Levetiracetam ameliorates ovarian function in streptozotocin-induced diabetic rats

Abstract

Diabetes mellitus can adversely affect gonadal function. In the present study, we aimed to investigate the protective effects and mechanism of action of levetiracetam (LEV) on the ovaries in a streptozotocin (STZ)-induced diabetes model in rats. Twenty-one adult female rats were assigned to three groups as control, diabetes group treated with 1?mL/kg/d saline (STZ?+?SP) and diabetes group treated with 600?mg/kg/d LEV (STZ?+?LEV). Following 4 weeks treatment, blood samples were collected for biochemical analysis and ovariectomy was performed for histopathological examination. Plasma anti-Mullerian hormone (AMH), glutathione and total anti-oxidant capacity values were significantly lower whereas lipid peroxides and transforming growth factor-β (TGF-β) values were significantly higher in STZ?+?SP group compared to control. LEV treatment successfully decreased lipid peroxidation and TGF-β levels, and also increased anti-oxidant parameters and AMH levels in diabetic rats. Saline-treated rats significantly displayed ovarian degeneration and decreased counts of follicles. However, treatment of diabetic rats with LEV effectively prevented the degenerative changes and follicle loss. Also, LEV suppressed ovarian nuclear factor-kappa B (NF-kB) immunoexpression in diabetic rats. Taken together, we propose that LEV can ameliorate the adverse effects of diabetes on ovarian function via decreasing NF-kB expression and oxidative stress and increasing anti-oxidant status in rats.     

Effects of smoking on plasma testosterone level and erectile function in rats

IntroductionThere have been several conflicting reports of the effects of smoking on plasma testosterone levels and erectile function in clinical and animal studies.AimThis study was conducted to determine the actual effects of smoking on plasma testosterone levels and erectile function in rat‐smoking models.MethodsFor the exposure to cigarette smoke, the rats in a cage had a constant influx of smoke using a specially constructed device. Twenty‐four Sprague Dawley (SD) rats for the acute cigarette exposure were allocated randomly into two groups: an experimental group and a control group. Thirty‐six SD rats for the chronic cigarette smoke exposure were randomly divided into three groups: a control group and two experimental groups.Main Outcome MeasuresAfter exposure to smoking, the rats were subjected to electrical field stimulation of the cavernosal nerve to assess the erectile function, and blood was collected to measure the levels of plasma thiocyanate, testosterone, luteinizing hormone, and follicle‐stimulating hormone. The histological changes of testes and corpora cavernosum (CC) were examined.ResultsIn the smoking groups, the thiocyanate levels were significantly higher than in the control group. Also, the mean arterial pressure (MAP) was significantly higher in the smoking groups, but the corpora cavernosal filling rate and maximal intracavernosal pressure/MAP were significantly lower than in the control group. The testosterone levels of experimental groups were significantly lower than those of control group, and the testosterone and thiocyanate levels were significantly correlated with erectile function components in chronic smoking groups. There was no significant histological change in the testes; however, in the CC, there was an increase in collagen fibers and decrease in smooth muscle and sinusoidal space in chronic smoking groups.Conclusions.The results suggest that both the vasoconstrictor effects of smoking and the decrease in testosterone levels after chronic smoking had some effects on erectile function in rats. Park MG, Ko KW, Oh MM, Bae JH, Kim JJ, and Moon DG. Effects of smoking on plasma testosterone level and erectile function in rats. J Sex Med 2012;9:472–481.     

Adrenomedullin mediates adipose tissue-derived stem cell-induced restoration of erectile function in diabetic rats

IntroductionErectile dysfunction (ED) is a major health problem. It is known that diabetic patients are more refractory to common treatments for ED.AimTo explore the better treatment for ED, we examined the effects of adipose‐derived stem cells (ASC) on ED using a diabetic rat model. We also analyzed the cytokines produced by ASC and implicated in ASC‐induced restoration of erectile function.MethodsMale Wistar rats were injected with streptozotocin (STZ) to induce diabetes. ASC or adenoviruses were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology and protein expression were analyzed 4 weeks after the injection of ASC or adenoviruses.Main Outcome MeasuresIntracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of proteins specific for vascular endothelial cells (VEC) was assessed by Western blot analysis.ResultsASC restored erectile function especially when they were cultured in medium containing growth factors for VEC. This restoration was associated with improvement in the histology of the cavernous body, and increased expression of VEC markers such as VE‐cadherin and endothelial nitric oxide synthase (eNOS). When the expression of adrenomedullin (AM), a vasoactive peptide originally isolated from human pheochromocytoma tissue, was knocked down, the effect of ASC on ED was significantly diminished. Knockdown of AM was associated with decreased expressions of VE‐cadherin and eNOS. Furthermore, overexpression of AM induced by adenovirus infection significantly improved erectile function in these diabetic rats. Overexpression of AM was associated with increased expressions of VE‐cadherin and eNOS.Conclusions.These results suggested that ASC have the potentials to restore erectile function and that AM produced by ASC plays a major role in the restoration of erectile function. Nishimatsu H, Suzuki E, Kumano S, Nomiya A, Liu M, Kume H, and Homma Y. Adrenomedullin mediates adipose tissue‐derived stem cell‐induced restoration of erectile function in diabetic rats. J Sex Med 2012;9:482–493.     

PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats

IntroductionAn important mechanism suggested to be responsible for diabetes‐associated erectile dysfunction (ED) involves increased apoptosis, increased collagen deposition, and reduced smooth muscle content in the corpus cavernosum.AimTo determine whether the activation of the pro‐apoptotic poly(adenosine diphosphate ribose) polymerase (PARP) pathway is involved in the induction of corporal apoptosis, and whether the administration of 3‐aminobenzamide (3‐AB), a specific PARP inhibitor, could ameliorate ED in diabetic rats.MethodsMale Sprague‐Dawley rats (8‐weeks‐old) were randomly divided into three groups: age‐matched controls (C), diabetic controls (DM), and 3‐AB‐treated diabetic group (DM + 3‐AB). Diabetes was induced by intraperitoneal (ip) injection of streptozotocin (50 mg/kg). Eight weeks after the induction of diabetes, DM + 3‐AB group treated with 3‐AB (30 mg/kg/day, ip) for 4 weeks.Main Outcome MeasuresAt 12 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis, Masson's trichrome stain and immunohistochemical analysis for smooth muscle alpha actin. Expression of poly(ADP‐ribose), phospho‐protein kinase B (Akt), phospho‐Bcl‐2‐associated death promoter (Bad), B‐cell leukemia/lymphoma 2 (Bcl‐2), Bcl‐2‐associated X Protein (Bax), and apoptosis‐inducing factor (AIF) were evaluated by Western blot. Caspase‐3 activity and malondialdehyde (MDA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD+) concentrations were also determined.ResultsDM group showed impaired erectile function, increased PARP activity and corporal apoptosis, and decreased smooth muscle contents. Expression of phospho‐Akt, phospho‐Bad, Bcl‐2, and concentrations of ATP and NAD+ were decreased in the DM group, whereas concentrations of MDA, expression of Bax, nuclear translocation of AIF, and caspase‐3 activity were increased. Treatment with 3‐AB restored erectile function and significantly reversed all molecular and histological alterations except for the increased MDA.ConclusionsOver‐activation of penile PARP pathway in diabetic rats enhances corporal apoptosis via energy depletion, suppression of Akt phosphorylation, and activation of the mitochondrial apoptotic pathway, which results in ED; these event could be prevented by treatment with 3‐AB. Li WJ, Zhou J, Li B, Wang H, Peng YB, and Wang Z. PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats.     

Change of erectile function and responsiveness to phosphodiesterase type 5 inhibitors at different stages of streptozotocin-induced diabetes in rats

IntroductionIt has been suggested that risk of erectile dysfunction (ED) increases with duration of diabetes and phosphodiesterase type 5 inhibitors (PDE5I) are not as effective in treatment of diabetes-associated ED. However, few studies have investigated time-dependent change in erectile function during the course of diabetes.AimTo investigate time-dependent change in erectile function and responsiveness to PDE5I in streptozotocin-induced diabetic rats and to understand the pathophysiology of diabetic ED.Main Outcome MeasuresAt 6, 8, 10, 12, and 14 weeks after diabetic induction, erectile function was assessed by cavernous nerve stimulation before and after administration of DA-8159, a novel PDE5I. Penile tissue was assessed for apoptosis with immunohistochemistry. Protein expression of Rho-kinase 2 (ROCK2), myosin phosphatase targeting subunit 1 (MYPT1), and endothelial nitric oxide synthase (eNOS) was evaluated by Western blot.MethodsStreptozotocin was injected into 50 8-week-old male Sprague-Dawley rats, which were then classified into five diabetic groups according to the observation period.ResultsDiabetic rats maintained normal erectile responses until 6 weeks of diabetes. Following 8 weeks, the rats showed lower erectile responses at higher frequencies of nerve stimulation, which were normalized to control by administration of DA-8159. In contrast, erectile responses were significantly decreased in 10-week diabetic rats, and administration of DA-8159 resulted in partial recovery of normal responses. At more than 12 weeks, rats demonstrated severe deterioration of erectile function, which did not fully respond to PDE5I. Corporal apoptosis was significantly increased after 10 weeks. Upregulation of ROCK2 was found at 6 weeks, and was followed by an increase of MYPT1 phosphorylation. Phosphorylation of eNOS showed marked suppression at 6 weeks and remained lower during the experimental period.ConclusionsImpairment of erectile function was followed by decreased responsiveness to PDE5I during the course of diabetes. The RhoA/ROCK pathway played an important role in diabetes-associated ED. Cho SY, Park K, Paick J-S, and Kim SW. Change of erectile function and responsiveness to PDE5 (Type 5 phosphodiesterase) inhibitors at different stages of streptozotocin-induced diabetes in rats.     

Intracavernous transplantation of bone marrow-derived mesenchymal stem cells restores erectile function of streptozocin-induced diabetic rats

IntroductionErectile dysfunction (ED) is a frequent complication of diabetes mellitus. The efficacy of common ED therapies is low for diabetes‐associated ED.AimTo explore the effects of transplantation of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) on improving erectile function of streptozocin (STZ)‐induced diabetic rats.MethodsMale Sprague Dawley rats were injected either with STZ to induce diabetes or with citrate buffer as controls. Rat BM‐MSCs were harvested and labeled with CM‐DiI (Chloromethylbenzamido derivatives of 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate), and then transplanted into corporal cavernosum of STZ‐induced diabetic rats. Four weeks after transplantation, all rats were analyzed for erectile function and penile histology.Main Outcome MeasuresErectile function was evaluated by the ratio between intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of cavernous nerve. Fate of transplanted BM‐MSCs was identified using immunofluorescence staining. Smooth muscle and endothelium in corpora cavernosum were assessed using immunohistochemistry.ResultsAfter BM‐MSCs transplantation, the ICP/MAP ratio was increased significantly compared with diabetic controls. Content of smooth muscle and endothelium in corporal cavernosa of BM‐MSCs transplanted rats was significantly increased compared to diabetic controls. Immunofluorescence analysis demonstrated that CM‐DiI‐labeled BM‐MSCs could stay in corporal cavernosa for at least 4 weeks and some of them expressed von Willebrand Factor, CD31, calponin, or α‐smooth muscle actin, cells markers for endothelial cells or smooth muscle cells, respectively.ConclusionIntracavernous transplantation of BM‐MSCs had beneficial effects on erectile function of diabetic rats and increased the content of endothelium and smooth muscle in corporal cavernosum. Qiu X, Lin H, Wang Y, Yu W, Chen Y, Wang R, and Dai Y. Intracavernous transplantation of bone marrow‐derived mesenchymal stem cells restores erectile function of streptozocin‐induced diabetic rats.     

High-dose atorvastatin ameliorates the uterine microenvironment in streptozotocin-induced diabetic rats

The aim of this study was to investigate whether atorvastatin can ameliorate the uterine microenvironment in diabetes mellitus. Six non-diabetic (control) and 12 diabetic mature female Sprague–Dawley albino rats were used in this study. Diabetes was induced by intraperitoneal injections of 60?mg/kg streptozotocin, and 10?mg/kg/day of oral atorvastatin was administered for 4?weeks via orogastric tubes. The animals were euthanized, and blood samples were collected via cardiac puncture for biochemical analysis. Bilateral hysterectomy was performed for the histopathologic examination. Endometrial gland degeneration and stromal fibrosis scores concomitant with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) immunoexpressions were analyzed. The endometrial gland degeneration scores, stromal fibrosis scores and VEGF immunoexpression was significantly lower, and the EGFR immunoexpression was significantly higher in the atorvastatin-treated diabetic rats when compared to the non-treated diabetic group, suggesting that atorvastatin ameliorates the uterine microenvironment in diabetes mellitus.     

Beneficial treatment effects of dietary nitrate supplementation on testicular injury in streptozotocin-induced diabetic male rats

Research questionDo low doses of dietary nitrate help to attenuate the progression of diabetic reproductive disorders in streptozotocin-induced diabetic male rats?DesignFifty male Wistar rats were divided into five groups: controls receiving distilled water; controls receiving 100 mg/l nitrate in distilled water; diabetic rats receiving distilled water; diabetic rats receiving insulin 2–4 U/day of neutral protamine hagedorn insulin; and diabetic rats receiving 100 mg/l nitrate in distilled water. Diabetes was induced by 45 mg/kg streptozotocin. Nitrate and insulin treatment were started 4 weeks after diabetes induction for 8 weeks. Serum insulin, nitrogen oxide, stereology of testis, apoptosis, sperm parameters, and mRNA expression of Pdcd4, Pacs2, p53 and miR-449a were assessed at the end of the study.ResultsBlood glucose, apoptotic index of seminiferous tubules and expression of p53, Pdcd4, and Pacs2 mRNA were significantly higher in the diabetic rats (P < 0.001). Decreased body weight, serum insulin and nitrogen oxide level, and miR-449a were observed in the diabetic group (P < 0.01 for insulin; P < 0.001 for others). Most sperm parameters and stereological results differed between diabetic and control rats; nitrate recovered almost all these alterations, including dead spermatozoa, sperm motility grade, sperm deformity index, spermatozoa with damaged DNA, malformations in abnormal spermatozoa, total volume of seminiferous tubule, germinal epithelium, capsule, lumen, interstitial tissue, seminiferous tubule diameter, germinal epithelium height, the number of spermatogenic, Sertoli and Leydig cells.ConclusionsTreatment with sodium nitrate could modulate apoptosis, which is a major cause of diabetic testicular disorder. These experiments suggest that nitric oxide plays an important role in the function of the reproductive system.     

Effects of different contrast media on glutathione peroxidase and superoxide dismutase activities in the heart and kidneys of normal and streptozotocin-induced diabetic rats.

BACKGROUND/PURPOSE: Hemodynamic changes and contrast nephropathy are well known complications of contrast media injection. However, the mechanisms of toxicity leading to these complications remain unclear. We hypothesized that contrast media toxicity would manifest as a change in antioxidant enzyme activity, thus leading to tissue damage. METHODS: This study investigated the effects of injection of ionic high-osmolar diatrizoate, ionic low-osmolar ioxaglate, and nonionic low-osmolar iopromide on the activities of two antioxidant enzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), in the heart and kidney tissue of normal male Wistar rats (n = 51) and streptozotocin (STZ)-induced diabetic rats (n = 54). Activities of GPX and SOD were assayed spectrophotometrically. RESULTS: Renal GPX activities were significantly decreased in both normal (458.3 +/- 64.6 to 385.5 +/- 63.4 mU/mg, p = 0.005) and diabetic rats (669.0 +/- 98.1 vs. 564.0 +/- 153.3 mU/mg, p = 0.035) at 1 hour after diatrizoate injection. Renal SOD activities were not affected after contrast injection. Ioxaglate and iopromide injection did not cause any change in renal antioxidant enzyme activity. In contrast to kidney tissue, there was no significant change in GPX and SOD activities in heart tissue at 1 hour after injection of different contrast media. CONCLUSION: Intravenous injection of ionic high-osmolar diatrizoate reduced renal GPX activity during the first hour in both normal and STZ-induced diabetic rats. Heart tissue was not prone to antioxidant enzyme activity changes after intravenous contrast media injection. GPX activity reduction can be an important mechanism of nephrotoxicity after contrast media injection.     

Effect of niacin on erectile function in men suffering erectile dysfunction and dyslipidemia

IntroductionDyslipidemia is closely related to erectile dysfunction (ED). Evidence has shown that the lipid‐lowering agent, 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitor (statins), can improve erectile function. However, information about the potential role of another class of lipid‐lowering agent, niacin, is unknown.AimTo assess the effect of niacin alone on erectile function in patients suffering from both ED and dyslipidemia.MethodsA single center prospective randomized placebo‐controlled parallel‐group trial was conducted. One hundred sixty male patients with ED and dyslipidemia were randomized in a one‐to‐one ratio to receive up to 1,500 mg oral niacin daily or placebo for 12 weeks.Main Outcome MeasuresThe primary outcome measure was the improvement in erectile function as assessed by question 3 and question 4 of the International Index of Erectile Function (IIEF Q3 and Q4). Secondary outcome measurements included the total IIEF score, IIEF‐erectile function domain, and Sexual Health Inventory for Men (SHIM) score.ResultsFrom the overall analysis, the niacin group showed a significant increase in both IIEF‐Q3 scores (0.53 ± 1.18, P < 0.001) and IIEF‐Q4 scores (0.35 ± 1.17, P = 0.013) compared with baseline values. The placebo group also showed a significant increase in IIEF‐Q3 scores (0.30 ± 1.16, P = 0.040) but not IIEF‐Q4 scores (0.24 ± 1.13, P = 0.084). However, when patients were stratified according to the baseline severity of ED, the patients with moderate and severe ED who received niacin showed a significant improvement in IIEF‐Q3 scores (0.56 ± 0.96 [P = 0.037] and 1.03 ± 1.20 [P < 0.001], respectively) and IIEF‐Q4 scores (0.56 ± 1.03 [P = 0.048] and 0.84 ± 1.05 [P < 0.001], respectively] compared with baseline values, but not for the placebo group. The improvement in IIEF‐EF domain score for severe and moderate ED patients in the niacin group were 5.28 ± 5.94 (P < 0.001) and 3.31 ± 4.54 (P = 0.014) and in the placebo group were 2.65 ± 5.63 (P < 0.041) and 2.74 ± 5.59 (P = 0.027), respectively. There was no significant improvement in erectile function for patients with mild and mild‐to‐moderate ED for both groups. For patients not receiving statins treatment, there was a significant improvement in IIEF‐Q3 scores (0.47 ± 1.16 [P = 0.004]) for the niacin group, but not for the placebo group.ConclusionsNiacin alone can improve the erectile function in patients suffering from moderate to severe ED and dyslipidemia. Ng C‐F, Lee C‐P, Ho AL, and Lee VWY. Effect of niacin on erectile function in men suffering erectile dysfunction and dyslipidemia. J Sex Med 2011;8:2883–2893.     

Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction

IntroductionChronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown.AimThe aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats.MethodsEight‐week‐old male Wistar‐ST rats were divided into four groups: sham‐operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low‐dose (0.4 mg/kg/day; VL group) or high‐dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature.Main Outcome MeasuresErectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)‐β₁, vascular endothelial growth factor‐A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real‐time PCR. Western blotting for TGF‐β₁ protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery.ResultsIn the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF‐β₁ mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05).ConclusionsChronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats. Hotta Y, Hattori M, Kataoka T, Ohno R, Mikumo M, Maeda Y, and Kimura K. Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction. J Sex Med 2011;8:705–711.     

Vardenafil restores erectile function to normal range in men with erectile dysfunction

IntroductionThe ability of oral phosphodiesterase type 5 (PDE5) inhibitor therapy to restore erectile function to normal is an important attribute to men with erectile dysfunction (ED).AimTo assess the ability of vardenafil to restore normal erectile function in men with general ED.MethodsIn two fixed‐dose, parallel‐group, double‐blind, placebo‐controlled, pivotal studies, patients received vardenafil (5, 10, or 20 mg) or placebo for 12/26 weeks.Main Outcome MeasureIn this retrospective analysis, the percentage of patients “returning to normal” erectile function at week 12 (as defined by scores ≥26 on erectile function domain of International Index of Erectile Function [IIEF‐EF]) was determined, with further stratification by baseline ED severity, etiology, age, and duration of ED.ResultsVardenafil 5, 10, and 20 mg returned 32%, 43%, and 49% of patients, respectively, to normal erectile function after 12 weeks, compared with 10% of patients receiving placebo (P < 0.0001). Return to normal IIEF‐EF domain scores was noted irrespective of severity, etiology, age, and duration of ED, and was observed even in challenging‐to‐treat subgroups. With vardenafil 20 mg, 39% of men with severe ED at baseline, 45–49% of men with ED of mixed or organic etiology, 35% of men aged ≥65 years, and 43% of men with ED of ≥3 years of duration returned to normal erectile function at week 12. Mean per‐patient SEP3 (question 3 on the Sexual Encounter Profile) success rates in patients achieving IIEF‐EF domain scores ≥26 ranged from 87% to 95%.ConclusionVardenafil improves the IIEF‐EF domain score to the normal range in a substantial proportion of men with ED. Padma‐Nathan H, Montorsi F, Giuliano F, Meuleman E, Auerbach S, Eardley I, McCullough A, Homering M, and Segerson T for the North American and European Vardenafil Study Group. Vardenafil restores erectile function to normal range in men with erectile dysfunction. J Sex Med 2007;4:152–161.     

Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action

IntroductionThe current pharmacotherapy for erectile dysfunction (ED) relies significantly on the use of phosphodiesterase type 5 (PDE5) inhibitors, but quite a proportion of ED patients are resistant to this therapy, necessitating a search for an alternative treatment. We reviewed available published data to analyze current evidence of hydrogen sulfide (H₂S) as a novel pharmacotherapeutic agent with supportive role in sexual function.AimTo discuss the role of H₂S in erectile function, its possible mechanism of action, and how this knowledge may be exploited for therapeutic use.MethodsPubmed and Medline search was conducted to identify original articles and reviews.Main Outcome MeasuresData from peer‐reviewed publications.ResultsAnimal studies using different species, including in vitro study done in humans, show evidence of H₂S's pro‐erectile effects. The mechanism behind is still unclear, but evidence in literature points out the involvement of K⁺_ATP channel, modulation of protein with anti‐erectile effects, as well as involvement of the nitrergic pathway through a complex cross‐talk. A new drug called H₂S‐donating sildenafil (ACS6), which incorporated an H₂S‐donating moiety in sildenafil, has been developed. While more studies are still needed, this heralded a new pharmacotherapeutical approach, which is multipronged in nature.ConclusionsGiven the mounting evidence of H₂S's role in erectile function and how it appears to achieve its pro‐erectile effects through different mechanisms, H₂S represents a potentially important treatment alternative or adjunct to PDE5 inhibitors. Liaw RL, Srilatha B, and Adaikan PG. Effects of hydrogen sulfide on erectile function and its possible mechanism(s) of action. J Sex Med 2011;8:1853–1864.     

Characterization of erectile function in elastin haploinsufficicent mice

IntroductionElastin fibers confer passive recoil to many tissues including the lung, skin, and arteries. In the penis, elastin is present in sinusoids, arterioles, and in the tunica albuginea. Although decreased penile elastin has been reported in men with erectile dysfunction, the exact role of elastin in physiologic processes integral to erection remains speculative.AimThe aim of this study was to characterize erectile function in elastin‐deficient mice.MethodsElastin haploinsufficient mice (Eln^+/?) and aged match Eln^+/+ (Wt) mice were used. Cavernosum was removed from some mice for quantification of elastin, collagen, and smooth muscle actin. Ex vivo assessment of contractile force generation was performed by myography. In vivo assessment of intracorporal pressure normalized to mean arterial pressure in response to electrical stimulation of the cavernosal nerve was measured. Veno‐occlusive function was determined by cavernosography.Main Outcome MeasuresThe main outcome measures of this study were the in vitro and in vivo assessment of cavernosal vasoreactivity, veno‐occlusive function and erection in mice deficient in elastin.ResultsEln^+/? mice exhibited ～33% less penile elastin than Wt mice, with no change in collagen. Cavernosal tissue from Eln^+/? mice has a significantly heightened contractile response, explained in part by increased smooth muscle cell content. Veno‐occlusive function was significantly altered in Eln^+/? mice. Interestingly, erectile function was impaired only at submaximal voltage (1 V) stimulation (there was no impairment during the higher 2‐V stimulus).ConclusionEln^+/? mice display a cavernosal phenotype consistent with developmental changes attributable to the loss of elastin. These alterations confer a degree of altered erectile function that is able to be overridden by maximal stimulatory input. Altogether, these data suggest that elastin is important for erectile function. Hidalgo‐Tamola J, Luttrell J, Jiang X, Li D, Mecham RP, and Chitaley K. Characterization of erectile function in elastin haploinsufficicent mice. J Sex Med 2011;8:3075–3085.     

Effects of norepinephrine on renal function in chronically hypoxic rats.

The sympathetic nervous system is activated in response to altitude hypoxia and activation of renal sympathetic nerves may cause vasoconstriction and fluid retention. However, renal excretion does not differ significantly between rats exposed to high altitude hypoxia and control rats. We hypothesize that renal response to norepinephrine (NE) is altered after chronic hypoxia. Female Wistar rats weighing 200 to 220 g were exposed to hypoxia in an altitude chamber (5,500 m, 380 torr) 15 hours/day for 4 weeks (HA, high altitude). Our findings showed that systemic infusion of NE (300 micrograms.kg-1.hr-1) produced less diuresis/natriuresis in HA rats that in sea level (SL) controls. With mechanical elevation of arterial blood pressure, both SL and HA rats showed no significant difference in their response to pressure diuresis. Direct intrarenal arterial NE (10 micrograms.kg-1.hr-1) administration reduced renal function more in HA rats than in SL rats. Intrarenal arterial administration of L-arginine (100 micrograms.kg-1.hr-1) did not alter the renal action of NE in HA rats. However, with intrarenal arterial infusion of phosphoramidon (100 micrograms.kg-1.hr-1), NE increased renal response in HA rats to almost the same level as that in SL rats. These results suggest that HA rats may have either an excess renal action of antidiuretic and antinatriuretic factors or an insufficient renal action of diuretic and natriuretic factors during NE administration.