vardenafil-dihydrochloride and Reperfusion-Injury

The aim of this study was to compare the effects of sildenafil, vardenafil and tadalafil in treatment for ischemia/reperfusion injury which is created experimentally in rat ovaries.. For this study, 30 female Wistar albino rats were used, and the rats were separated randomly intofive groups consisting of six rats each: normal, torsion-detorsion, torsion-detorsion + sildenafil 1.4 mg/kg, torsion-detorsion+ vardenafil 1.7 mg/kg and torsion-detorsion + tadalafil 5.0 mg/kg. The agents were given intraperitoneally 30 minutesbefore detorsion. An ovarian torsion procedure was implemented in all other groups for 3 hours with the exception of thenormal group. Then, a detorsion procedure was implemented to the groups for 3 hours.. The sildenafil and vardenafil treatments showed protective effect by preventing significant increase in inflammationparameters. (p = 0.058, 0.138). The tadalafil treatment was only protective for cellular degeneration (p = 0.140). Thevardenafil treatment was protective for edema (p = 0.238), vascular congestion (p = 0.111), inflammation (p = 0.138) andcellular degeneration (p = 0.532). Sildenafil, vardenafil and tadalafil inhibited the increase of atretic follicle. AMH levels werestatistically different between torsion and detorsion and vardenafil group (p = 0.004, 0.004), whereas tadalafil and sildenafilgroups were similar to normal group (p = 0.108, 0.108).. PDE inhibitors were found to be effective in reducing ovarian ischemia/reperfusion injury. Sildenafil andtadalafil seem to be more effective than the vardenafil in protecting the ovarian reserve.

Topics: Animals; Female; Ovarian Diseases; Ovary; Protective Agents; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Tadalafil; Torsion Abnormality; 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

Ischaemia reperfusion (IR) injury occurs during vascular graft harvesting and implantation during vascular/cardiac surgery. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective endothelial protection in different pathophysiological conditions. The hypothesis that the phosphodiesterase-5 inhibitor vardenafil would protect vascular grafts against IR injury by upregulating the nitric oxide-cGMP pathway in the vessel wall of the bypass graft was investigated.. Lewis rats (n = 6-7/group) were divided into Group 1, control; Group 2, donor rats received intravenous saline; Group 3, received intravenous vardenafil (30 μg/kg) 2 h before explantation. Whereas aortic arches of Group 1 were immediately mounted in an organ bath, aortic segments of Groups 2 and 3 were stored for 2 h in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium dependent and independent vasorelaxations were investigated. TUNEL, CD-31, ICAM-1, VCAM-1, α-SMA, nitrotyrosine, dihydroethidium and cGMP immunochemistry were also performed.. The results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction of an arterial graft after bypass surgery, which can effectively be prevented by vardenafil. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery.

Topics: Actins; Animals; Aorta, Thoracic; Cold Ischemia; Cyclic GMP; Cytoprotection; DNA Damage; Intercellular Adhesion Molecule-1; Male; Nitrosative Stress; Phosphodiesterase 5 Inhibitors; Platelet Endothelial Cell Adhesion Molecule-1; Rats, Inbred Lew; Reperfusion Injury; Signal Transduction; Tissue and Organ Harvesting; Tyrosine; Vardenafil Dihydrochloride; Vascular Cell Adhesion Molecule-1; Vascular System Injuries; Vasodilator Agents; Warm Ischemia

The purpose of the study is to evaluate the effect of vardenafil on the histopathology and biochemical parameters in reducing damage in experimental ovarian ischemia and ischemia/reperfusion injury in a rat model and to compare the effect of two different doses of vardenafil.. Forty-two rats with experimental ovarian torsion. Group-I: sham; Group-II: ovarian ischemia; Group-III: 2 hours of ischemia followed by a 2-hour reperfusion. Group-IV: two hours before the sham operation, rats received 1mg/kg vardenafil; Group V and VI: A 2-hour period of ovarian ischemia was applied, in which rats were treated with intraperitoneal vardenafil 1 and 2mg/kg dose, after 1.5 hours of ovarian ischemia. After 2 hours of reperfusion, the ovaries on the right side were removed for examination. The ovarian ischemia/reperfusion injury was evaluated by calculating total antioxidant status, total oxidant status and oxidative stress index; and histopathologic examination of all ovarian rat tissue.. The histologic findings in vardenafil treatment groups were statistically significant decreased edema and follicle degeneration, with vascular congestion, hemorrhage and follicle degeneration being dose-dependent. There were no statistically significant changes in the biochemical parameters.. According to histopathological examination, low and high dose vardenafil is effective in attenuating ischemia-reperfusion induced ovary injury.

Topics: Animals; Antioxidants; Female; Ischemia; Ovarian Diseases; Ovary; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Torsion Abnormality; Vardenafil Dihydrochloride; Vasodilator Agents

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

Based upon the well known protective effect of intracellular cyclic guanosine monophosphate (cGMP) accumulation, we tested the hypothesis that storage solution enriched with optimal concentration of the phosphodiestherase-5 inhibitor vardenafil could provide better protection of vascular grafts against reperfusion injury after long-term cold ischaemic storage.. Isolated thoracic aorta obtained from rats underwent 24-h cold ischaemic preservation in physiological saline or vardenafil (10(-11) M)-supplemented saline solution. Reperfusion injury was simulated by hypochlorite (200 μM) exposure for 30 minutes. Endothelium-dependent vasorelaxation was assessed, and histopathological and molecular-biological examination of the aortic tissue were performed.. Compared with the control group, the saline group showed significantly attenuated endothelium-dependent maximal relaxation (Rmax) to acetylcholine after hypoxia-reoxygenation, which was significantly improved by vardenafil supplementation (Rmax control: 98 ± 1%; saline: 48 ± 6%; vardenafil: 75 ± 4%; p < .05). Vardenafil treatment significantly reduced DNA strand breaks (control: 10.6 ± 6.2%; saline: 72.5 ± 4.0%; vardenafil: 14.2 ± 5.2%; p < .05) and increased cGMP score in the aortic wall (control: 8.2 ± 0.6; saline: 4.5 ± 0.3; vardenafil: 6.7 ± 0.6; p < .05).. Our results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction induced by cold storage warm reperfusion, which can be effectively reversed by pharmacological phosphodiesterase-5 inhibition.

Topics: Animals; Aorta, Thoracic; Apoptosis; Cold Ischemia; Cyclic GMP; Cytoprotection; DNA Damage; Dose-Response Relationship, Drug; Endothelium, Vascular; Gene Expression Regulation; Imidazoles; Male; Organ Preservation; Organ Preservation Solutions; Phosphodiesterase 5 Inhibitors; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfones; Time Factors; Triazines; Vardenafil Dihydrochloride; Vascular Grafting; Vascular System Injuries; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To evaluate the effect of vardenafil on renal function after renal ischemia-reperfusion (IR) injury (IRI) in a rat model.. Seventy-one Wistar rats were divided into 7 groups including (1) a vehicle-treated group, (2) a vehicle pretreated-IR group, (3-6) vardenafil pretreated-IR groups in doses of 0.02, 0.2, 2 and 20 μg/kg, respectively, (7) a group of IR followed by treatment with 2 μg/kg of vardenafil. Vardenafil or vehicle solution was administered one hour before unilateral nephrectomy and the induction of 45 min of ischemia on the contralateral kidney by clamping of renal pedicle. Four hours of reperfusion were allowed after renal ischemia. Studied parameters were serum creatinine, fractional excretion of sodium (FENa), and histological evaluation of renal specimens. In addition, renal tissue cGMP levels, ERK1/2 phosphorylation as well as renal function by renal scintigraphy were also evaluated.. Administration of vardenafil before the induction of ischemia resulted in a significant reduction in creatinine and FENa levels as well as in less histological lesions observed in treated kidneys in comparison with the vehicle-treated group. The underlying mechanism of cytoprotection was cGMP depended and involved the phosphorylation of ERK proteins. Renal scintigraphy confirmed that PDE5 inhibition attenuates renal IRI.. Vardenafil attenuates renal IRI. Based on similar results from relevant studies on other PDE-5 inhibitors in renal and cardiac IRI, it can be assumed that all PDE-5 inhibitors share a common mechanism of cytoprotection.

Topics: Animals; Cyclic GMP; Imidazoles; Ischemic Preconditioning; Kidney; Male; MAP Kinase Signaling System; Models, Animal; Phosphodiesterase 5 Inhibitors; Piperazines; Rats; Rats, Wistar; Reperfusion Injury; Sulfones; Time Factors; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

To investigate the effects of vardenafil HCl on testicular germ cell apoptosis and the expressions of iNOS and eNOS within the bilateral testes after unilateral torsion/detorsion (T/D) in a pig model.. 12 male pigs weighing 50-55 kg were divided randomly into three groups (n = 4). Sham operation and T/D was performed in groups 1 and 2, respectively. Group 3 underwent T/D and received vardenafil (0.4 mg/kg) orally 45 min before detorsion. The testes were left in torsion for 2 h. In all groups, both testes were removed 8 h after the operation for histopathological analysis.. Except for group 1, the histopathologic parameters of the ipsilateral testes were higher than in the contralateral testes, and this difference was statistically significant (p < 0.05). Testicular ischemia/reperfusion (I/R) (group 2) resulted in marked increases in germ cell apoptosis, iNOS and eNOS in the ischemic testes compared to the sham-operated group. The pigs treated with vardenafil (group 3) also showed significantly increased apoptotic cells, iNOS and eNOS levels compared to the sham-operated group.. The results suggest that vardenafil HCl worsened histopathological changes related to oxidative stress in testicular injury and had no protective effect on testicular I/R injury in pigs.

Topics: Animals; Apoptosis; Germ Cells; Imidazoles; Immunohistochemistry; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Random Allocation; Reperfusion Injury; Spermatic Cord Torsion; Sulfones; Swine; Triazines; Vardenafil Dihydrochloride

We investigated the effect of intraperitoneal vardenafil (1 mg/kg) administration during an ischemic period in a rat model of testicular torsion/detorsion (T/D). Twenty-one adult Wistar rats were equally randomized into a control group, a T/D group and a vardenafil group. The control group was designed to collect basal values for biochemical and histopathological parameters. The T/D group underwent testicular torsion for 1 hour. The vardenafil group received vardenafil (1 mg/kg) intraperitoneally at 30 minutes after torsion. All rats were sacrificed 4 hours after reperfusion to evaluate the tissue levels of malondialdehyde and total antioxidant status. Germ cell apoptosis was evaluated using the apoptosis protease activating factor 1 antibody in all groups. The expressions of endothelial nitric oxide synthase (NOS) and inducible NOS were also assessed in both testes of all rats. The malondialdehyde levels in the T/D group were significantly higher than in the control and vardenafil groups. There were also significant decreases in total antioxidant status in the T/D group compared with the control and vardenafil groups. Vardenafil treatment significantly reduced apoptosis protease activating factor 1, endothelial NOS and inducible NOS levels in the vardenafil group compared with the T/D group. Administration of 1 mg/kg vardenafil during testicular torsion decreased ischemia/reperfusion cellular damage. Our results indicate that the reduction in oxidative stress by vardenafil may play a major role in its cytoprotective effects.

Topics: Animals; Antioxidants; Germ Cells; Imidazoles; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion; Sulfones; Testis; Triazines; Vardenafil Dihydrochloride

Recently, the infarct reducing and cardioprotective effects of phosphodiesterase-5-inhibitors were described. In this study, we investigated these effects on ischemia/reperfusion injury in a rat model of heart transplantation. Three groups were assigned for our study: a vardenafil preconditioning group, an ischemic control, and a nonischemic control. Hemodynamic parameters were significantly increased in the vardenafil group (Pmax: 82+/-4 vs. 110+/-12 vs. 127+/-13 mm Hg; dP/dtmax: 1740+/-116 vs. 3197+/-599 vs. 4397+/-602 mm Hg/sec; ischemic control vs. vardenafil vs. nonischemic control; P<0.05 vs. ischemic control). Furthermore, we recorded increased ATP levels and significantly less apoptosis in the treatment group after terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (apoptosis index: 27.23%+/-1.54% vs. 16.77%+/-1.42% vs. 18.86%+/-1.07%; ischemic control vs. vardenafil vs. nonischemic control; P<0.05 vs. ischemic control). Our current results support the concept that the cGMP-PKG-pathway plays an important role in ischemia/reperfusion injury. We could show that up-regulating this pathway has a preconditioning-like effect and can effectively reduce ischemia/reperfusion injury.

Topics: Animals; Aorta, Abdominal; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Transplantation; Hemodynamics; Imidazoles; Male; Myocardial Contraction; Phosphodiesterase Inhibitors; Piperazines; Postoperative Complications; Rats; Rats, Inbred Lew; Reperfusion Injury; Sulfones; Systole; Transplantation, Heterotopic; Transplantation, Isogeneic; Triazines; Vardenafil Dihydrochloride; Vena Cava, Inferior; Ventricular Function, Left

cGMP and opening of mitochondrial K(ATP) channel play an important role in preconditioning of the heart following ischemia/reperfusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra), a highly selective and biochemically potent inhibitor of phosphodiesterase-5 (PDE-5) that enhances erectile function in men through up-regulation of cGMP. Rabbits were treated with VAR (0.014 mg/kg, iv) or volume-matched saline, 30 min prior to 30 min of sustained regional ischemia followed by 3 h of reperfusion. 5-hydroxydecanoate (5-HD, 5 mg/kg, iv) or HMR 1098 (HMR, 3 mg/kg, iv), the respective blockers of mitochondrial or sarcolemmal K(ATP) channels were administered 10 min before I/R. Infarct size was measured by computer morphometry of tetrazolium stained sections. Vardenafil treatment caused decrease in mean arterial blood pressure from 93.5+/-2.6 to 82.2+/-1.5 mmHg and increase in heart rate from baseline value of 151+/-20 to 196+/-4.6 bpm (mean+/-standard error of mean (S.E.M.), P<0.05) within 5 min. The infarct size (% of risk area) was reduced from 33.8+/-1.3 in control rabbits to 14.3+/-2.2 (58% reduction, P<0.05). 5-HD abolished VAR-induced protection as demonstrated by increase in infarct size to 34.5+/-2.3 (P<0.05, N=6 per group). In contrast, HMR failed to block the protective effect of VAR (infarct size, 14.3+/-2.2 versus 16.3+/-1.0 in VAR + HMR, P>0.05). Neither inhibitors of the K(ATP) channel influenced the infarct size in the control rabbits, as shown by infarct size of 34.9+/-1.1 and 33.3+/-1.4 in animals treated with 5-HD and HMR, respectively. For the first time, we demonstrate that VAR induces protective effect against I/R injury via opening of mitochondrial K(ATP) channel. These results further support our hypothesis that the novel class of PDE-5 inhibitors induce protective effect in the ischemic heart, in addition to their well known clinical effects in the treatment of erectile dysfunction in men.

Topics: Adenosine Triphosphate; Animals; Cardiotonic Agents; Hemodynamics; Imidazoles; Male; Mitochondria, Heart; Myocardial Infarction; Piperazines; Potassium Channels; Rabbits; Random Allocation; Reperfusion Injury; Sulfones; Triazines; Vardenafil Dihydrochloride