da-8159 and Disease-Models--Animal

Management of the burn injuries is still a problematic issue because the stasis zone may become necrotic. We hypothesized that udenafil, a potent phospodiesterase inhibitor, can be beneficial in burn treatment by enhancing the viability of the stasis zone.. Fifteen Wistar rats were randomly divided into 3 groups. Comb burn injury model was conducted bilaterally on the back of rats in each subject. Group 1 received 1 mL/d of saline orally for 7 days. Group 2 received 10 mg/kg per day of udenafil for 7 days. Group 3 received 20 mg/kg per day of udenafil for 7 days. At the end of seventh day, gross morphological and histopathological samples of stasis zone survival were evaluated.. Histopathological examination of groups 2 and 3 revealed that the stasis zone was mostly viable. The mean necrotic area and severity of inflammation was significantly higher in the control group compared with the treatment groups. Significant differences were determined in treatment groups compared with control group in terms of vital stasis zone area and histopathological parameters.. Udenafil treatment improved tissue survival on zone of stasis in. Future experimental studies should be conducted to develop zone of stasis treatment protocols combining udenafil with potent anti-inflammatory and antioxidant drugs.

Topics: Animals; Burns; Disease Models, Animal; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sulfonamides

Nonalcoholic fatty liver disease (NAFLD) refers to a series of diseases, including simple steatosis, caused by the excessive accumulation of fat in hepatocytes, nonalcoholic steatohepatitis with inflammation and fibrosis, and more advanced forms of cirrhosis. The pathogenic mechanisms underlying fatty liver and the progression from simple fatty liver to hepatitis and cirrhosis remain unclear. One potentially unifying mechanism may be a dysregulation of free fatty acid oxidation. The oversupply of fatty acids to the liver can result in mitochondrial dysfunction leading to the accumulation of lipids in the liver. Interestingly, there have been several reports showing that inhibitors of phosphodiesterase 5 (PDE5) can increase mitochondrial biogenesis, preserve mitochondrial function in vitro. And, we have recently demonstrated that the phosphodiesterase type 5 inhibitor udenafil improves insulin sensitivity by increasing mitochondrial function in adipocytes. In this study, we aimed to examine the effects of the PDE5 inhibitor udenafil on NAFLD in the ob/ob mouse model. Treatment of ob/ob mice for 6 weeks with udenafil reduced fat mass and fasting glucose. Importantly, udenafil caused a reduction in lipid accumulation in the liver of these mice, including hepatic triglyceride (TG) and cholesterol levels. Mechanistically, udenafil decreased the proinflammatory cytokines in the liver. Also, udenafil increased the levels in the liver of the important lipolytic enzymes and the levels of several mitochondrial β-oxidation related genes. Similar effects were seen in udenafil treated primary hepatocytes. We believe that our study makes a significant contribution to the literature because the results from our study suggest that udenafil may be an effective treatment for NAFLD by improving mitochondrial function.

Topics: Animals; Cells, Cultured; Cytokines; Disease Models, Animal; Fatty Acids; Hepatocytes; Inflammation Mediators; Insulin Resistance; Lipid Metabolism; Lipolysis; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sulfonamides

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

The aim of this study was to investigate the antioxidant properties of udenafil citrate (1.4 mg kg(-1) -2.8 mg kg(-1) ), dexmedetomidine 25 μg kg(-1) and piracetam 200 mg kg(-1) administered on ipsilateral/contralateral testes after ischaemia in a rat model of testicular torsion/detorsion (T/D) and define its protective effect histologically. Fifty-six Wistar albino rats were included and randomly assigned into 6 groups. No intervention was performed in control group (Group 1, n = 8) and in torsion/detorsion group, (Group 2, n = 8). Udenafil 1.4 mg kg(-1) was given to torsion/detorsion group (Group 3, n = 10), udenafil 2.8 mg kg(-1) was given to torsion/detorsion group (Group 4, n = 10), piracetam 200 mg kg(-1) was given to torsion/detorsion group (Group 5, n = 10) and dexmedetomidine 25 μg kg(-1) was given to torsion/detorsion group (Group 6, n = 10) intraperitoneally after 60 mins of testicular torsion. Biochemical and histopathological testicular injury were evaluated. When the tissue was examined by TOS values, Group 3, Group 4 and Group 5 were significantly lower than Group 2. In contrary Group 6 values were significantly higher than Group 2. The increasing doses of udenafil demonstrated antioxidant properties on the testis tissue and histopathological that protects the testicles.

Topics: Animals; Dexmedetomidine; Disease Models, Animal; Male; Piracetam; Protective Agents; Pyrimidines; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion; Sulfonamides; Treatment Outcome

To investigate the pathogenesis of hyperlipidemia-related erectile dysfunction and the effects of DA-8159, a new phosphodiesterase-5 inhibitor, on protein expression, we performed a proteomic analysis of differentially expressed proteins in the corpus cavernosum of hyperlipidemic rats by two-dimensional electrophoresis-mass spectrometry. Rats were fed high-cholesterol diet and treated with 5 mg·kg(-1)·day(-1) DA-8159 concurrently. After 5 months apparent hyperlipidemia and significantly decreased maximal intra-cavernous pressure were observed in the control group with the alteration of 8 proteins, which were restored by DA-8159 treatment. The proteins whose levels decreased >2-fold and attenuated by DA-8159 were determined alcohol dehydrogenase, aldolase A, annexin 1, and tropomyosin-rat, whereas proteins increased>2-fold and recovered by DA-8159 were found to be aldehyde dehydrogenase complex, guanine deaminase, creatine kinase-B, and phosphoglycerate mutase type B subunit.

Topics: Animals; Biomarkers; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Erectile Dysfunction; Hyperlipidemias; Male; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Proteins; Proteomics; Pyrimidines; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfonamides; Time Factors

Ischemia-reperfusion injury can cause testicular damage and phosphodiesterase inhibitors are reported to regulate antioxidant activity. We investigated the prevention of ipsilateral and contralateral testicular damage using 2 phosphodiesterase inhibitors after testicular detorsion in rats.. A total of 28 adult male rats were randomly divided into 4 groups of 7 each, including group 1-sham operation, group 2-testicular torsion and detorsion, group 3- testicular torsion and detorsion with sildenafil administration before detorsion and group 4- testicular torsion and detorsion with udenafil administration before detorsion. Tissue levels of malondialdehyde, total sulfhydryl and nitrite were evaluated, and histopathological changes in the groups were examined.. Compared to group 1 significantly increased tissue malondialdehyde (p = 0.001), significantly decreased total sulfhydryl (p = 0.038) and insignificantly increased nitrite were found in group 2. Compared to group 2 malondialdehyde decreased significantly and total sulfhydryl increased significantly in groups 3 and 4. The decrease in nitrite was insignificant in the latter 2 groups. Histopathology revealed increased hemorrhage, congestion and edema in group 2 rats. The testicular injury score was lower in groups 3 and 4. In group 2 grades II to IV injury was detected while most specimens in treated groups showed grade II injury.. This study indicates that intraperitoneal administration of sildenafil and udenafil efficiently suppresses radical production while decreasing histological changes after testicular ischemia-reperfusion injury.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Injections, Intraperitoneal; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrimidines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfonamides; Sulfones; Testicular Diseases; Testis

The cyclosporin A (CsA) nephrotoxicity limits its usefulness as an immunosuppression. We studied the administration of both nitroprusside and phosphodiesterase-5 inhibitor (udenafil) in order to determine whether these agents could ameliorate the renal injury in CsA nephrotoxicity.. 30 8-week-old SD rats were divided into 5 groups: the control (1), SQ with 15 mg/kg CsA (Group 2), CsA along with 5 mg/kg IP nitroprusside (Group 3), CsA with 10 mg/kg PO udenafil (Group 4), and CsA with udenafil and nitroprusside (Group 5).. Group showed an increase in creatinine compared o the control group. Group 5 showed a decrease in creatinine compared to Group 2. In TUNEL, Group 2 increased apoptosis in proximal tubules compared to control. Group 5 showed a decrease in apoptosis compared to Groups 2, 3, and 4. In IHC, the eNOS in Group 2 was stronger than in the controls. Groups 3, 4, and 5 showed decreased staining intensity compared to Group 2. In IHC, the VEGF in Groups 2, 3, and 4 increased compared to the controls. The eNOS protein expression was increased in both Groups 3 and 5 compared to the controls. The VEGF protein expression was increased in Groups 3 and 5 compared to Group 2. The eNOS mRNA was decreased in Group 2 compared to the control group and tended to increase in Groups 3, 4, and 5 compared to Group 2. The VEGF mRNA was increased in Group 2 and tended to increase more in Groups 3 and 5.. The udenafil and nitroprusside ameliorated renal injury in rat model of CsA nephrotoxicity. The mechanism appears to be associated with decreasing tubular apoptosis by decreasing eNOS and increasing VEGF.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Apoptosis; Blood Urea Nitrogen; Creatinine; Cyclosporine; Disease Models, Animal; Kidney Tubules, Proximal; Male; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Nitroprusside; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Statistics, Nonparametric; Sulfonamides; Vascular Endothelial Growth Factor A

Preservation of the cavernous nerves (CNs) during radical prostatectomy is crucial for the patient's erectile function. Despite advances in operative technique, the majority of men report compromised erectile function postprostatectomy or complete loss of potency due to CN trauma even with nerve-sparing modifications..   This study was designed to investigate whether repeated dosing of udenafil, a phosphodiesterase type 5 inhibitor, helps to improve erectile function after CN injury.. Using the CN crush injury model, 8-week-old male Sprague Dawley rats were divided into the following groups; sham-operated group, bilateral CN crush injury exposed to either no udenafil (vehicle) or udenafil (5, 20 mg/kg) daily for two different durations (4 and 8 weeks, p.o.).. At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expressions of hypoxia-inducible factor 1-alpha (HIF-1α), transforming growth factor-beta (TGF-β1), nerve growth factor (NGF), endothelin B receptor (ET(B) ), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and sonic hedgehog homolog (SHH) in penile tissue were examined. Immunohistochemical antibody staining was performed for NGF, eNOS, nNOS, CD31, and alpha-smooth muscle actin (α-SMA). Additionally, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay was performed to quantify apoptosis and the tissue slides were stained for Masson's trichrome to assess the smooth muscle/collagen ratio.. Udenafil improved erectile function in a dose- and time-dependent manner with the maximum erectile function recovery achieved by 20 mg/kg udenafil at an 8-week time point. CN injury increased the expression of HIF-1α, TGF-β1, NGF, and ET(B) , however, decreased the expression of eNOS, nNOS, and SHH. Udenafil significantly suppressed these alterations. The results from the histological analyses show that udenafil markedly reduces apoptosis induced by CN injury and augments the smooth muscle/collagen ratio.. CN injury induces significantly impaired erectile function and altered gene/protein expression. Chronic administration of udenafil preserves erectile function and has a beneficial role against the pathophysiological consequences of CN injury.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Erectile Dysfunction; Hedgehog Proteins; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Nerve Growth Factor; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Sulfonamides; Transforming Growth Factor beta1

Erectile dysfunction (ED) is a major complication of diabetes mellitus (DM). This study investigates the relationship between ED and the downregulation of constitutive nitric oxide synthase (cNOS) in the corpus cavernosum (CC) of diabetic rats. It also examines the effects of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on ED and cNOS expression levels. After 16 weeks of daily oral treatment with udenafil in diabetic rats, the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio was recorded to measure erectile function, and cNOS expression was measured using reverse transcriptase (RT)-PCR and immunoblots. Although the ICP/MAP ratio and the expression levels of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the CC were markedly decreased in diabetic rats, long-term udenafil treatment improved the erectile function and increased cNOS expression compared with diabetic controls. These findings suggest that ED in DM is closely related to decreased cNOS expression in the CC and that udenafil has the ability to compensate for this pathological change by modulating cNOS expression. Udenafil also has an inhibitory role in cGMP (cyclic guanosine monophosphate) degradation.

Topics: Animals; Base Sequence; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; DNA Primers; Electric Stimulation; Erectile Dysfunction; Gene Expression Regulation, Enzymologic; Male; Nitric Oxide Synthase Type I; Penis; Phosphodiesterase Inhibitors; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides

This study was performed to investigate the effect of DA-8159, a selective phosphodiesterase 5 (PDE5) inhibitor, on benign prostatic hyperplasia (BPH) both in vitro and in vivo.. We assessed the influence of DA-8159 on the contractility of rat prostate tissues in an organ-bath experiment. In addition, in order to investigate whether chronic administration of DA-8159 prevents the increase of electrostimulation-induced intraurethral pressure (IUP) responses associated with BPH, BPH was induced by steroid hormones (testosterone plus 17beta-estradiol) and DA-8159 (5, 20 mg/kg) was concomitantly administered once a day for 8 weeks. After that the electrostimulation-induced IUP responses were measured. Finally, we investigated the acute treatment effect of DA-8159 on IUP responses in an established BPH model after a single intravenous injection of DA-8159 (0.3, 1 mg/kg).. DA-8159 concentration-dependently reduced the contraction of the isolated prostate strips with an IC50 value of 70 microM. In chronic treatment study, while the BPH control rats showed a significantly increased IUP both at the baseline and by electrostimulation, the chronic DA-8159 treatment significantly attenuated the increase in IUP responses in a dose- and frequency-dependent manner. In the acute treatment study, a single intravenous injection of DA-8159 also prevented the increase in urethral pressure in a dose-dependent manner.. These results suggest that DA-8159 may be beneficial on lowering the urethral pressure associated with BPH via dilatation of the prostate, but a further evaluation of the efficacy on humans needs to be performed.

Topics: Animals; Disease Models, Animal; Male; Muscle Contraction; Muscle, Smooth; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pressure; Prostate; Prostatic Hyperplasia; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sulfonamides; Urethra

DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.

Topics: Administration, Oral; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Erectile Dysfunction; Half-Life; Male; Nitroprusside; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Rabbits; Sulfonamides; Time Factors

DA-8159 is a pyrazolopyrimidinone derivative showing potent and selective phosphodiesterase 5 (PDE5) inhibition. In the previous study, DA-8159 induced a dose-dependent increase in the intracavernous pressure (ICP) in anaesthetized dogs. The aim of this study was to investigate the effects of DA-8159 on penile erection in conscious and acute spinal cord injured (ASCI) rabbits.. DA-8159 was given orally (0.3 to 10mg/kg) to normal rabbits and ASCI rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion. The erection was evaluated in a time-course manner by measuring the length of the uncovered penile mucosa in the absence or presence of intravenous sodium nitroprusside (SNP), a nitric oxide (NO) donor.. DA-8159 induced a dose-dependent penile erection in both the conscious and ASCI rabbits. The efficacy of DA-8159 was potentiated and the effective doses were significantly decreased by an intravenous injection of SNP. Potentiation of the effect by a nitric oxide donor implies that DA-8159 can enhance the erectile activity during sexual arousal.. These results demonstrate that DA-8159 may be a useful treatment option for erectile dysfunction in patients with or without a spinal cord injury, but further evaluation of the effects of DA-8159 on humans must be performed.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Nissl Bodies; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Rabbits; Spinal Cord Injuries; Sulfonamides

DA-8159 is a pyrazolopyrimidinone derivative which exhibits potent and selective phosphodiesterase type 5 (PDE5) inhibition. The aim of this study was to investigate the effects of DA-8159 on inducing a penile erection in rabbits with an acute spinal cord injury (ASCI). DA-8159 was given either orally (1, 3, or 10 mg/kg) or intravenously (0.1 or 0.3 mg/kg) to conscious male albino rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion SCI rabbits. Erection was evaluated in a time-course manner by measuring the length of the uncovered penile mucosa. DA-8159 induced a dose-dependent erection in both transection and ischemic-reperfusion ASCI rabbits. The efficacy of DA-8159 was potentiated by an intravenous injection of sodium nitroprusside, a nitric oxide donor. Potentiation of the effect by nitric oxide donor implies that DA-8159 can enhance the erectile activity during sexual arousal. These results suggest that DA-8159 may be useful for treating erectile dysfunction in patients with an SCI.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Area Under Curve; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Erectile Dysfunction; Male; Penile Erection; Pyrimidines; Rabbits; Reperfusion Injury; Spinal Cord; Spinal Cord Injuries; Sulfonamides