vardenafil-dihydrochloride and Disease-Models--Animal

The anesthetized rabbit model is useful and has many advantages: ability to perform neurophysiological studies; more administration routes, including intracavernous injection; haemodynamic measurements in parallel to measurements of intracavernous pressure or penile volume; and direct measurement of intracavernosal pressure and blood flow. This model has been evaluated with many different types of drugs. The conscious rabbit model is a simple and valid model for the assessment of compounds with potential for treatment of ED. It offers several methodological advantages as a screening model for compounds with erection stimulating properties. It was clearly successful in demonstrating the efficacy and the mechanism of the new potent and selective PDE5 inhibitor vardenafil. The model was also effective in demonstrating erection-generating properties through other mechanisms, eg PDE3 inhibitors and alpha-receptor blockers. In conclusion, both anaesthetized rabbit model and the newly developed conscious-rabbit models are well-suited for studies in impotence research.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Experimental; Disease Models, Animal; Erectile Dysfunction; Imidazoles; Male; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Rabbits; Research; Sulfones; Triazines; Vardenafil Dihydrochloride

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. In this study, we aimed to determine the ameliorating effects of vardenafil in the ASD rat model induced by propionic acid (PPA) in terms of neurobehavioral changes and also support these effects with histopathological changes, brain biochemical analysis and magnetic resonance spectroscopy (MRS) findings.. Twenty-one male rats were randomly assigned into three groups. Group 1 (control, 7 rats) did not receive treatment. Rats in groups 2 and 3 were given PPA at the dose of 250 mg/kg/day intraperitoneally for 5 days. After PPA administration, animals in group 2 (PPAS, 7 rats) were given saline and animals in group 3 (PPAV, 7 rats) were given vardenafil. Behavioral tests were performed between the 20th and 24th days of the study. The rats were taken for MRS on the 25. Three chamber sociability and passive avoiding test, histopathological results, lactate levels derived from MRS, and biochemical biomarkers revealed significant differences among the PPAV and PPAS groups.. We concluded that vardenafil improves memory and social behaviors and prevent loss of neuronal and Purkinje cell through its anti-inflammatory and neuroprotective effect.

Topics: Animals; Anti-Inflammatory Agents; Autism Spectrum Disorder; Disease Models, Animal; Glial Fibrillary Acidic Protein; Interleukin-17; Interleukin-2; Lactates; Male; Nerve Growth Factors; Neuroprotective Agents; Propionates; Rats; Tumor Necrosis Factor-alpha; Vardenafil Dihydrochloride

Phosphodiesterase 5 inhibitors (PDE5is) inhibit the hydrolysis of cyclic guanosine 5'-monophosphate in smooth muscle cells and are a widely known treatment for erectile dysfunction. Accumulating evidence also suggests that PDE5is exhibit potential benefits in cardiovascular and chronic kidney diseases. In this study, we examined the therapeutic effects of a PDE5i, vardenafil (VAR), in a focal segmental glomerulosclerosis (FSGS) mouse model.. FSGS was induced in BALB/c mice by the intravenous administration of Adriamycin (AD, 11 mg/kg of body weight). After 24 h, VAR (at 12.5 μg/ml) was given in drinking water ad libitum until the animals were sacrificed. At the end of the experiment, plasma and kidney samples were harvested to evaluate clinical parameters, histopathological changes, and alterations in transcriptome and protein expressions.. In this study, VAR treatment attenuated the deterioration of proteinuria, renal dysfunction, and hypercholesterolemia in AD-induced FSGS. Treatment with VAR exhibited reductions in the severity of both glomerulosclerosis and tubulointerstitial injury in the histological analysis. In addition to relieving AD-induced podocyte loss, VAR also preserved endothelial cells in glomerular capillaries and ameliorated the accumulation of collagen fibers in the mesangial area and Bowman's capsule basement membrane. In addition, VAR showed an ability to suppress transforming growth factor-β-induced fibroblast-to-myofibroblast transdifferentiation.. Our data suggest that VAR exhibited reno-therapeutic effects via attenuating podocyte loss, preserving the integrity of the glomerular vasculature, and ameliorating fibrotic changes. These findings suggest that PDE5is might be a promising treatment modality for nephrotic syndrome.

Topics: Animals; Collagen; Disease Models, Animal; Doxorubicin; Drinking Water; Endothelial Cells; Glomerulosclerosis, Focal Segmental; Guanosine Monophosphate; Male; Mice; Mice, Inbred BALB C; Phosphodiesterase 5 Inhibitors; Podocytes; Transforming Growth Factors; Vardenafil Dihydrochloride

Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-β1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-β1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required.

Topics: Animals; Bleomycin; Cell Proliferation; Cells, Cultured; Collagen Type I; Disease Models, Animal; Drug Synergism; Extracellular Matrix; Female; Fibroblasts; Fibronectins; Gene Expression Regulation; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred C57BL; Phosphorylation; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Survival Analysis; Transforming Growth Factor beta1; Vardenafil Dihydrochloride

We aimed to investigate the radiological, biomechanical, histopathological, histomorphometric, and immunohistochemical effects of different doses of vardenafil on fracture healing.. Fifty-one rats were divided into three groups. Group V5 was given 5 mg/kg/day of vardenafil; Group V10 was given 10 mg/kg/day of vardenafil; and the control group was given the same volume of saline. Six rats from each group were sacrificed on Day 14 (early period) and the remaining rats were sacrificed on Day 42 (late period). Callus/femoral volume and bone mineral density were measured using micro-computed tomography. Five femurs from each group in the late period were examined by biomechanical tests. In addition to the histopathological and histomorphometric evaluations, immunohistochemical analyses were performed to examine the levels of inducible nitric oxide synthase (iNOS), transforming growth factor-3 (TGF-β3), and nuclear factor kappa B (NF-κB) proteins.. Both doses of vardenafil increased primary bone volume and maximal bone fracture strength in late period, compared to the control group (p<0.05). Histological healing scores of vardenafil groups were significantly higher in early period (p<0.001). While cartilaginous callus/total callus ratio in early period was higher, callus diameter/femoral diameter ratio in late period was lower in vardenafil groups (p<0.01). The NF-κB immunopositivity in V10 group decreased in early period, compared to control group (p<0.001). The TGF-β3 and iNOS immunopositivity increased in both V5 and V10 groups, compared to the control group in early period, but returned to normal in late period.. During the first period of fracture healing process in which vasodilation is mostly required with increasing inflammation, vardenafil has ameliorating effects on the bone union and supports fracture healing.

Topics: Animals; Biomechanical Phenomena; Bone Density; Bony Callus; Disease Models, Animal; Femoral Fractures; Femur; Fracture Healing; Male; NF-kappa B; Nitric Oxide Synthase Type II; Phosphodiesterase 5 Inhibitors; Rats; Transforming Growth Factor beta3; Vardenafil Dihydrochloride; X-Ray Microtomography

Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.. To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD.. We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD.. The new assay was able to detect transforming growth factor-β1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy.. This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models.. This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Extracellular Matrix; Fibrosis; High-Throughput Screening Assays; Humans; Male; Myofibroblasts; Penile Induration; Penis; Phenotype; Phosphodiesterase 5 Inhibitors; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Tamoxifen; Vardenafil Dihydrochloride

An experimental study was performed to evaluate the effects of Vardenafil on ischemia-reperfusion (I/R) injury in an experimental volvulus model by histochemical and biochemical methods.. Thirty-five male Wistar rats were divided in five groups (n = 7). In Group 1, a 5 cm segment of small intestine 2 cm proximal to cecum was excised to have a control group. In the second group, 5 cm segment of small intestine 2 cm proximal to cecum was rotated 360° clockwise direction and sutured with 4/0 polyglactin to generate an experimental model of volvulus. At the end of 2 h of ischemia, the same intestinal segment was sampled. In group 3, after achieving ischemia similar to group 2, two hours of reperfusion injury was obtained by removing the sutures. Rats in Group 4 received vardenafil after 1.5 h of ischemia and then 2 h of reperfusion. And finally, in Group 5, vardenafil was administered 2 h before laparotomy and 5 cm of intestine was removed without I/R injury. Intestinal segments were evaluated for total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) with biochemical and histopathological analysis.. Serum TOS levels and OSI were not significantly different between groups (p = 0.910, P = 0,43 respectively). The serum TAS level was decreased in group 3 as compared to vardenafil groups 4 and 5, without a statistical significance (p = 0.428). In histopathologic analysis, we found that vardenafil, partially reduced I/R injury. The villus structure was preserved but, congestion and inflammation were moderate.. Vardenafil partially reduced I/R injury histopathologically on intestine. Our study shows that it does not have statistically antioxidant effect on intestinal I/R injury in experimental model of volvulus. However, effects of vardenafil in I/R injury of liver, kidney, heart, testis, over and brain which were cited in literature were not confirmed with I/R injury on intestine.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Evaluation, Preclinical; Intestinal Volvulus; Intestine, Small; Male; Oxidative Stress; Postoperative Complications; Rats; Rats, Wistar; Reperfusion Injury; Vardenafil Dihydrochloride; Vasodilator Agents

Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals. Rats were randomly allocated into five groups. Group I: Normal control group received only saline. Group II: Rats injected with epinephrine and served as arrhythmia group. Groups III, IV, and V: Rats received daily oral sildenafil (0.5 mg/kg), vardenafil (3 mg/kg), and tadalafil (10 mg/kg), respectively, for 30 days prior to epinephrine injections. Injection of epinephrine to rats decreased heart rate and QTc interval but increased RR interval and duration of arrhythmia. Epinephrine group had lower serum reduced glutathione (GSH) and adiponectin levels and higher serum malondialdehyde (MDA), nitric oxide (NO), heart LDH, and CK contents. Histopathological investigations of epinephrine group provoked necrotic changes with strong positive immunoreactivity for caspases-3. While pretreatment of rats with PDE-5 inhibitors improved GSH and adiponectin contents, ameliorated serum MDA and NO levels and heart LDH and CK contents and corrected epinephrine-induced histopathological changes. PDE-5 inhibitors may delay epinephrine-induced arrhythmia through expression of adiponectin and downregulation of heart LDH and CK.

Topics: Adiponectin; Animals; Anti-Arrhythmia Agents; Apoptosis; Arrhythmias, Cardiac; Caspase 3; Creatine Kinase; Disease Models, Animal; Electrocardiography; Epinephrine; Glutathione; Heart Rate; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardium; Necrosis; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride

Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice. We found that a 3-week chronic treatment with a combination of sub-efficacious doses of the cAMP-specific PDE4-I roflumilast (0.01 mg/kg) and the cGMP-specific PDE5-I vardenafil (0.1 mg/kg) improved recognition, spatial and contextual fear memory. Importantly, the cognitive enhancement persisted for 2 months beyond administration. This long-lasting action, and the possibility to minimize side effects due to the low doses used, might open feasible therapeutic strategies against AD.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Protein Precursor; Animals; Benzamides; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Cyclopropanes; Disease Models, Animal; Female; Humans; Male; Memory; Mice, Transgenic; Nootropic Agents; Phosphodiesterase Inhibitors; Random Allocation; Vardenafil Dihydrochloride

Osteoporosis is a major public health problem associated with many factors, and it affects more than 50% of women over 50 years old. In the current study, our purpose was to investigate the effects of phosphodiestarase-5 inhibitors on osteoporosis via the nitric oxide/3',5'-cyclic guanosine monophosphate/protein kinase G signalling pathway. A total of 50 female albino Wistar rats were separated into five groups. The first group was appointed as the healthy control group with no ovariectomy. All animals in the other groups underwent a bilateral ovariectomy. Six months after the ovariectomy, vardenafil, udenafil and tadalafil were given to the third, fourth and fifth groups, respectively, but were not administered to the positive control group (10 mg/kg per day for two months). The bone mineral density values were determined using a densitometry apparatus for all groups pre- and post-ovariectomy as well as after treatment. The levels of nitric oxide, endothelial nitric oxidesynthase, asymmetric dimethylarginine, 3',5'-cyclic guanosine monophosphate, protein kinase G, phosphodiestarase-5, pyridinoline, deoxypyridinoline, carboxyterminal telopeptide fragments and plasma carboxy terminal propeptide of type I collagen were determined using an enzyme linked immunosorbent assay. The levels of malondialdehyde, 8-hydroxy-2-deoxy guanosine, deoxyguanosine and coenzyme Q10 were determined by a high-performance liquid chromatography assay. Additionally, the right femoral trabecular bone density and the epiphyseal plate were measured in all groups. Angiogenesis was histologically observed in the bone tissue. In addition, we determined that the inhibitors may have caused a positive impact on the increased bone mass density and reduction of bone resorption markers. We also observed the positive effects of these inhibitors on oxidative stress. In conclusion, these phosphodiestarase-5 inhibitors increase angiogenesis in bone tissue and improve the re-formation rate of bone in rats with osteoporosis. Chemical compounds studied in this article Udenafil (PubChem CID: 6918523); Tadalafil (PubChem CID: 110635); Vardanafil (PubCham CID: 110634). Impact statement The results in our study appear to establish the osteoporosis model and provide evidence of the positive effects of three separate PDE5 inhibitors (vardenafil, udenafil, and tadalafil). The positive effects of these PDE5 inhibitors are investigated and demonstrated by the bone mass density and bone resorption markers. Th

Topics: Animals; Biomarkers; Bone and Bones; Bone Density; Chromatography, High Pressure Liquid; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Osteoporosis; Ovariectomy; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats, Wistar; Sulfonamides; Tadalafil; Treatment Outcome; Vardenafil Dihydrochloride

Vardenafil is a selective phosphodiesterase-5 inhibitor used for erectile dysfunction treatment. The hepatoprotective role of vardenafil against acute hepatitis is not reported yet. Hence, this study aims to explore the protective role of vardenafil against concanavalin A (Con A) induced acute liver injury. Mice were pretreated with vardenafil (0.17 mg/kg/day) for seven consecutive days, and then subjected to a single IV injection of Con A. The results demonstrated that the vardenafil pretreatment significantly reduced the elevated serum levels of transaminases and alkaline phosphatase. Histopathological examination showed marked necrosis and inflammation in Con A-treated mice which was significantly ameliorated in vardenafil pretreated animals. Vardenafil pretreatment significantly alleviated the expression of nuclear factor kappa-B and inducible nitric oxide synthase in the hepatic tissue. Additionally, serum levels of nitric oxide and tumor necrosis factor-alpha were decreased in vardenafil pretreated animals compared to the Con A group. Therefore, our results demonstrate that vardenafil has hepatoprotective effect and this could be linked to decrease inflammatory mediators.

Topics: Alkaline Phosphatase; Animals; Concanavalin A; Disease Models, Animal; Erectile Dysfunction; Hepatitis; Inflammation; Liver; Male; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Transaminases; Tumor Necrosis Factor-alpha; Vardenafil Dihydrochloride

To investigate the effect of vardenafil in kidney of rats submitted to acute ischemia and reperfusion.. Twenty-eight rats were randomly distributed into two groups. Right nephrectomy was performed and the vardenafil group received vardenafil solution (at a concentration of 1 mg/ml in 10 mg/kg) while the control group received 0.9% saline solution (SS) one hour prior to the ligature of the left renal pedicle. After one hour of ischemia, animals were submitted to twenty-four hours of reperfusion, followed by left nephrectomy. The kidney's histological parameters evaluated on the study included vacuolar degeneration and tubular necrosis. Apoptosis was assessed by immunohistochemistry for cleaved caspase-3 using the point-counting and digital methods (Cytophotometry). Also, a biochemical analysis for creatinine was conducted.. There were statistically significant differences between groups only with regards to the vacuolar degeneration parameter and to the cleaved caspase-3 digital method.. Vardenafil showed a protective effect on the kidney of rats subjected to acute ischemia and reperfusion in this model.

Topics: Animals; Apoptosis; Caspase 3; Disease Models, Animal; Imidazoles; Immunohistochemistry; Ischemia; Kidney; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Random Allocation; Rats, Wistar; Reperfusion Injury; Reproducibility of Results; Sulfones; Time Factors; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

In previous studies, we have shown that phosphodiesterase type 5 inhibitors (PDE5-Is) can improve early consolidation of object memory. These conclusions were based on the timing of drug administration relative to the learning trial (i.e. before or after). However, there are very little pharmacological data available about the pharmacokinetic profile of orally administered PDE5-Is in the rat. Furthermore, there is still debate whether these effects are achieved via central or peripheral mechanisms and if acquisition processes are improved. In the current study, we tested the effects of the PDE5-I vardenafil in a cholinergic-deficit model and compared the effects after intracerebroventricular (ICV) versus oral (PO) administration. We found that PO vardenafil restored a scopolamine-induced memory impairment when dosed within 2 min after the learning trial while ICV vardenafil was able to restore memory when injected within 4 min after learning. Because the test trial was within 10 min after the learning trial, this suggests that these effects on object memory are related to acquisition processes that may still be ongoing in a time window after the learning trial. To further elucidate the extent of this acquisition window, we investigated the pharmacokinetic profile of vardenafil after PO administration where it was detected within 4 min post-dose. Taken together, our data suggest that PDE5 is involved in acquisition processes, which may linger for at least 4-6 min after learning. Further studies are needed to exclude that these effects could also be explained on basis of an effect on early consolidation processes. Additionally, the effectiveness of ICV-administered vardenafil provides further experimental evidence that PDE5-Is improve memory via a central mechanism.

Topics: Administration, Oral; Animals; Brain; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Infusions, Intraventricular; Learning; Male; Memory Disorders; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Recognition, Psychology; Scopolamine; Time Factors; Vardenafil Dihydrochloride

The most important issue in flap surgery is flap viability. This study aimed to compare the effects of most commonly used phosphodiesterase type 5 (PDE5) inhibitors on flap survival.. A 3 × 9 cm flap was elevated from the dorsum of 32 Wistar albino rats. In the control group, saline was administered 2 hours before the flap elevation and continued for 2 days after the surgery. In the sildenafil, tadalafil, and vardenafil groups, the related drug was administered. Blood flow in the flaps was monitored with laser Doppler flowmetry. On postoperative day 7, flaps were photographed and biopsies were obtained.. The ratios of flap necrosis area in the tadalafil, sildenafil, and vardenafil groups were lower than that in the control group, but without significant difference (p = 0.077). Histopathological evaluation revealed no significant difference among the groups.. The ratio of flap necrosis area tended to be lower in the groups receiving oral PDE5 inhibitors than in the control group, although not statistically significant. The role of PDE5 inhibitors needs to be evaluated in larger studies before a conclusion can be made regarding their effects on flap viability.

Topics: Animals; Biopsy, Needle; Blood Flow Velocity; Disease Models, Animal; Female; Graft Rejection; Immunohistochemistry; Infusions, Intravenous; Laser-Doppler Flowmetry; Microcirculation; Random Allocation; Rats; Rats, Wistar; Reference Values; Sildenafil Citrate; Skin Transplantation; Surgical Flaps; Tadalafil; Vardenafil Dihydrochloride; Wound Healing

Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis.. Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified.. The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001).. Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated with vascular smooth muscle and platelet functions.

Topics: Animals; Colitis, Ischemic; Colon; Disease Models, Animal; Female; Hemodynamics; Imidazoles; Malondialdehyde; Pentoxifylline; Phosphodiesterase 5 Inhibitors; Piperazines; Random Allocation; Rats, Wistar; Reproducibility of Results; Sulfones; Time Factors; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH.. Sprague-Dawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg⁻¹ day⁻¹ for 21 days (n = 12). Treatment-naive patients (n = 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2α and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue.. Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy.

Topics: Adolescent; Adult; Animals; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Male; Monocrotaline; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sulfones; Triazines; Vardenafil Dihydrochloride; Young Adult

To further explore the implication of the serotonin (5-HT) system in the improvement of rat short-term object recognition after administration of the type 2 phosphodiesterase inhibitor (PDE-I) BAY 60-7550 and the type 5 PDE-I vardenafil, the effect of PDE2 and PDE5 inhibition upon central amino acid levels, 5-HT, and related parameters were measured after applying acute tryptophan depletion (ATD).. Wistar rats were orally administered saline or a protein-carbohydrate mixture with or without tryptophan (TRP). TRP-depleted animals additionally received an oral vehicle injection or the PDE inhibitors BAY 60-7550 or vardenafil at a dose known to improve object memory performance.. Although ATD significantly decreased TRP levels in the hippocampus 2 h after administration, 5-HT levels appeared only moderately affected, without any changes observed in the amount of 5-HIAA or 5-HT turnover rate. Moreover, no effects of PDE inhibition upon 5-HT or related parameters were observed.. Changes in 5-HT neurotransmitter activity might be excluded as a potential underlying mechanism of the previously reported ability of PDE inhibitors to improve short-term object memory in rats. It is suggested that a decrease in cerebral blood flow potentially underlies ATD-induced object memory deficits, most likely due to decrease in NO synthesis.

Topics: Animals; Behavior, Animal; Diet Therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Imidazoles; Male; Memory Disorders; Memory, Short-Term; Phosphodiesterase 5 Inhibitors; Piperazines; Rats; Rats, Wistar; Recognition, Psychology; Serotonin; Sulfones; Synaptic Transmission; Triazines; Tryptophan; Vardenafil Dihydrochloride

We investigated the effect angiotensin II (Ang II), a corpus cavernosal smooth muscle (CCSM) constrictor peptide, has on tissue taken from rabbits following chronic partial bladder outlet obstruction (PBOO), as this model is characterized by an increase in corpus cavernosal collagen deposition and a marked reduction and impaired relaxation of CCSM cells.. To determine the interaction between Ang II and nitric oxide (NO) and the development of oxidative stress (OS) in a rabbit model of chronic PBOO.. Corpus cavernosal tissue was obtained from 12 sham-operated and 20 PBOO rabbits. Organ bath studies determined Ang II/NO interaction on CCSM function using losartan (AT1 receptor antagonist), sodium nitroprusside (SNP, NO donor), electrical field stimulation (EFS), and vardenafil (phosphodiesterase type 5 inhibitor). The role of OS in the Ang II response was also determined using diphenylene iodonium chloride (DPI), the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, which inhibits superoxide production and superoxide dismutase (SOD, the enzyme that accelerates the breakdown of superoxide).. Action of Ang II and AT1 receptor antagonist, as well as SOD and DPI on CCSM function.. Ang II caused a dose-dependent contraction of CCSM strips that was enhanced in PBOO rabbits and inhibited by losartan, DPI, and SOD. CCSM relaxation induced by SNP/EFS was impaired in this model and improved by vardenafil and losartan.. These findings imply that the increased Ang II contractile response is a pathological consequence of PBOO and that AT1 receptor inhibition may be a therapeutic approach to treat ED associated with PBOO.

Topics: Angiotensin II; Animals; Disease Models, Animal; Electric Stimulation; Erectile Dysfunction; Imidazoles; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Nitroprusside; Oxidative Stress; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Rabbits; Sulfones; Triazines; Urinary Bladder Neck Obstruction; Vardenafil Dihydrochloride

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension. Four weeks after monocrotaline-administration rats exhibited a significant increase in right ventricular pressure (RVSP, 94mmHg vs. 25mmHg; p=0.001) right ventricular weight (right ventricle/left ventricle+septum, 59 vs. 23; p=0.001) and pulmonary vascular remodeling (medial wall area 104% vs. 66%; p<0.05) as compared to controls, with a corresponding reduction in exercise capacity (% from baseline value: 67%; p<0.05). Vardenafil treatment resulted in decreased RVSP (56mmHg vs. 95mmHg; p=0.008), right ventricular weight (41 vs. 59; p=0.013), pulmonary vascular remodeling (medial wall area 64% vs. 104%; p<0.05) and a significant better exercise capacity (% from baseline value: 84% vs. 67%; p<0.05) compared to monocrotaline only treated animals. In conclusion, Vardenafil exerts beneficial effects on monocrotaline-induced pulmonary hypertension in rats. Whether it is a treatment option for patients with pulmonary hypertension needs to be elucidated.

Topics: Animals; Disease Models, Animal; Hypertension, Pulmonary; Imidazoles; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Physical Conditioning, Animal; Piperazines; Rats; Rats, Wistar; Sulfones; Triazines; Vardenafil Dihydrochloride

We tested the hypothesis that vardenafil, a common drug used for improving erectile dysfunction and able to partially normalize transepithelial chloride transport in cystic fibrosis (CF), modulates CF lung inflammation.. Inflammatory markers in lungs of F508del-CF and wild-type mice were monitored in response to lipopolysaccharide from Pseudomonas aeruginosa (LPS). The effect of pretreatment with vardenafil (0.14 mg/kg) was evaluated.. A latent inflammatory status, characterized by neutrophil infiltrate, mouse macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-α, was found in baseline conditions in F508del-CF mice. Inflammatory markers were increased after LPS with higher responses in CF. Vardenafil globally attenuated inflammatory responses in both genotypes however reduction of macrophage infiltration, macrophage chemoattractant chemokine and interleukin-1β was observed in the CF group only.. Vardenafil reduces lung inflammation with a more pronounced effect in F508del-CF mice, particularly on macrophage cell markers.

Topics: Animals; Animals, Outbred Strains; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Imidazoles; Immunomodulation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, 129 Strain; Mice, Inbred CFTR; Phosphodiesterase 5 Inhibitors; Piperazines; Pneumonia; Pseudomonas Infections; Sulfones; Triazines; Vardenafil Dihydrochloride

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF).. We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling.. Complete T7-T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250-275 g).. At 21-29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n=7) or vardenafil 1 mg/kg (n=8) was delivered intravenously. NVCs and BANF were recorded for 45 min.. In all SCI rats, BANF was already present and regular at resting conditions (26.2±4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08±0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186±37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline (p<0.001) and BANF (52% decrease vs 28% in saline after 45 min; p<0.001).. Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.

Topics: Animals; Decerebrate State; Disease Models, Animal; Female; Imidazoles; Neurons, Afferent; Phosphodiesterase 5 Inhibitors; Piperazines; Pressure; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Spinal Nerve Roots; Sulfones; Triazines; Urinary Bladder; Urinary Bladder, Overactive; Vardenafil Dihydrochloride

Chronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown.. The aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats.. Eight-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.. Erectile 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)-β(1), 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-β(1) protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery.. In 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-β(1) mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05).. Chronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats.

Topics: Animals; Blotting, Western; Disease Models, Animal; Imidazoles; Impotence, Vasculogenic; Male; Nitric Oxide Synthase Type II; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sulfones; Triazines; Vardenafil Dihydrochloride

Topics: Administration, Oral; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Cystic Fibrosis; Disease Models, Animal; Epithelial Sodium Channels; Genetic Therapy; Humans; Imidazoles; Infant, Newborn; Mice; Mutation; Neonatal Screening; Oocytes; Piperazines; Sulfones; Triazines; Vardenafil Dihydrochloride; Xenopus

Radical prostatectomy (RP) is frequently responsible for erectile dysfunction (ED). Post-RP patients often show a failure to respond to phosphodiesterase type 5 (PDE5) inhibitors.. The acute effect of BAY 60-4552, the soluble guanylate cyclase (sGC) stimulator, and vardenafil were evaluated alone or in combination on erectile responses to electrical stimulation of the cavernous nerve (ES CN) in rats with cavernous nerve (CN) crush injury-induced ED.. Male adult Sprague-Dawley rats underwent laparotomy (sham, n=10) or bilateral CN crush injury (n=56). After 3 wk of recovery, erectile function was evaluated under urethane anaesthesia following ES CN at different frequencies.. The acute effects of intravenous (IV) injection of vehicle, vardenafil 0.03 mg/kg, BAY 60-4552 0.03 mg/kg or 0.3 mg/kg, or a BAY 60-4552 0.03 mg/kg plus vardenafil 0.03 mg/kg combination were evaluated in CN-crushed rats.. Bilateral CN crush injury followed by a 3-wk recovery period decreased erectile responses to ES CN by about 50%. In CN-crushed rats, IV vardenafil 0.03 mg/kg and BAY 60-4552 (0.03 or 0.3 mg/kg) increased erectile responses to ES CN to the same extent: Δ intracavernosal pressure/mean arterial pressure (ICP/MAP) at 10 Hz ES CN was 21±1% after vehicle, 25±3% (p<0.001) after vardenafil, and 26±5% and 27±5% after BAY 60-4552 0.03 mg/kg (p<0.01) and 0.3 mg/kg (p<0.001), respectively. The combination of vardenafil with BAY 60-4552 in CN-crushed rats totally restored erectile responses to ES CN equivalent to sham rats (ΔICP/MAP at 10 Hz ES CN: 34±4% after BAY 60-4552/vardenafil combination vs 39±4% in sham rats; not significant).. The present study supports the concept that the combined administration of a sGC stimulator, BAY 60-4552, and vardenafil provides synergistic beneficial effects and might therefore salvage patients who experience treatment failures with PDE5 inhibitors after RP.

Topics: Animals; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Enzyme Activation; Enzyme Activators; Erectile Dysfunction; Guanylate Cyclase; Imidazoles; Male; Nerve Crush; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfones; Time Factors; Treatment Failure; Triazines; Vardenafil Dihydrochloride

We examined whether phosphodiesterase-5 (PDE5) inhibition can promote ischemia-induced angiogenesis.. Unilateral hindlimb ischemia was generated by resecting right femoral artery in wild-type C3H/He mice, treated with either vehicle or a PDE5 inhibitor vardenafil (10 mg/kg per day). Four weeks after surgery, vardenafil significantly enhanced blood flow recovery and augmented capillary collateral formation in ischemic muscle (blood flow ratios of ischemic/nonischemic leg: 0.52+/-0.17 [vehicle] versus 0.92+/-0.09 [vardenafil], P<0.01). Vardenafil upregulated protein expression of vascular endothelial growth factor and hypoxia-inducible factor (HIF)-1 alpha in ischemic muscle and enhanced mobilization of Sca-1/Flk-1-positive endothelial progenitor cells (EPCs) in peripheral blood and bone marrow, contributing to neovascularization. Vardenafil also promoted capillary-like tube formation of human umbilical vein endothelial cells and increased the number of human blood mononuclear cell-derived EPCs in vitro. Furthermore, reporter assays showed that vardenafil and cGMP activated the transactivation activity of HIF-1 under hypoxia. These effects of vardenafil were markedly inhibited by genetic ablation of endothelial nitric oxide synthase, a soluble guanylate cyclase inhibitor, and a protein kinase G inhibitor, respectively.. Our results suggest that PDE5 inhibition enhances ischemia-induced angiogenesis with mobilization of EPCs through a protein kinase G-dependent HIF-1/vascular endothelial growth factor pathway. PDE5 inhibition may have a therapeutic potential to treat ischemic cardiovascular diseases.

Topics: Angiogenesis Inducing Agents; Animals; Capillaries; Cell Hypoxia; Cell Movement; Cells, Cultured; Collateral Circulation; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelial Cells; Green Fluorescent Proteins; Hindlimb; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Ischemia; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Recovery of Function; Regional Blood Flow; RNA Interference; Signal Transduction; Stem Cells; Sulfones; Time Factors; Transfection; Triazines; Vardenafil Dihydrochloride; Vascular Endothelial Growth Factor A

To investigate whether vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor, would protect the bladder from decompensatory changes in a 4-week rat bladder outlet obstruction (BOO) model, as evidence has been accumulating that PDE-5 inhibitors improve lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH).. In all, 50 12-week-old female Sprague-Dawley rats were divided into five equal groups; group 1, sham operated vehicle control rats; group 2, BOO vehicle rats; group 3-5, BOO rats given oral vardenafil at 5, 20, 80 mg/L, respectively. Vardenafil was given in drinking water from the day of surgery. At 4-weeks after the introduction of BOO, vardenafil was washed-out by giving water for 24-48 h, and then the bladder was excised and dissected into four longitudinal strips for isometric organ-bath assay. Contractile responses of bladder strips to electrical field stimulation (EFS), carbachol and KCl was determined for each group.. BOO induced a significant increase in bladder weight in group 2 compared with group 1. Bladder weights of groups 3-5 were not significantly different from that of group 2. The contractile forces in response to EFS, carbachol and KCl in group 2 were 30.7-51.7% of those in group 1. Vardenafil treatment in groups 3-5 generally did not block the BOO-induced reduction of contractile force in the bladder strips. However, treatment with a high dose of vardenafil resulted in a significant increase in the contractile response to carbachol (78.4% group 5 vs 51.7% group 2).. Chronic treatment with a high dose of vardenafil protected the rat bladder from BOO-induced contractile dysfunction to carbachol.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Female; Imidazoles; Muscle Contraction; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Sulfones; Triazines; Urinary Bladder; Urinary Bladder Neck Obstruction; Vardenafil Dihydrochloride

Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the development of erectile dysfunction (ED). Vardenafil, a phosphodiesterase type 5 inhibitor has been used to treat ED. The aim of this study was to assess the in vitro and in vivo effects of vardenafil on diabetic rabbit CSMR.. Organ bath studies were used.. Sodium nitroprusside (SNP)- and electrical field stimulation (EFS)-induced CSMR in diabetic rabbits given the vehicle was significantly impaired when compared with controls. The in vitro addition of vardenafil significantly enhanced SNP-induced CSMR in diabetic animals given the vehicle. SNP-induced CSMR in diabetic animals given in vivo vardenafil was significantly increased when compared with the diabetic untreated group. The in vitro addition of vardenafil significantly enhanced SNP and EFS-induced CSMR in cavernosal tissue taken from diabetic animals given vardenafil in vivo.. The present findings suggest that the combination of in vitro and in vivo vardenafil enhance diabetic CSMR, reinforcing the use of vardenafil for the treatment of diabetes-induced ED.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Erectile Dysfunction; Imidazoles; Male; Muscle Relaxation; Muscle, Smooth; Nitroprusside; Penis; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Rabbits; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Recent experimental studies in rodents suggest that treatment with inhibitors of phosphodiesterase type 5 (PDE5) (tadalafil, sildenafil, zaprinast) not only increases cerebral blood flow but also improves functional recovery after stroke. Here, we investigated in a mouse model of stroke the effects of vardenafil on survival, functional outcome and lesion size after experimental stroke. Mice were subjected to experimental stroke by occlusion of the middle cerebral artery (MCAO) for 45 min. A group of mice received vardenafil (twice 10 mg/kg body weight per day orally over 14 days) starting 3 h after MCAO. Control animals received the vehicle only. Survival, body weight, and behavior were monitored over 4 weeks and brain lesions were measured by T2-weighted MRI, hematoxylin/eosin -- as well as GFAP-staining of cryostat sections, subsequently. The mortality in MCAO-operated animals amounted to 45% until day 10 after stroke and no significant difference in survival between the vardenafil- and vehicle-treatment groups was observed. Compared to sham-operated animals, MCAO-operated mice from both treatment groups demonstrated a significant weight loss until day 5 and regained their body weight by day 14 after ischemia. There was no significant difference between the vardenafil and vehicle-treated MCAO groups. In behavioral studies (sucrose consumption and pole test), analyzing sensorimotor functions as well as a parameter of depression-like symptoms, we observed no significant effect of vardenafil treatment on functional recovery in our model of stroke. Although we observed a trend towards less hemispherical atrophy in the vardenafil compared to the vehicle-treated group four weeks after MCAO our data do not suggest a functionally relevant CNS-tissue protective or regenerative effect in murine stroke.

Topics: Animals; Body Weight; Brain; Cerebrovascular Circulation; Depression; Disease Models, Animal; Feeding Behavior; Glial Fibrillary Acidic Protein; Imidazoles; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Recovery of Function; Stroke; Sulfones; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

Phosphodiesterase-5 inhibitors and elevated myocardial cyclic guanosine monophosphate levels can induce potent cardioprotection-like effects against ischaemia-reperfusion injury. We investigated the effects of vardenafil, a selective phosphodiesterase-5 inhibitor on myocardial and endothelial functions during reperfusion in a canine model of cardioplegic arrest and extracorporal circulation.. Vehicle-treated (control, n=8) and vardenafil-treated (30 microgkg(-1) intravenous (IV); n=8) anaesthetised dogs underwent hypothermic cardiopulmonary bypass with 60 min of hypothermic cardiac arrest. Left and right ventricular end-systolic pressure volume relationship (E(es)) was measured by a combined pressure-volume conductance catheter at baseline and after 60 min of reperfusion. Left anterior descending coronary blood flow and endothelium-dependent vasodilatation to acetylcholine were determined. Isolated coronary arterial rings were investigated for vasomotor function using an in vitro organ bath system.. Pharmacological preconditioning with vardenafil led to significantly higher plasma cyclic guanosine monophosphate levels and myocardial adenosine triphosphate content to a better recovery of left and right ventricular E(es) (Delta left ventricular E(es) given as percent of baseline: 74.2+/-4.5% vs 50.4+/-5.0%, p<0.05) and to a higher coronary blood flow (58+/-12 vs 24+/-7 mlmin(-1), p<0.05). Endothelium-dependent vasodilatory responses to acetylcholine - measured both in vivo and in vitro - were improved in the vardenafil group.. Application of vardenafil improves myocardial and endothelial functions after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects imply that phosphodiesterase-5 inhibition could be a novel therapeutic option in the protection against ischaemia-reperfusion injury in cardiac surgery.

Topics: Adenosine Triphosphate; Animals; Cardiopulmonary Bypass; Cardiotonic Agents; Cyclic GMP; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Endothelium, Vascular; Hemodynamics; Imidazoles; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Preanesthetic Medication; Sulfones; Triazines; Vardenafil Dihydrochloride; Ventricular Function, Left; Ventricular Function, Right

Matrix expansion and mesangial proliferation are hallmarks of mesangial proliferative glomerulonephritis. Specific inhibition of PDE-5, an enzyme catalyzing the intracellular degradation of cyclic GMP, can be achieved by the inhibitor vardenafil. In this study, we investigated the effects of PDE-5 inhibition in the anti-Thy1 model in the rat in vivo.. After disease induction, rats received 10 mg/kg bw vardenafil twice a day via gavage. On Days 2 and 6, renal biopsies, as well as glomerular isolates, urine and blood samples were taken to compare vardenafil- and placebo-treated groups during the course of disease.. Small amounts of PDE-5 were detected in healthy kidneys, but induced in a typical mesangial pattern during disease (by IHC and WB). Specific PDE-5 inhibition resulted in increased glomerular levels of cGMP. Treated animals demonstrated inhibition of MC proliferation and matrix accumulation while renal function and influx of inflammatory cells were not affected. Due to PDE-5 inhibition, the endogenous TGF-beta-activating protein TSP-1 and the TGF-beta-signalling protein p-smad-2/3 were decreased suggesting this as an antifibrotic mechanism of action of vardenafil in this model.. Considering the availability and safety profile of vardenafil, the beneficial antiproliferative and antifibrotic effect in experimental glomerulonephritis may potentially be applicable to the treatment of mesangial proliferative glomerulonephritis in man.

Topics: Animals; Antibodies, Monoclonal; Biopsy; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Extracellular Matrix; Glomerulonephritis; Imidazoles; Mesangial Cells; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Smad2 Protein; Smad3 Protein; Sulfones; Thrombospondin 1; Thy-1 Antigens; Transforming Growth Factor beta; Triazines; Vardenafil Dihydrochloride

The underlying mechanism of short-term memory improvement after inhibition of specific phosphodiesterases (PDEs) is still poorly understood. The present study aimed to reveal the ability of PDE5 and PDE2 inhibitors, that increase cyclic guanosine monophosphate (cGMP) and both cyclic adenosine monophosphate (cAMP) and cGMP, respectively, to reverse an object recognition deficit induced by acute tryptophan depletion. Acute tryptophan depletion is a pharmacological challenge tool to lower central serotonin (5-hydroxytryptamine; 5-HT) levels by depleting the availability of its dietary precursor tryptophan. Short-term object memory was tested in male Wistar rats by exposing them to the object recognition task. First, the effects of acute tryptophan depletion upon object recognition 2 h after administration of the nutritional mixture were established. Subsequently, acute tryptophan depletion was combined with the PDE5 inhibitor vardenafil (1, 3 and 10 mg/kg) or with the PDE2 inhibitor BAY 60-7550 (0.3, 1 and 3 mg/kg), 30 min prior to testing. Acute tryptophan depletion significantly lowered plasma tryptophan levels and impaired object recognition performance. Vardenafil (3 and 10 mg/kg) and BAY 60-7550 (3 mg/kg) were able to attenuate the acute tryptophan depletion induced object recognition impairment. Thus, both PDE5 and PDE2 inhibition improved short-term object recognition performance after an acute tryptophan depletion induced deficit. The underlying mechanisms, however, remain poorly understood and further studies are needed to determine whether the present findings can be explained by a direct effect of enhanced cAMP and cGMP levels upon 5-HT activity, or even other neurotransmitter systems, and possibly an interaction with synthesis of nitric oxide or effects upon cerebral blood flow function.

Topics: Animals; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Male; Memory; Memory Disorders; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Wistar; Serotonin; Sulfones; Triazines; Tryptophan; Vardenafil Dihydrochloride

Sildenafil has been implicated in the activation of cystic fibrosis transmembrane conductance regulator (CFTR) protein. The effect was observed in vitro and in the presence of doses roughly 300 times larger than those commonly used for treating erectile dysfunction.. To evaluate in vivo the therapeutic efficacy of clinical doses of sildenafil and vardenafil, two clinically approved phosphodiesterase 5 inhibitors, for activating ion transport in cystic fibrosis.. We used transepithelial potential difference in vivo across the nasal mucosa as a measure of sodium and chloride transport. The effect of a single intraperitoneal injection of sildenafil (0.7 mg/kg) or vardenafil (0.14 mg/kg) was investigated in F508del, cftr knockout and normal homozygous mice.. In F508del mice, but not in cftr knockout mice, the chloride conductance, evaluated by perfusing the nasal mucosa with a chloride-free solution in the presence of amiloride and with forskolin, was corrected 1 hour after sildenafil administration. A more prolonged effect, persisting for at least 24 hours, was observed with vardenafil. The forskolin response was increased after sildenafil and vardenafil in both normal and F508del mutant animals. In F508del mice, the chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid, an inhibitor of alternative chloride channels, was much higher after sildenafil injection than after placebo treatment. No effect on the sodium conductance was detected in any group of animals.. Our results provide preclinical evidence that both drugs stimulate chloride transport activity of F508del-CFTR protein.

Topics: Animals; Chlorides; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Imidazoles; Injections, Intraperitoneal; Ion Transport; Membrane Potentials; Mice; Mice, Inbred CFTR; Nasal Mucosa; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Protein Modification, Translational; Purines; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride

Topics: Animals; Chlorides; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Imidazoles; Membrane Potentials; Mice; Mice, Inbred CFTR; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Protein Modification, Translational; Purines; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride

Diabetic men generally have reduced efficacy with PDE-5 inhibitors (PDE5i) for the treatment of erectile dysfunction (ED).. To determine whether chronic vardenafil exposure alters cavernous protein expression predicting improved erectile function in diabetes.. Forty-two adult male Sprague Dawley rats with streptozotocin-induced (50mg/kg IP) diabetes for 4 wk, were exposed to either vehicle or vardenafil for 6 wk. Assessments compared the impact of vardenafil given at 1h and 20 h to erectile function and cellular alterations and downstream translation of cavernous protein profiles were aimed.. Vehicle or vardenafil 0.5mg/kg/day by oral gavage for 6 wk.. Erectile function, penile tissue morphology, protein expression and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI) protein profiling were determined.. A significant increase of intracavernous pressure was seen in both treatment arms compared to diabetic rats not receiving vardenafil. Immunohistochemical staining showed improved endothelial and smooth muscle cell staining with chronic vardenafil use. Western blot analysis demonstrated increased endothelial cell eNOS and smooth muscle alpha-actin protein content. SELDI protein profiling showed enhanced proteins expression at molecular weights of 14.7, 20, 41.9, 66.2, and 83.9 kDa in the chronically treated vardenafil group.. Vardenafil was effective in treating diabetic-induced ED with the greatest effect achieved through chronic dosing, with no additive effect measured with the final acute dose. Changes noted in the histology and protein expression indicate that vardenafil may have a protective effect in this disease state. This finding may serve as a basis for further work evaluating the utility of chronic vardenafil dosing in diabetic men.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Administration Schedule; Endothelium; Erectile Dysfunction; Imidazoles; Male; Penile Erection; Penis; Phosphodiesterase Inhibitors; Piperazines; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfones; Triazines; Vardenafil Dihydrochloride

Benign prostate hyperplasia is the most common disease in the aging male, often comorbid with erectile dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) decrease lower urinary tract symptoms in patients with erectile dysfunction and BPH. We studied PDE5 expression and activity in the human bladder and PDE5i effects both in vitro (human and rat) and in vivo (rat). PDE5 is highly expressed in rat and human bladder and immunolocalized in vascular endothelium and muscle fibers. Sildenafil, tadalafil, and vardenafil blocked 70% of the total cGMP-catabolizing activity; vardenafil was the most potent (IC(50) = 0.3 nm). In human bladder cells and in rat strips, a PDE-resistant cGMP analog, SP-8-Br-PET-cGMPS, induced, respectively, a consistent antiproliferative and relaxant effect. In contrast, the nitric oxide donor sodium nitroprusside (SNP) was almost ineffective. However, blocking PDE5 with vardenafil increased SNP antiproliferative and relaxant activity up to the level observed with SP-8-Br-PET-cGMPS. We also found that castration decreased, and T supplementation restored, PDE5 gene expression in rat bladder. Accordingly, bladder strips from castrated rats were more sensitive to SNP-induced relaxation than strips from control or T-replaced rats, whereas in the presence of vardenafil, all groups showed the same SNP sensitivity. To discover whether vardenafil affects bladder activity in vivo, the rat bladder outlet obstruction model was used. Chronic treatment with 10 mg/kg.d vardenafil significantly reduced nonvoiding contractions (47%, P < 0.05 vs. placebo) up to tamsulosin level (51%). Overall, these results demonstrate that PDE5 regulates bladder smooth muscle tone, strongly limiting the nitric oxide/cGMP signaling, and that vardenafil, by blocking PDE5, may be a possible therapeutic option for bladder dysfunction by ameliorating irritative lower urinary tract symptoms.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Aged, 80 and over; Androgens; Animals; Cell Proliferation; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Humans; Imidazoles; Male; Middle Aged; Muscle Relaxants, Central; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Sulfones; Triazines; Urinary Bladder; Urinary Bladder Neck Obstruction; Vardenafil Dihydrochloride

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

To assess pro-erectile responses to vardenafil, a new selective PDE5 inhibitor, in vitro in isolated rabbit corpora cavernosa, and in vivo in anaesthetized rats.. Rabbit cavernosal strips were precontracted with 10 microM phenylephrine. Dose-response relaxation curves to cumulative dosings of vardenafil (1 nM-10 microM) were constructed alone and in the presence of 10 mM L-NAME. Relaxation responses to electrical field stimulation (EFS) (2 Hz, 2 ms, 10 V) were compared in control preparations and in the presence of vardenafil (1-10 nM). Male Sprague-Dawley rats were anaesthetized with urethane and prepared for measurement of blood pressure and intracavernous pressure. Erectile responses (ICPmax/dBP x 100) to cavernous nerve submaximal stimulation (10 Hz, 1 ms, 0.45-1.6 V) were determined before, and 3, 10 and 23 min after i.v. administration of saline, vardenafil or sildenafil (0.1, 1 mg/kg).. Vardenafil was effective in relaxing precontracted rabbit cavernosal strips (IC50 54 +/- 18 nM). This relaxing activity was partially antagonized with 10 mM L-NAME, increasing the IC50 to 620 +/- 81 nM. Vardenafil significantly increased (more than 4 times) relaxation of precontracted rabbit cavernosal strips to EFS at 10 nM. In anaesthetized rats, erectile responses were significantly facilitated 3 and 13 min after 0.1 and 1 mg/kg vardenafil was administered. In contrast, 1 mg/kg sildenafil only significantly increased erectile responses at 3 min post-injection.. Vardenafil relaxes rabbit corpus cavernosum in vitro and is effective at a lower dose than sildenafil in facilitating erectile responses to cavernous nerve stimulation in anaesthetized rats.

Topics: Animals; Culture Techniques; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Penile Erection; Piperazines; Probability; Purines; Rabbits; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride

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.. 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.. 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.. 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.

Topics: Animals; Disease Models, Animal; Imidazoles; Male; Penile Erection; Phosphodiesterase Inhibitors; Piperazines; Rabbits; Sulfones; Triazines; Vardenafil Dihydrochloride