ED in diabetics.Vacuum erection devices are an additional treatment asa non-invasive treatment option.Local administration of vasoactive medication via urethral suppository or intracorporalinjection can be effective with minimal side-effects.Patients with irreversible damage of the erectile mechanism arecandidates for penile implantation.Future strategies in the evolution of the treatment of ED are aimed at correcting ortreating the underlying mechanisms of ED.With an appropriate vector,researchers have been able to transfectdiabetic animals with agents such as neurotrophic factors and nitric oxide synthase(NOS).Further studies in genetherapy are needed to fully ascertain its safety and utility in humans.(Asian J Androl 2006 Nov;8:675-684)     

Daily use of sildenafil improves endothelial function in men with type 2 diabetes

Diminished vascular endothelial function results in decreased vasodilator capacity and is associated with erectile dysfunction (ED) in patients afflicted with type 2 diabetes. The current study was designed to evaluate whether daily use of sildenafil could alter endothelial function and improve penile rigidity in a group of patients with diabetic ED. A double-blind, placebo-controlled, prospective trial was conducted with 24 men with type 2 diabetes who were randomized into 2 groups: one receiving daily sildenafil (50 mg, n = 12) and the other placebo (n = 12) for 10 weeks. Erectile function was captured subjectively using the International Index of Erectile Function (IIEF-5), and endothelial function was objectively monitored via brachial artery flow-mediated dilation. Among the placebo and sildenafil groups, there were no significant differences in average patient age, time from type 2 diabetes diagnosis, duration of ED, or baseline IIEF-5 scores. Past medical histories, including smoking, alcohol consumption, hypertension, and hyperlipidemia, were also similar. At the conclusion of the 10-week trial, patients who received daily sildenafil had significantly improved erectile rigidity as captured by IIEF-5 (P < .001) and increased endothelial function via brachial artery flow-mediated dilation (P < .01). Endothelial function in men with type 2 diabetes was enhanced with daily sildenafil. Improved erectile rigidity and enhanced vascular circulation was noted after 10 weeks of daily sildenafil use.     

Daily treatment with sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance

OBJECTIVES: Patients with insulin resistance exhibit endothelial dysfunction with decreased nitric oxide (NO) production and increased oxidative stress. We postulated that daily sildenafil improved endothelial function in fructose-fed rats. METHODS AND RESULTS: Wistar rats were fed a standard or fructose-enriched diet (FFR) for 9 wk. From weeks 6-8, sildenafil was administered twice daily (sc, 20 m g/kg), followed by a 1-wk washout. Concentration-response curves (CRCs) to endothelium-dependent (acetylcholine [Ach] and A23187) and -independent (sodium nitroprusside [SNP]) relaxing agents were performed on isolated precontracted aortas and superior mesenteric arteries (SMAs). Vascular cyclic guanosine monophosphate (cGMP) content, urinary excretion of nitrates/nitrites (NOx) and 8-isoprostanes (IPT), and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were evaluated. Relaxations to ACh were significantly reduced in aortas and SMAs of FFR. Sildenafil restored ACh-induced relaxations in aortas and provoked a significant leftward shift of the CRC to ACh in SMAs, whereas it did not modify the enhanced relaxations to SNP in FFR. IL-6, TNF-alpha, vascular cGMP, and urinary NOx levels were not modified by the fructose or sildenafil treatment. Urinary IPT levels were significantly elevated in FFR and normalized by sildenafil. CONCLUSIONS: Endothelial dysfunction and oxidative stress associated with insulin resistance can be reversed by daily sildenafil, even 1 wk after treatment cessation.     

Combination therapy for erectile dysfunction: where we are and what's in the future

Penile erection occurs in response to visual, olfactory, imaginative, and tactile stimuli initiated within the brain and/ or on the periphery. Responses to these stimuli are mediated by efferent autonomic outflow originating in the sacral spinal cord and transmitted by the cavernosal and penile nerves. A number of neurotransmitters can play an integral role in corpus cavernosum smooth muscle relaxation, in part regulating penile erection through increased smooth muscle synthesis of the secondary messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In addition to directacting agents, there are indirect-acting smooth musclerelaxing agents. Phosphodiesterase (PDE) inhibitors such as sildenafil act indirectly and require sexual stimulation and endogenous nitric oxide production to activate the cGMP pathway effectively. In contrast, agents such as prostaglandin E₁ (PGE₁) act directly on the trabecular smooth muscle, binding to specific e-prostanoid receptors and increasing cAMP synthesis. For this reason the direct-acting agents do not require sexual stimulation for efficacy. Combination pharmacotherapy has been used experimentally to treat erectile dysfunction for 25 years, using combinations of cAMP synthesis augmentors, smooth muscle relaxants and PDE inhibitors, and α-blockers administered via intracavernosal injection. The present era of oral pharmacotherapy treatment has resulted in significant awareness in the field of sexual dysfunction; however, a single agent may not be ideal to sustain penile rigidity, especially if comorbidities and severity of erectile dysfunction are accounted for. The rationale for and recent reports on combination therapy are presented in this review.     

Chronische PDE-5-Hemmung bei erektiler Dysfunktion

Erectile dysfunction (ED) is often associated with increased cardiovascular risk. There is increasing evidence suggesting that dysfunction of the vascular endothelium with reduced bioavailability of nitric oxide (NO) may be the pathogenetic link between ED and cardiovascular disease. The crucial importance of the NO-guanylatecyclase-cGMP-phosphodiesterase pathway for penile erection is mirrored by the efficacy of phosphodiesterase-5 (PDE5) inhibitors in the treatment of ED. In contrast to other currently available PDE5 inhibitors with a half-life time of about 4 h Tadalafil has a half-life time of about 17.5 h resulting in erectile responsiveness for up to 36 h after 1 single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but meanwhile several studies were able to demonstrate that Tadalafil given daily in low (2.5 and 5 mg) doses is both highly effective and well-tolerated. In three randomized, double-blind, placebo-controlled multi-center trials, various validated measures of erectile function indicated that once daily Tadalafil at doses of 2.5, 5, and 10 mg was significantly superior to placebo. In another mono-center trial, once daily Tadalafil has shown significant efficacy even after failure of on-demand treatment. In a controlled cross-over study of on-demand versus daily Tadalafil treatment, 72% of the patients preferred once daily administration, mainly because of superior and longer efficacy allowing a more spontaneous sexual life. Interestingly in a pilot study of on-demand versus chronic administration of Tadalafil for 4 weeks, only regular dosing improved several markers of endothelial function.     

B-type natriuretic peptide prevents acute hypertrophic responses in the diabetic rat heart: importance of cyclic GMP

Stimulation of cardiomyocyte guanosine 3',5'-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by high-glucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [(3)H]phenylalanine incorporation and atrial natriuretic peptide and beta-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.     

Nitrotyrosine and 8-isoprostane formation indicate free radical-mediated injury in hearts of patients subjected to cardioplegia

OBJECTIVE: Myocardial ischemia and reperfusion induced by cardioplegic arrest subjects the heart to free radical-mediated stress. The purpose of our study was to investigate the effect of cardioplegia-induced ischemia and reperfusion on myocardial formation and distribution of (1) nitrotyrosine as an indicator for peroxynitrite-mediated tissue injury resulting from increased nitric oxide release and (2) 8-isoprostane as an indicator for oxygen-derived free radical-mediated lipid peroxidation. METHODS: In 10 patients undergoing coronary artery operations (64 +/- 6 [mean +/- SD] years, 3 women and 7 men) subjected to cardiopulmonary bypass and intermittent cold blood cardioplegia, we collected transmural left ventricular biopsy specimens before and at the end of cardiopulmonary bypass. Specimens were cut at 10 micro m and subjected to immunocytochemical staining against the nitric oxide-producing enzyme constitutive nitric oxide synthase, cyclic guanosine monophosphate (intracellular second messenger of nitric oxide), nitrotyrosine, and 8-isoprostane by using polyclonal antibodies. For global left ventricular function determination, we measured the fractional area of contraction using transesophageal echocardiography. RESULTS: Nitric oxide synthase activity in cardiac myocytes increased from 34 +/- 10 gray units before cardiopulmonary bypass to 47 +/- 12 gray units at the end of bypass (P =.015), and all hearts showed increased cyclic guanosine monophosphate content in both myocytes and endothelial cells at the end of bypass. The number of nitrotyrosine-positive capillaries increased from 36 +/- 29/mm(2) before bypass to 82 +/- 47/mm(2) at the end of bypass (P =.012), and 8-isoprostane-positive capillaries increased from 92 +/- 72/mm(2) before bypass to 209 +/- 108/mm(2) at the end of bypass (P =.005). The fractional area of contraction was 53% +/- 12% before bypass and 56% +/- 12% after bypass (P =.47) but was slightly decreased to 45% +/- 14% at 4 hours after bypass (P =.121). CONCLUSIONS: Our data show that cardioplegia-induced myocardial ischemia and reperfusion is associated with nitrotyrosine and 8-isoprostane formation mainly in the coronary endothelium, indicating injury mediated by both peroxynitrite and oxygen-derived free radicals. Because nitric oxide synthase activation was accompanied with increased cyclic guanosine monophosphate, these data suggest that direct effects of nitric oxide on cardiac myocytes, as well as nitric oxide-mediated coronary endothelial injury, might contribute to injury associated with cardioplegia and cardiopulmonary bypass.     

Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia

We evaluated the effects of extended-release alfuzosin HCl 10 mg once daily (q.d.) on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). In a randomized, double-blind, placebo-controlled study of men aged > or = 50 years, after a 28-day placebo run-in period, patients were randomized to receive alfuzosin 10 mg q.d. or matching placebo for 28 days. The mean change from baseline (day 1) in sexual function on day 29 was assessed using the Danish Prostate Symptom Score Sex (DAN-PSSsex) questionnaire. A total of 372 patients were randomized to receive alfuzosin (n=186) or placebo (n=186), with 355 completing the study. At baseline, 64% of the patients reported erectile dysfunction (ED) and 63% reported ejaculatory dysfunction (EjD). For the 320 patients who completed the DAN-PSSsex, alfuzosin treatment was associated with a significant improvement in the mean change from baseline in erectile function on day 29 compared with placebo (P=0.02). No significant difference was observed between the two treatment groups in the mean change from baseline in ejaculatory function on day 29. For patients with ED at baseline, a marginal improvement in erectile function was demonstrated with alfuzosin treatment (P=0.09 vs placebo). For patients with EjD at baseline, the mean change from baseline in ejaculatory function with alfuzosin was comparable to that with placebo. Dizziness was the most common adverse event with alfuzosin treatment (5 vs 0% with placebo), with other adverse events reported with comparable frequency in both treatment groups. After 1 month of treatment, alfuzosin 10 mg q.d. significantly improved erectile function in men with lower urinary tract symptoms/ benign prostatic hypertrophy and had no adverse effect on ejaculatory function.     

Direct effects of selective type 5 phosphodiesterase inhibitors alone or with other vasodilators on the erectile response in cats

PURPOSE: Zaprinast, dipyridamole and sildenafil were injected into the corpora cavernosa of cats to determine whether changes in the steady state level of cyclic guanosine monophosphate (cGMP) induced by inhibiting type 5 phosphodiesterase would cause an erectile response. MATERIALS AND METHODS: Increases in intracavernous pressure, penile length and erectile response duration were determined after intracavernous injection of the type 5 cGMP specific phosphodiesterase inhibitors zaprinast, dipyridamole and sildenafil as well as combined zaprinast and prostaglandin E1 (PGE1), and zaprinast and sodium nitroprusside. Systemic arterial pressure was concurrently assessed in these experiments. All responses to phosphodiesterase inhibitors were compared to a control triple drug combination of 1.65 mg papaverine, 0.5 microg PGE1 and 25 microg phentolamine. RESULTS: Each selective type 5 phosphodiesterase inhibitor caused dose related increases in intracorporeal pressure and penile length. However, none of the compounds was as effective as the control drug combination of papaverine, phentolamine and PGE1. Combining zaprinast with sodium nitroprusside led to further increases in pressure and erectile response duration that more closely resembled the control drug response. Combining zaprinast with PGE1 led to a response that was indistinguishable from the control response. CONCLUSIONS: The results of these feline studies establish that administering a type 5 phosphodiesterase inhibitor without concomitant administration of a nitric oxide donor or stimulation of the cavernous nerves may have a direct effect on the erectile response. These data also suggest that combining a selective type 5 phosphodiesterase inhibitor with PGE1 may be highly effective local therapy for erectile dysfunction and an acceptable alternative to other current forms of treatment.     

Melatonin prevents deterioration of erectile function in streptozotocin-induced diabetic rats via sirtuin-1 expression

A review of the literature indicated that sirtuin-1 expression, a regulator of nitric oxide bioavailability in erectile dysfunction (ED) after melatonin therapy, has not yet been investigated. The objective of this study was to evaluate the protective effects of melatonin for erectile function with sirtuin-1 protein expression in type 1 diabetic rat models. Fifty male Sprague Dawley rats were placed into five groups. Except for those in the control group (C), each animal received a single dose (60 mg/kg) of streptozotocin to induce diabetes. The animals were placed into the diabetes (D) group, insulin (I) group (6 U/kg/day), melatonin (Mel) group (10 mg kg⁻¹ day⁻¹) and combined treatment (I + Mel) group. Ten weeks later, the serum testosterone levels, intracavernosal pressure (ICP), mean arterial pressure (MAP), malondialdehyde (MDA), cyclic guanosine monophosphate (c-GMP), 8-hydroxydeoxyguanosine (8-OHdG), nitric oxide synthase (NOS), caspase-3 activity, sirtuin-1 and endothelial nitric oxide synthase (eNOS) protein expression and histological findings were assessed. The mean ICP/MAP ratio for the D group was lower than the mean ratios for the other groups. The treatment groups, particularly the I + Mel group, exhibited lower 8-OHdG and MDA levels and caspase-3 activity than the D group. The sirtuin-1 and eNOS expression and cavernosal tissue (CT) histology seemed to have been preserved by the melatonin and/or insulin therapy. These results were indicative of a profound protective effect of melatonin by the activation of sirtuin-1 protein expression against hyperglycemia-induced oxidative CT injury.     

Intracisternal sodium nitroprusside fails to prevent vasospasm in nonhuman primates

OBJECTIVE: Hemoglobin contributes to vasospasm after subarachnoid hemorrhage. One mechanism may involve binding of nitric oxide, destruction of nitric oxide, or both. Support for this mechanism would be evidence that nitric oxide donors prevent vasospasm. This study attempted to provide such evidence. METHODS: A randomized, blinded study was conducted in which 13 monkeys underwent cerebral angiography and creation of a right subarachnoid hemorrhage. Subcutaneous osmotic pumps were implanted to deliver sodium nitroprusside (n = 7) or vehicle (n = 6) via catheters into the right basal cisterns. Seven days later, angiography was repeated, and the animals were humanely killed. Levels of cyclic nucleotides, hemoglobins, and thiocyanate were measured. RESULTS: Significant vasospasm of the right middle cerebral artery was present in animals treated with sodium nitroprusside (35 +/- 22% reduction in diameter, P < 0.05, paired t test) and placebo (28 +/- 20% reduction, P < 0.05, not significantly different from nitroprusside group by unpaired t test). Adequate delivery of sodium nitroprusside was supported by the finding of a significant increase in cyclic guanosine monophosphate levels in the cerebral arteries of treated animals compared with placebo (P < 0.05, unpaired t test). Thiocyanate was not present in significantly increased amounts in animals treated with nitroprusside, although this group did display elevated concentrations of nitrosyl hemoglobin (measured by electron paramagnetic resonance spectroscopy) and cyanomethemoglobin (measured by spectrophotometry) in the cerebrospinal fluid on Day 7. CONCLUSION: The lack of effect of sodium nitroprusside was not the result of inadequate drug delivery because cyclic guanosine monophosphate levels were significantly increased in vasospastic arteries. Vasospasm may not have been prevented because of a toxic effect of sodium nitroprusside metabolites, involvement of smooth muscle relaxation or contraction processes downstream of cyclic guanosine monophosphate, or both.     

Testosterone and erectile dysfunction

The role of testosterone on sexual desire, interest and motivation is well established, but its effects on erectile function remain controversial. Animal data show that experimental or medical castration results in loss of the intracavernosal pressure, smooth muscle/connective tissue balance, and penile tissue concentration of nitric oxide synthase-containing nerves, which alter the fibroelastic properties of penile tissue compliance, leading to veno-occlusive dysfunction and therefore erectile dysfunction. Castration also induces apoptosis of penile erectile tissue, and new DNA synthesis is induced by treatment with testosterone. In an animal model of venogenic erectile dysfunction, intracavernous vascular endothelial growth factor (VEGF), in addition to testosterone, restores the smooth muscle/connective tissue balance, endothelial cell hypertrophy and hyperplasia and normalizes the diameter of the dorsal nerve fibres, thereby preventing veno-occlusive dysfunction. There is some evidence that treatment with testosterone may be beneficial to men with erectile dysfunction who have low baseline testosterone levels. Androgens may also control the expression and activity of phosphodiesterase type-5 (PDE-5) in the penile corpus cavernosum. Oral drug therapy with PDE-5 inhibitors fails in some patients with erectile dysfunction. However, when testosterone is used together with a PDE-5 inhibitor, sexual function is restored in these patients, creating the potential for pharmacological combination therapy with testosterone for the treatment of erectile dysfunction.