sildenafil-citrate and Reperfusion-Injury

The phosphodiesterese-5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), tadalafil (Cialis™) and avanafil (Stendra™) have been developed for the treatment of erectile dysfunction. Moreover, sildenafil and tadalafil have been approved for the management of pulmonary arterial hypertension. A number of preclinical studies have shown that PDE5 inhibitors have powerful protective effect against several clinical scenarios including myocardial ischemia/reperfusion injury, doxorubicin and post-MI, heart failure, cardiac hypertrophy, heart transplantation, Duchenne muscular dystrophy and preconditioning of stem cells. Based on these studies, it appears that sildenafil and other PDE5 inhibitors hold promise for further development as novel drug therapies in cardioprotection.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Doxorubicin; Heart; Heart Transplantation; Muscular Dystrophy, Duchenne; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rabbits; Reperfusion Injury; Sildenafil Citrate; Sulfones

To perform a randomized control trial (RCT) assessing the effect of phosphodiesterase 5 inhibitor (PDE5i) used prior to hilar clamping during robot assisted partial nephrectomy (RAPN) for renoprotection.. We performed an institutional review board approved, placebo controlled, double blinded RCT evaluating a single 100 mg oral dose of sildenafil immediately prior to RAPN. Primary end point was accrual, participation and retention of patients with secondary endpoints assessing post-operative renal functional outcomes and safety. Exclusion criteria included history of coronary artery disease, solitary kidney, suspected benign pathology, PDE5i intolerance or pregnant females.. Of 40 eligible consecutive patients undergoing RPN between 9/2013 and 12/2014, 30 (75%) were randomized to treatment and there was 100% participation and retention. The groups were well matched for all measured comorbidities. Intraoperative outcomes including warm ischemia time (median 15 vs. 16.5 min, P = 0.29) were similar. Change in eGFR demonstrated similar decrease between sildenafil versus placebo at 1 day (-8% vs. -10%, P = 0.53), 2 days (-9% vs. -9%, P = 0.77), and 1 month (-4% vs. -6%, P = 0.31) following RAPN. Intermediate follow up (median 183 days) demonstrated similar results (-8% vs. -1%, P = 0.16) between the two cohorts. Safety profiles were similar between the two cohorts without any adverse reactions to the sildenafil.. Successful retention of patients was achieved in this RCT. The secondary outcome of renoprotection was not identified. J. Surg. Oncol. 2016;114:785-788. © 2016 2016 Wiley Periodicals, Inc.

Topics: Acute Kidney Injury; Administration, Oral; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Hemostasis, Surgical; Humans; Laparoscopy; Male; Middle Aged; Nephrectomy; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Preoperative Care; Prospective Studies; Protective Agents; Reperfusion Injury; Robotic Surgical Procedures; Sildenafil Citrate; Treatment Outcome

Sildenafil and nitroglycerin (GTN) are effective pharmacological preconditioning agents, protecting from the adverse effects of ischemia and reperfusion (I/R). The objective of the present study was to determine whether repeated, daily administration of sildenafil or GTN provides sustained preconditioning from I/R in the human forearm vasculature. Thirty-six healthy volunteers participated in this investigator-blind, randomized, placebo-controlled trial. Subjects received transdermal GTN (0.6 mg/h, 2 h/day), sildenafil (50 mg once daily), or placebo. Twenty-four hours after the first dose of medication, subjects underwent an assessment of flow-mediated dilation (FMD) before and after I/R (15 min of upper arm ischemia followed by 15 min of reperfusion). Subjects continued their study medication for 7 days, at which point FMD measurements were repeated before and after I/R. Venous blood samples were obtained for the determination of myeloperoxidase, P-selectin, and myoglobin before and after each I/R episode. Twenty-four hours after the first dose, both sildenafil and GTN (but not placebo) provided protection from the adverse effects of I/R. After 7 days of repeated daily doses and 24 h after the last dose, FMD was significantly blunted after I/R in placebo- and GTN-treated groups. In contrast, repeated daily administration of sildenafil provided continued protection from the adverse effects of I/R on endothelial function. There was no significant change in plasma levels of myeloperoxidase, P-selectin, or myoglobin at any time point. In conclusion, the present study establishes, for the first time in humans, that sildenafil, but not GTN, provides sustained pharmacological preconditioning of the endothelium and protection from adverse I/R effects on vascular function.

Topics: Administration, Cutaneous; Adolescent; Adult; Biomarkers; Drug Administration Schedule; Endothelium, Vascular; Forearm; Healthy Volunteers; Hemodynamics; Humans; Male; Myoglobin; Nitroglycerin; P-Selectin; Peroxidase; Piperazines; Purines; Radial Artery; Reperfusion Injury; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

Acute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants.. Eight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants.. Postischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor.. Administration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. TYPE: Basic science.. N/A.

Topics: Animals; Disease Models, Animal; Humans; Injections, Intraperitoneal; Intestinal Mucosa; Male; Mesenteric Artery, Superior; Mesenteric Ischemia; Mesentery; Mice; Phosphodiesterase 5 Inhibitors; Reperfusion Injury; Sildenafil Citrate; Treatment Outcome

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Synergism; Humans; Male; Malondialdehyde; Oxidative Stress; Pregnatrienes; Reperfusion Injury; Sildenafil Citrate; Superficial Back Muscles; Surgical Flaps; Swine; Tumor Necrosis Factor-alpha

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

Investigate the short-term effect of sildenafil on microcirculation, especially the velocity, the pattern of the flow and the recruitment of the leukocyte in postcapillaries.. In male Sprague-Dawley rats, the microcirculatory consequences of 60 min experimental testicular torsion, followed by 240 min of reperfusion, were examined. Using fluorescence intravital microscopy, changes in red blood cell velocity in post-capillary venules and rolling as well as adhesion of leukocytes in the postcapillary venules were examined before the torsion and every hour during the reperfusion period. Sildenafil was given 10 min prior to reperfusion (iv 0.7 mg/kg, n = 6), while control animals received saline vehicle (n = 5).. The characteristic flow motion disappeared in the affected testicular during the torsion. Red blood cell velocity values were dramatically decreased (by > 50%) and both rolling and adhesion of leukocytes increased during the reperfusion phase. Sildenafil treatment resulted in significantly higher red blood cell velocity values during the entire reperfusion period, but exerted only a temporary positive effect on the plost-ischaemic leukocyte-endothelial interactions.. Intraoperative administration of sildenafil during surgical detorsion may provide marked testicular microperfusion benefits, but failed to influence the overall leukocyte-driven microcirculatory inflammatory reactions.

Topics: Animals; Blood Flow Velocity; Cell Adhesion; Disease Models, Animal; Intravital Microscopy; Leukocyte Rolling; Leukocytes; Male; Microcirculation; Microscopy, Fluorescence; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Sildenafil Citrate; Spermatic Cord Torsion; Testis; Vasodilator Agents

The aim of this study was to better understand the role of apoptosis in a retinal ischaemia-reperfusion injury model and to determine whether sildenafil citrate treatment can prevent retinal cell apoptosis. Thirty-six rats were divided into a control group (n = 6) and two experimentally induced ischaemia-reperfusion groups (7 and 21 days; n = 15 per group). The induced ischaemia-reperfusion groups were treated with sildenafil for 7 and 21 days (n = 10 per group), and 10 animals were treated with a placebo for the same period (n = 5 per group). Paracentesis of the anterior chamber was performed with a 30-G needle attached to a saline solution (0.9%) bag positioned at a height of 150 cm above the eye for 60 min. Intraocular pressure was measured by rebound tonometer (TonoVet

Topics: Animals; Apoptosis; Drug Evaluation, Preclinical; Eye Proteins; Gene Expression Regulation; Intraocular Pressure; Male; Optic Nerve; Rats, Inbred Lew; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells; Retinal Vessels; Sildenafil Citrate; Vasodilator Agents

Retinal ischemia is a common cause of visual impairment and blindness. Sildenafil, a PDE5 inhibitor which inhibits cGMP degradation and in turn prolongs the effect of nitric oxide, has been shown to be protective in a number of ischemia/reperfusion (I/R) injuries, as well as in neuronal damage. We hypothesized that treatment with sildenafil might be neuroprotective in a model of acute retinal I/R injury.. Anterior chamber cannulation was performed to induce unilateral I/R injury in 38 Lewis rats. Animals received intraperitoneal injections of sildenafil (0.5 and 1 mg/kg once a day, for a period of 7 and 18 days, respectively), or saline. Electroretinography recordings, retinal ganglion cell (RGC) counts following retrograde labeling with fluorogold, histopathology, and immunohistochemistry (IHC) using antibodies against PDE5, NOS2, caspase-3, caspase-9, and Bcl-2 were conducted.. No significant differences in electroretinography, RGC counts, or retinal morphometry were observed between experimental eyes of sildenafil- and saline-treated animals. A tendency toward less necrosis in histopathology, and a slight trend toward lower PDE5, NOS2, and caspase-9 and higher Bcl-2 IHC scores were evident in experimental retinas of sildenafil-treated animals.. Electroretinography, RGC counts, and retinal morphometry failed to show any neuroprotective effect of sildenafil in acute retinal I/R injury in rats. A slight positive effect of sildenafil was qualitatively indicated by histopathology and IHC.

Topics: Animals; Caspase 3; Caspase 9; Cell Count; Disease Models, Animal; Electroretinography; Immunohistochemistry; In Situ Nick-End Labeling; Male; Phosphodiesterase 5 Inhibitors; Rats; Rats, Inbred Lew; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells; Sildenafil Citrate; Treatment Outcome

Sildenafil is a phosphodiesterase inhibitor used clinically for treating erectile dysfunction. Few studies suggest sildenafil to be a renoprotective agent. The present study investigated the involvement of peroxisome proliferator-activated receptor γ (PPAR-γ) in sildenafil-mediated protection against ischemia-reperfusion-induced acute kidney injury (AKI) in rats.. The rats were subjected to ischemia-reperfusion injury (IRI) with 40 min of bilateral renal ischemia followed by reperfusion for 24 h. The renal damage was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, electrolytes, and microproteinuria in rats. The thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels were measured to assess oxidative stress in renal tissues. The hematoxylin-eosin staining was carried out to demonstrate histopathologic changes in renal tissues. Sildenafil (0.5 and 1.0 mg/kg, intraperitoneal) was administered 1 h before subjecting the rats to renal IRI. In a separate group, bisphenol A diglycidyl ether (30 mg/kg, intraperitoneal), a PPAR-γ receptor antagonist, was given before sildenafil administration followed by IRI.. The ischemia-reperfusion demonstrated marked AKI with significant changes in serum and urinary parameters, enhanced oxidative stress, and histopathologic changes in renal tissues. The administration of sildenafil demonstrated significant protection against ischemia-reperfusion-induced AKI. The prior treatment with bisphenol A diglycidyl ether abolished sildenafil-mediated renal protection, thereby confirming involvement of PPAR-γ agonism in the sildenafil-mediated renoprotective effect.. It is concluded that sildenafil protects against ischemia-reperfusion-induced AKI through PPAR-γ agonism in rats.

Topics: Acute Kidney Injury; Animals; Benzhydryl Compounds; Drug Evaluation, Preclinical; Epoxy Compounds; Kidney; Kidney Function Tests; Male; Oxidative Stress; Phosphodiesterase 5 Inhibitors; PPAR gamma; Proteinuria; Random Allocation; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate

The purpose of this study was to investigate the effects of sildenafil on retinal injury following neonatal hypoxia-ischemia (HI) at term-equivalent age in rat pups.. Hypoxia-ischemia was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-hour exposure to 8% oxygen. Sham-operated rats served as the control group. Both groups were administered vehicle or 2, 10, or 50 mg/kg sildenafil, twice daily for 7 consecutive days. Retinal function was assessed by flash electroretinograms (ERGs) at P29, and retinal structure was assessed by retinal histology at P30.. Hypoxia-ischemia caused significant functional (i.e., attenuation of the ERG a-wave and b-wave amplitudes and photopic negative response) and structural (i.e., thinning of the total retina, especially the inner retinal layers) retinal damage in the left eyes (i.e., ipsilateral to the carotid ligation). Treatment with the different doses of sildenafil led to a dose-dependent increase in the amplitudes of the ERG a- and b-waves and of the photopic negative response in HI animals, with higher doses associated with greater effect sizes. Similarly, a dose response was observed in terms of improvements in the retinal layer thicknesses.. Hypoxia-ischemia at term-equivalent age induced functional and structural damage mainly to the inner retina. Treatment with sildenafil provided a dose-dependent recovery of retinal function and structure.

Topics: Administration, Oral; Animals; Animals, Newborn; Disease Models, Animal; Electroretinography; Female; Follow-Up Studies; Hypoxia; Male; Phosphodiesterase 5 Inhibitors; Rats; Rats, Long-Evans; Reperfusion Injury; Retina; Retinal Diseases; Sildenafil Citrate

We aimed to examine the effects of sildenafil and n-acetylcystein on ischemia/reperfusion injury in femoral artery endothelium and gastrocnemius muscle.. 32 rats of Sprague-Dawley breed were randomly divided into four groups (n=8). Median laparotomy was performed, then a 120-minute ischemia was created by microvascular clamping of infrarenal aorta, followed by the release of clamping. In sildenafil group, 1 mg/kg of sildenafil infusion and in the n-acetylcystein group, 100 mg/kg of n-acetylcystein infusion was administered after release of clamps. Blood samples and tissue samples of femoral artery and gastrocnemius muscle were extracted for a histopathological evaluation.. Serum levels of malondialdehyde in ischemia/reperfusion group (6.16±0.79) were higher compared to the control group (4.69±0.33), whereas a significant decrease was detected in sildenafil (5.17±0.50) and n-acetylcystein (4.96±0.49) groups. Femoral artery tissue sections of the control group, mean tumor necrosis factor alpha and hypoxy-induced factor-1 alpha immunoreactivity were found to be negative. In the ischemia/reperfusion group, mean tumor necrosis factor α immunoreactivity was intense and mean hypoxy-induced factor-1 alpha immunoreactivity was 51-75%. In the ischemia/reperfusion+Sildenafil and ischemia/reperfusion+NAS groups, mean tumor necrosis factor α immunoreactivity was slight and mean hypoxy-induced factor-1 alpha immunoreactivity was 26-50%.. In conclusion, sildenafil and n-acetylcystein may reduce femoral artery endothelium and gastrocnemius muscle injury following lower extremity ischemia/reperfusion.

Topics: Acetylcysteine; Animals; Antioxidants; Biomarkers; Cytoprotection; Disease Models, Animal; Endothelium, Vascular; Femoral Artery; Hypoxia-Inducible Factor 1, alpha Subunit; Lipid Peroxidation; Malondialdehyde; Muscle, Skeletal; Oxidative Stress; Piperazines; Purines; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfonamides; Time Factors; Tumor Necrosis Factor-alpha; Vasodilator Agents

The aim of this study was to evaluate the protective activity of sildenafil treatment against ischemia-reperfusion damage created experimentally in rat ovaries.. For this study, 42 female Wistar rats were used, and the rats were separated randomly into six groups consisting of seven rats each: sham, torsion, torsion-detorsion, torsion-detorsion + saline, torsion-detorsion + sildenafil 0.7 mg/kg and torsion-detorsion + sildenafil 1.4 mg/kg. With the exception of the sham group, an ovarian torsion procedure was implemented in all other groups for 2 h. Then, a detorsion procedure was implemented to the groups for 2 h, with the exception of the torsion group. Medications were given intraperitoneally, one-half hour before the detorsion procedure in the saline, 0.7 and 1.4 mg/kg sildenafil groups. Finally, 2 ml of blood samples was drawn for markers of oxidative stress, while the ovaries which were torsioned for the histological examination were extracted from all rats.. According to the histopathological damage scores, the least damage was seen in the sham group and the most damage was seen in the torsion-detorsion group. The sildenafil treatment appeared to be effective in decreasing tissue damage; however, there were no differences between the dosages. Additionally, it was determined that the oxidative stress levels were higher in the torsion-detorsion group, while the sildenafil treatment caused a significant decrease in the oxidative stress levels.. The results of the current study showed that the sildenafil treatment can be effective in preventing tissue damage and oxidative stress induced by the ischemia-reperfusion created in rat ovaries.

Topics: Animals; Female; Humans; Ischemia; Models, Animal; Ovarian Diseases; Ovary; Oxidative Stress; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

To study the possible renoprotective effect of sildenafil against renal ischemia/reperfusion (I/R) injury and its effect on the expression of some antioxidant, antiapoptotic gene and proinflammatory cytokine genes in rat model of renal I/R injury.. One hundred and twenty male Sprague Dawley rats were subdivided into three equal groups: sham (underwent right nephrectomy without ischemia), control (underwent right nephrectomy and left ischemia for 45 min) and study [as control with 1 mg/kg sildenafil (per oral) 60 min before anesthesia]. Serum creatinine and BUN were measured at the baseline and the study endpoints (2, 24, 48 h and 7 days), and the left kidney was harvested at study endpoints for histopathological examination as well as for assessment of the expression of antioxidant genes (Nrf-2, HO-1 and NQO-1), antiapoptotic gene (Bcl-2) and inflammatory cytokines, e.g., TNF-a, IL-1β and ICAM-1.. I/R caused significant increase in serum creatinine, BUN, histopathological damage score (p < 0.001) and significant reduction in antioxidant genes (nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) with significant increase in TNF-a, IL-1β and ICAM-1 genes in kidney tissues. Pretreatment with sildenafil caused significant attenuation of serum creatinine and BUN as well as significant increase in the expression of antioxidant genes and Bcl-2 genes with significant reduction in the expression of proinflammatory cytokine genes (p value < 0.001).. The renoprotective effect of sildenafil against renal I/R might be due to the activation of antioxidant genes (Nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) and attenuation of proinflammatory cytokines (TNF-a, IL-1β and ICAM-1).

Topics: Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Gene Expression; Heme Oxygenase-1; Intercellular Adhesion Molecule-1; Interleukin-1beta; Male; NAD(P)H Dehydrogenase (Quinone); Nephrectomy; NF-E2-Related Factor 2; Phosphodiesterase 5 Inhibitors; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Tumor Necrosis Factor-alpha; Warm Ischemia

Sildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the cGMP level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.. Male Sprague-Dawley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after reperfusion, while cerebral infarction, edema, Nissl staining, Fluoro-Jade B staining, and electron microscopy studies were carried out 24 h poststroke. The cGMP-dependent Nogo-66 receptor (Nogo-R) pathway, synaptophysin, PSD-95/neuronal nitric oxide synthases (nNOS), brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB), and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were measured.. Sildenafil enhanced neurological recovery and inhibited infarction, even following delayed administration 4 h after stroke onset. Furthermore, sildenafil reduced the loss of neurons and modulated the expressions of the cGMP-dependent Nogo-R pathway. Moreover, sildenafil protected the structure of synapses and mediated the expressions of synaptophysin, PSD-95/nNOS, BDNF/TrkB, and NGF/TrkA.. Sildenafil produces significant neuroprotective effects on injured neurons in acute stroke, and these are mediated by the cGMP-dependent Nogo-R pathway, NGF/TrkA, and BDNF/TrkB.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Survival; Disks Large Homolog 4 Protein; GPI-Linked Proteins; Infarction, Middle Cerebral Artery; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myelin Proteins; Nerve Growth Factor; Nerve Net; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type I; Nogo Receptor 1; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Receptor, trkA; Receptor, trkB; Receptors, Cell Surface; Recovery of Function; Reperfusion Injury; Sildenafil Citrate; Stroke; Sulfones; Synapses; Synaptophysin

Tissue damage in testicular torsion/detorsion is caused not only by the ischemia, but also by the ischemia/reperfusion injury after detorsion. Erythropoietin and sildenafil are considered to protect against ischemia/reperfusion injury. Here, we studied and compared their actions in testicular torsion/detorsion in adult rats.. Twenty-two adult male Wistar Albino rats were divided into four groups. Rats in group A (n = 5) were sham operated. Rats in group B (n = 5), group C (n = 6) and group D (n = 6) underwent torsion of the right testis and detorsion after 90 min. No pharmaceutical intervention was performed in group B. Erythropoietin (1,000 IU/kg) and sildenafil (0.7 mg/kg) were injected intraperitoneally in groups C and D, respectively, after 60 min of torsion. All animals were killed 24 h after detorsion, and their right testis was extracted, placed into 10 % formalin solution and sent for histopathological examination. The histological changes in the testes were scored according to the four-point grading system proposed by Cosentino et al.. All rats in group A had normal testicular architecture (grade 1). The untreated group B had a mean grade of 3.81 (range 3.65-4). The treated groups C (mean grade 3.24; range 3.05-3.45) and D (2.69, range 2.4-2.9) presented statistically significant better results (lower grades) compared with the untreated group B. Group D had significantly better results (lower grades) than group C.. The intraperitoneal injection of erythropoietin and sildenafil protects against ischemia/reperfusion injury after testicular torsion and detorsion. Sildenafil may have a stronger action than erythropoietin at the doses used in this study.

Topics: Animals; Erythropoietin; Injections, Intraperitoneal; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Spermatic Cord Torsion; Sulfones; Testis

It has been well documented that phosphodiesterase-5 inhibitor, sildenafil (SIL) protects against myocardial ischemia/reperfusion (I-R) injury. SIRT1 is part of the class III Sirtuin family of histone deacetylases that deacetylates proteins involved in cellular stress response including those related to I-R injury.. We tested the hypothesis that SIL-induced cardioprotection may be mediated through activation of SIRT1.. Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p.), Resveratrol (RSV, 5 mg/kg, a putative activator of SIRT1 used as the positive control), or saline (0.2 mL). The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis.. Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001) as compared to the saline-treated controls 24 hours after drug treatment. In isolated ventricular cardiomyocytes, pretreatment with SIL (1 µM) or RSV (1 µM) for one hour in vitro also upregulated SIRT1 activity (P<0.05). We further examined the causative relationship between SIRT1 activation and SIL-induced late cardioprotection. Pretreatment with SIL (or RSV) 24 hours prior to 30 min ischemia and 24 hours of reperfusion significantly reduced infarct size, which was associated with a significant increase in SIRT1 activity (P<0.05). Moreover, sirtinol (a SIRT1 inhibitor, 5 mg/kg, i.p.) given 30 min before I-R blunted the infarct-limiting effect of SIL and RSV (P<0.001).. Our study shows that activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury. This newly identified SIRT1-activating property of SIL may have enormous therapeutic implications.

Topics: Analysis of Variance; Animals; Benzamides; Blotting, Western; Cardiotonic Agents; Enzyme Activation; Male; Mice; Mice, Inbred ICR; Naphthols; Piperazines; Purines; Reperfusion Injury; Sildenafil Citrate; Sirtuin 1; Sulfones

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

To evaluate the effects of sildenafil on antioxidant enzyme activities, lipid peroxidation and histopathological changes in ovarian tissue after ischemia-reperfusion (I/R) injury in a rat model.. A total of 18 adult female Wistar albino rats weighing 200-250 g were studied as follows: (1) control group: sham operation, (2) I/R group: 3 h of reperfusion after 3 h of ischemia and (3) I/R + sildenafil group: 3 h of reperfusion after 3 h of ischemia; half an hour before reperfusion, sildenafil (1.4 mg·kg(-1)) was given by oral gavage. At the end of the reperfusion periods, the ovarian tissues were removed for histopathological examination and to determine malondialdehyde (MDA) levels and glutathione peroxidase, myeloperoxidase (MPO) and superoxide dismutase (SOD) activities.. The I/R group had higher ovarian tissue MDA levels than the control group and the IR + sildenafil group (p = 0.016 and p = 0.044, respectively). MPO activity was lower in the IR + sildenafil group compared with the I/R group (p = 0.022). SOD activity was lower in the I/R group compared with the control group and the I/R + sildenafil group (p = 0.030 and p = 0.015, respectively). The I/R + sildenafil group had improved histological appearance which was not different to the control group (p > 0.05).. The biochemical and histopathological results of this experimental study demonstrated that I/R injury in the ovary is ameliorated by sildenafil treatment.

Topics: Animals; Disease Models, Animal; Female; Ovarian Diseases; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfonamides

We evaluated the role of sildenafil in a rat liver ischemia-reperfusion model. Forty male rats were randomly allocated in four groups. The sham group underwent midline laparotomy only. In the sildenafil group, sildenafil was administered intraperitoneally 60 minutes before sham laparotomy. In the ischemia-reperfusion (I/R) group, rats were subjected to 45 minutes of hepatic ischemia followed by 120 minutes of reperfusion, while in the sild+I/R group rats were subjected to a similar pattern of I/R after the administration of sildenafil, 60 minutes before ischemia. Two hours after reperfusion, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured and histopathological examination of the lobes subjected to ischemia as well as TUNEL staining for apoptotic bodies was performed. Additionally, myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) were analyzed. Serum markers of hepatocellular injury were significantly lower in the sild+I/R group, which also exhibited lower severity of histopathological lesions and fewer apoptotic bodies, as compared to the I/R group. The I/R group showed significantly higher MPO activity and higher expression of ICAM-1, as compared to the sild+I/R group. Use of sildenafil as a preconditioning agent in a rat model of liver I/R exerted a protective effect.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Gene Expression Regulation; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Liver; Liver Diseases; Male; Peroxidase; Piperazines; Purines; Rats, Wistar; Reperfusion Injury; RNA, Messenger; Sildenafil Citrate; Staining and Labeling; Sulfones

Phosphodiesterase-5 inhibitors prevent the breakdown of cyclic guanosine 3',5'-monophosphate (cGMP) and therefore may be useful in reducing the detrimental effects of ischemia-reperfusion (I/R) injury. The aim of this study was to assess the effects of the phosphodiesterase-5 inhibitor sildenafil, on I/R injury in a porcine model of donation after circulatory death kidney transplantation.. Kidneys were subjected to 20 min warm ischemia followed by 2 or 18 hr of cold storage (n=6 kidneys per group). After preservation kidneys were reperfused on an ex vivo perfusion system for 3 hr with an oxygenated blood based solution. Kidneys were treated with 1.4 mg/kg sildenafil infused 10 min before and for 20 min after reperfusion (n=6 kidneys per group). Renal function and injury markers were measured throughout reperfusion.. Prolonged cold ischemia (CI) significantly reduced levels of cGMP (2 hr 3.5 [1.5-5.7] vs. 18 hr 1.2 [0.3-2.8] pmol/mL; P=0.010). The administration of sildenafil significantly increased the levels (P=0.047, 0.064). Sildenafil improved the renal blood flow for the first 30 min in the 2-hr group (sildenafil, 81.8 [43.8-101.9] vs. control 40.2 [6.4-76.9] mL/min/100 g; P=0.026) and up to 60 min in the 18-hr group (sildenafil, 67.4 [38.0-87.0] vs. control 36.2 [30.5-50.0] mL/min/100 g; P=0.009) during reperfusion. Renal function was significantly impaired after 18-hr CI (P=0.0.26), and treatment with sildenafil did not improve renal function in the 2-hr (P=0.384) or 18-hr CI (P=0.099) groups.. Sildenafil had a vasodilatory action and increased levels of cGMP but did not affect recovery of renal function or protect against I/R injury.

Topics: Animals; Area Under Curve; Cold Ischemia; Creatine; Cyclic GMP; Endothelin-1; Kidney; Kidney Transplantation; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Renal Circulation; Reperfusion Injury; Sildenafil Citrate; Sulfones; Swine; Time Factors; Warm Ischemia

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP-sensitive potassium channels to attenuate ischaemia-reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil-mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague-Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham-operated rats (control; n = 5); (ii) IR-injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR-injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil-treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil-treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm(2) , respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm(2) ; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.

Topics: Animals; Mitochondria, Heart; Mitochondrial Swelling; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Piperazines; Potassium Channels; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfonamides

To investigate the effect of sildenafil citrate (SC) on skeletal muscle ischemia-reperfusion (IR) injury in rats.. Adult male Wistar rats were randomized into three groups: vehicle-treated control (CTG), sildenafil citrate-treated (SCG), and sham group (SG). CTG and SCG had femoral artery occluded for 6 hours. Saline or 1 mg/kg of SC was given 5.5 hours after occlusion. SG had a similar procedure without artery occlusion. Soleus muscle samples were acquired 4 or 24h after the reperfusion. Immunohistochemistry caspase-3 analysis was used to estimate apoptosis using the apoptotic ratio (computed as positive/negative cells). Wilcoxon rank-sum or Kruskal-Wallis tests were used to assess differences among groups.. Eighteen animals were included in the 4h reperfusion groups and 21 animals in the 24h reperfusion groups. The mean apoptotic ratio was 0.18 ± 0.1 for the total cohort; 0.14 ± 0.06 for the 4h reperfusion groups and 0.19 ± 0.08 for the 24h groups (p<0.05). The SCG had lower caspase-3 ratio compared to the control groups at the 24h reperfusion time point (p<0.05).. Sildenafil citrate administration after the onset of the ischemic injury reduces IR-induced cellular damage in skeletal muscle in this rat hindlimb ischemia model.

Topics: Animals; Caspase 3; Disease Models, Animal; Extremities; Male; Muscle, Skeletal; Phosphodiesterase 5 Inhibitors; Piperazines; Protective Agents; Purines; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfones; Time Factors

This study evaluated the protective effect of sildenafil on liver injury induced by intestinal ischemia-reperfusion.. Forty female Sprague Dawley rats were divided into 4 groups: sham-control (SC), ischemia (I), ischemia-reperfusion (IR), and ischemia-reperfusion+sildenafil (SIL; sildenafil gavaged at 50mg/kg before operating). A 2-h ischemia-reperfusion was performed by clamping the superior mesenteric artery. Liver function, plasma alanine (ALT) and aspartate (AST) aminotransferase, and intestinal and liver malondialdehyde (MDA) were measured at the end of the experiment. Intestinal and liver tissue damage was examined by histology. Liver samples were immunologically stained for endothelial nitric oxide synthase (eNOS) and proliferating cell nuclear antigen (PCNA).. The ALT and AST levels were highest in the IR group and were lower in the SIL group (p<0.05). Intestinal MDA levels were statistically higher in the IR group than in the SC, I and SIL groups. Liver MDA levels were significantly higher in the IR group than in the I and SC groups (p<0.05) and higher than in the SIL group (p>0.05). Intestinal damage based on Chiu scoring was more severe in the IR than in the SIL group (p<0.05). Sildenafil reduced damage and also increased eNOS and PCNA immunoreactivity in liver tissue.. Sildenafil shows a protective effect on intestinal ischemia-reperfusion-induced liver injury, possibly by decreasing vascular resistance through increased nitric oxide levels.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Constriction; Drug Evaluation, Preclinical; Female; Intestines; Ischemia; Liver; Liver Glycogen; Malondialdehyde; Mesenteric Artery, Superior; Mesenteric Ischemia; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Piperazines; Proliferating Cell Nuclear Antigen; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Vascular Diseases; Vascular Resistance; Vasodilator Agents

Lung ischemia-reperfusion (I/R) injury plays an important role in lung transplantation. Less well known is the role of sildenafil in lung I/R injury; therefore, we attempted to determine whether sildenafil could alleviate lung apoptosis and tissue injury in a rat model.. Forty male Sprague-Dawley rats were randomized into four groups: saline + sham, saline + I/R, sildenafil + sham, and sildenafil + I/R groups. Three hours before the operation, each rat received normal saline or sildenafil (10 mg/kg) by lavage. The animals designed to I/R injury were subjected to 2 h of ischemia induced by occlusion of left pulmonary artery, veins, and bronchus, followed by reperfusion for 2 h. The lung tissue was harvested for the analysis of the expression of Bax, Bcl-2, p53, caspase 3, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and wet/dry (W/D) weight ratio.. Compared with the saline + sham group, the saline + I/R group had significant increases in Bax, p53, Bax/Bcl-2 ratio, caspase 3, IL-6, TNF-α, and W/D weight ratio but a decrease in Bcl-2 (P < 0.05). Compared with the saline + I/R group, sildenafil + I/R group had significant decreases in Bax, p53, Bax/Bcl-2 ratio, caspase 3, IL-6, TNF-α level, and W/D weight ratio but an increase in Bcl-2 expression (P < 0.05). Compared with the sildenafil + sham group, there were significant increases in p53 and TNF-α expression in the sildenafil + I/R group (P < 0.05).. Pretreatment with sildenafil alleviates lung apoptosis and tissue injury in a rat model.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Disease Models, Animal; Interleukin-6; Lung; Lung Transplantation; Male; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pulmonary Circulation; Purines; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Vasodilator Agents

To explore the protective effect of the phosphodiesterase-5 inhibitor, sildenafil, on lung ischemia-reperfusion injury, 30 rats were randomly divided into 3 groups of 10: a sham-operated group A, a lung ischemia-reperfusion injury group B, and a sildenafil preconditioned group C. A 0.1% sildenafil solution was administrated orally 2 h before establishing an in-vivo lung ischemia-reperfusion model in group C; 0.9% normal saline solution was used in the controls. The lung wet-to-dry ratio, malondialdehyde content, myeloperoxidase and nitric oxide synthase activity in groups B and C were significant higher than those in group A, while the partial pressure of oxygen in arterial blood and cyclic guanosine-3',5'-monophosphate content in groups B and C were significant lower than those in group A. Compared to group B, lung wet/dry ratio, malondialdehyde content, myeloperoxidase and nitric oxide synthase activity in group C were significantly lower, while arterial O(2) and cyclic guanosine-3',5'-monophosphate content in group C were significantly higher. The expected histological and cytological changes were significantly alleviated in group C. Oral preconditioning with sildenafil prevented rat lung ischemia-reperfusion injury and improved pulmonary function. The mechanisms of this effect might be prevention of cyclic guanosine monophosphate degradation and inhibition of nitric oxide synthase activity.

Topics: Alveolar Epithelial Cells; Animals; Cyclic GMP; Endothelium, Vascular; Lung Diseases; Male; Malondialdehyde; Nitric Oxide Synthase; Peroxidase; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones

The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, Tadalafil and Sildenafil, on inducible NOS (iNOS), endothelial NOS (eNOS) and p53 genes expressions and apoptosis in ischemia/reperfusion (I/R) induced oxidative injury in rat renal tissue. Eighty Sprague-Dawley rats (300-350 g) were divided into four groups. In ischemia/reperfusion group, rats were subjected to renal ischemia by clamping the left pedicle for 60 min, and then reperfused for 90 min. On the other hand, in other two groups the rats were individually pretreated with Tadalafil and Sildenafil 1 h before the induction of ischemia. Malondialdehyde (MDA) is determined in renal tissue homogenates by high-performance liquid chromatography, the number of apoptotic cell were calculated by TUNEL method and p53 and eNOS expression were detected with immunohistochemistry. On the other hand, myeloperoxidase (MPO) levels were measured by spectrophotometric method and the mRNA level of iNOS in renal tissue was determined by Real-time PCR (RT-PCR). Our results indicate that MDA and MPO levels were increased in the I/R group than those in the control group. Both Tadalafil and Sildenafil treatment decreased the MDA levels in ischemia/reperfusion group, whereas this effect was more potent with Sildenafil. RT-PCR results showed that, iNOS gen expression increased in the I/R group, but decreased in the PDE5 inhibitory drugs treated group. Apoptotic cells, eNOS levels and p53 positive cells were also decreased in PDE5 inhibitory drugs treated group. We suggest that Tadalafil and Sildenafil have beneficial effects against I/R related renal tissue injury and this protective effect is clearer for Sildenafil than Tadalafil.

Topics: Animals; Apoptosis; Carbolines; Gene Expression; Ischemia; Kidney; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Tadalafil; Tumor Suppressor Protein p53

The aim of the present study was to evaluate the effects of phosphodiesterase type 5 (PDE5) inhibitory drugs, sildenafil and tadalafil, in ischemia/reperfusion (I/R)-induced oxidative injury in fetal rat brain.. Timed pregnant adult Wistar rats were randomly assigned to the following groups (n = 6 for each group): saline + none I/R (1), saline + I/R (2), sildenafil + none I/R (3); sildenafil + I/R (4), tadalafil + none I/R (5) and tadalafil + I/R (6). Fetal ischemia was induced by clamping the utero-ovarian artery bilaterally. Fetuses were delivered and 268 fetal rats were decapitated. Malondialdehyde (MDA) levels and, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were assessed in fetal brain tissue homogenates by spectrophotometric methods.. In saline + I/R group, MDA levels were increased and, SOD and GSH-Px activities were decreased significantly comparing with saline + none I/R group. Both tadalafil and sildenafil treatment decreased the MDA levels significantly in ischemia/reperfusion groups, whereas this effect was significantly more potent with tadalafil. SOD levels were significantly decreased in all groups after I/R. Tadalafil seems to be more effective than sildenafil by means of increasing GSH-Px activity significantly after I/R.. Our results indicate some beneficial effects of PDE5 inhibitory drugs, especially tadalafil, on oxidative I/R injury in fetal rat brains.

Topics: Animals; Brain; Carbolines; Female; Fetus; Glutathione Peroxidase; Malondialdehyde; Piperazines; Pregnancy; Purines; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfones; Superoxide Dismutase; Tadalafil; Vasodilator Agents

This study was designed to investigate prevention of contralateral testicular injury with sildenafil citrate after unilateral testicular torsion/detorsion.. Thirty-seven adult male rats were divided into four groups: sham operated (group 1, n = 7), torsion/detorsion + saline (group 2, n = 10), torsion/detorsion + 0.7 mg of sildenafil citrate (group 3, n = 10) and torsion/detorsion + 1.4 mg of sildenafil citrate (group 4, n = 10). Unilateral testicular torsion was created by rotating the right testis 720º in a clockwise direction for 2 h in other groups, except for group 1, which was served as sham group. After torsion (2 h) and detorsion (2 h) periods, rats were killed.. The level of reduced glutathion (GSH) (p < 0.05) and the activities of catalase (p < 0.01) and glutathione peroxidase (p < 0.05) in the contralateral testis from group 2 were significantly lower and nitric oxide (NO) (p < 0.05) level in the contralateral testis were significantly higher than those of group 1. Administration of low-dose sildenafil citrate (group 3) prevented the increases in malondialdehyde and NO levels and decreases in glutathione peroxidase activities and GSH values induced by testicular torsion. However, administration of high-dose sildenafil citrate (group 4) had no effect on these testicular parameters (p > 0.05). Histopathological changes were detected in groups 2, 3 and 4.. These results suggest that biochemically and histologically torsion/detorsion injury occurs in the contralateral testis following 2-h torsion and 2-h detorsion and that administration of low-dose sildenafil citrate before detorsion prevents ischemia/reperfusion cellular damage in testicular tissue.

Topics: Animals; Catalase; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protective Agents; Purines; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Spermatic Cord Torsion; Sulfones; Testis

We designed an experimental model of renal ischemia-reperfusion to evaluate the preemptive effect of intravenous sildenafil according to the dose administered (0.7 vs 1.4 mg/kg) and the time of administration (30 minutes before ischemia or during ischemia).. A total of 20 minipigs were divided into groups of 4 each, including group 1-control, group 2-sildenafil 0.7 mg/kg intravenously 30 minutes before vascular clamping, group 3-sildenafil 0.7 mg/kg intravenously during warm ischemia, group 4-sildenafil 1.4 mg/kg intravenously 30 minutes before vascular clamping and group 5-sildenafil 1.4 mg/kg intravenously during warm ischemia. The ischemia-reperfusion model was applied using laparotomy and right kidney vascular clamping for 30 minutes, followed by unclamping and reperfusion for 45 minutes. Renal vascular flow and systemic mean arterial pressure were recorded for 45 minutes after unclamping. Mean values were compared using Student t test with significance considered at p <0.05.. Sildenafil led to a decrease in arterial pressure compared to that in controls, especially at the dose of 1.4 vs 0.7 mg/kg, including 113.77, 109.76, 106.12, 97.41 and 82.85 mm Hg in groups 1 to 5, respectively. Renal vascular flow was significantly higher in groups 2 and 3 than in groups 1, 4 and 5 (112.82 and 111.33 vs 88.25, 87.91 and 84.37 ml per minute, respectively, p = 0.000).. The effect of intravenous sildenafil as a preemptive drug against the hemodynamic effects of renal ischemia-reperfusion is dose dependent. The 0.7 mg/kg dose significantly increased reperfusion renal vascular flow with a small decrease in arterial pressure compared to the 1.4 mg/kg dose.

Topics: Animals; Hemodynamics; Ischemic Preconditioning; Kidney; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Reperfusion Injury; Sildenafil Citrate; Sulfones; Swine; Swine, Miniature; Warm Ischemia

The aim of this work was to determine effects of intrapertoneally-administered sildenafil citrate (SC) for prevention testicular injury after unilateral testicular torsion/detorsion (T/D) in rats on red blood cell (RBC) and plasma lipid peroxidation, antioxidants and blood hematology.. Thirty seven adult male Wistar albino rats were divided into four groups: sham operated (group 1), T/D+saline (group 2), T/D+0.7mg SC (group 3) and T/D+1.4mg SC (group 4). Testicular torsion was created by rotating the right testis 720° in a clockwise direction for 2h in all the groups, except for group 1.. Our results showed that that testicular injury significantly induced erythrocyte reduced glutathion (GSH) (p<0.05), malondialdehyde (MDA) in RBC (p<0.01) and plasma (p<0.05) and blood lymphocyte (p<0.01) counts. Administration of low dose SC led to significantly increase in the levels of RBC GSH (p<0.05), plasma paraoxonase (PON1) (p<0.01), nitric oxide (NO) (p<0.01) and blood lymphocyte counts (p<0.01), but to decreases in the levels of MDA in plasma and RBC, blood mean corpuscular volume (MCV) (p<0.05) and eosinophil counts (p<0.05). Treatment with high dose SC caused a significantly increase in PON1, vitamin E and β-carotene in plasma, levels of GSH in RBC and blood lymphocyte counts. On the other hand, results showed that high dose sildenafil significantly decreased plasma and RBC MDA levels. Total tissue damage scores of the group 2 were significantly higher than group 1 and 3.. Low dose SC appears to be beneficial in reducing the effects of injury to the testicular torsion.

Topics: Animals; Antioxidants; Aryldialkylphosphatase; Dose-Response Relationship, Drug; Eosinophils; Erythrocytes; Glutathione; Ischemia; Leukocyte Count; Lipid Peroxidation; Lymphocytes; Male; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfones; Testis; Torsion Abnormality

The aim of the study was to investigate the effects of sildenafil citrate (SC) on renal ischemia reperfusion (I/R) injury in a rat model. Forty eight male Wistar albino rats were randomly assigned into six groups: sham, ischemia, I/R, SC+sham, SC+ischemia and SC+I/R. In the I/R groups, the right kidney was removed and the artery and vein of the left kidney were clamped for 45 min followed by reperfusion for 1 h. In the SC-treated groups, SC dissolved in saline solution was given as a single dose (1 mg/kg) 60 min before the operation. Renal histology was analyzed by scoring the tubular damage and neutrophil infiltration. Tissue myeloperoxidase activity and lipid peroxidation were analyzed. The histological damage and the neutrophil infiltration induced by I/R were significantly less in the SC+I/R group (p = 0.004 and p = 0.003, respectively). Pretreatment with SC significantly diminished the tissue myeloperoxidase activity, indicating the prevention of the neutrophil sequestration into the kidney in the SC+I/R group (p = 0.004); however, it did not result in any changes in lipid peroxidation. Our results in a rat model of ischemia-reperfusion indicate that pre-ischemic treatment with sildenafil citrate can significantly attenuate ischemia/reperfusion-induced renal injury by decreasing leukocyte infiltration.

Topics: Animals; Kidney; Male; Neutrophil Infiltration; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Sulfones; Vasodilator Agents

The phosphodiesterase type-5 inhibitor sildenafil has powerful cardioprotective effects against ischemia-reperfusion injury. PKG-mediated signaling has been implicated in this protection, although the mechanism and the downstream targets of this kinase remain to be fully elucidated. In this study we assessed the role of phospholemman (PLM) phosphorylation, which activates the Na(+)/K(+)-ATPase, in cardioprotection afforded by sildenafil administered during reperfusion. Isolated perfused mouse hearts were optimally protected against infarction (indexed by tetrazolium staining) by 0.1 muM sildenafil treatment during the first 10 min of reperfusion. Extended sildenafil treatment (30, 60, or 120 min at reperfusion) did not alter the degree of protection provided. This protection was PKG dependent, since it was blocked by KT-5823. Western blot analysis using phosphospecific antibodies to PLM showed that sildenafil at reperfusion did not modulate PLM Ser63 or Ser68 phosphorylation but significantly increased Ser69 phosphorylation. The treatment of isolated rat ventricular myocytes with sildenafil or 8-bromo-cGMP (PKG agonist) enhanced PLM Ser69 phosphorylation, which was bisindolylmaleimide (PKC inhibitor) sensitive. Patch-clamp studies showed that sildenafil treatment also activated the Na(+)/K(+)-ATPase, which is anticipated in light of PLM Ser69 phosphorylation. Na(+)/K(+)-ATPase activation during reperfusion would attenuate Na(+) overload at this time, providing a molecular explanation of how sildenafil guards against injury at this time. Indeed, using flame photometry and rubidium uptake into isolated mouse hearts, we found that sildenafil enhanced Na(+)/K(+)-ATPase activity during reperfusion. In this study we provide a molecular explanation of how sildenafil guards against myocardial injury during postischemic reperfusion.

Topics: Analysis of Variance; Animals; Blotting, Western; Cardiotonic Agents; Cells, Cultured; Heart; Membrane Proteins; Mice; Muscle Cells; Myocardium; Phosphoproteins; Phosphorylation; Piperazines; Purines; Reperfusion Injury; Signal Transduction; Sildenafil Citrate; Sodium-Potassium-Exchanging ATPase; Sulfones

To evaluate the effect of sildenafil, administered prior to renal ischemia/reperfusion (I/R), by scintigraphy and histopathological evaluation in rats.. Twenty-four rats were divided randomly into two groups. They received 0.1 ml of 99mTechnetium-etilenodicisteine intravenous, and a baseline (initial) renal scintigraphy was performed. The rats underwent 60 minutes of ischemia by left renal artery clamping. The right kidney was not manipulated. The sildenafil group (n=12) received orally 1 mg/kg of sildenafil suspension 60 minutes before ischemia. Treatment with saline 0.9% in the control group (n=12). Half of the rats was assessed after 24 hours and half after seven days I/R, with new renal scintigraphy to study differential function. After euthanasia, kidneys were removed and subjected to histopathological examination. For statistical evaluation, Student t and Mann-Whitney tests were used.. In the control group rats, the left kidneys had significant functional deficit, seven days after I/R, whose scintigraphic pattern was consistent with acute tubular necrosis, compared with the initial scintigraphy (p<0.05). Sildenafil treatment resulted in better differential function of the left kidneys 24h after reperfusion, compared with controls. Histopathologically, the left kidney of control rats (24 hours after I/R) showed a higher degree of cellular necrosis when compared with the sildenafil treated rats (p<0.05).. Sildenafil had a protective effect in rat kidneys subjected to normothermic I/R, demonstrated by scintigraphy and histomorphometry.

Topics: Animals; Disease Models, Animal; Kidney; Piperazines; Purines; Radionuclide Imaging; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Vasodilator Agents

There is evidence demonstrating the protective effect of cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors against ischemic injury in certain tissues. In this study, sildenafil, a potent inhibitor of PDE5, was tested for its beneficial effects in the prevention of disrupted ileal contractility and damage to tissue caused by intestinal ischemia-reperfusion in rats. Male Sprague-Dawley rats were divided into four groups: sham-operated; sham-operated with sildenafil pretreatment; ischemia-reperfusion with vehicle pretreatment; and ischemia-reperfusion with sildenafil pretreatment. The superior mesenteric artery was occluded for 45 min to induce ischemia. The clamp was then removed for a 60 min period of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to the surgical procedure in the ischemia-reperfusion and sham-operated groups. Isometric contractions of the ileal segments in response to acetylcholine or electrical field stimulation (120 V, 2 ms pulse for 5 s, 1-20 Hz) were recorded. Additionally, levels of thiobarbituric acid reactive substances and myeloperoxidase activity were measured in addition to a histopathological examination of the ileal tissue. The contractions induced by both acetylcholine and electrical field stimulations were markedly inhibited after ischemia-reperfusion. Sildenafil pretreatment (1 mg/kg, i.v.) abolished the inhibition of responses to acetylcholine. The increased levels of thiobarbituric acid reactive substances and myeloperoxidase activity caused by ischemia-reperfusion were reversed to control levels with sildenafil pretreatment. Intestinal ischemia-reperfusion caused severe ischemic injury in rat ileum, which was prevented by sildenafil. These results suggest that sildenafil pretreatment has a protective effect against ileal dysfunction and damage induced by intestinal ischemia-reperfusion in the rat.

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Ileum; Intestinal Mucosa; Isometric Contraction; Lipid Peroxidation; Male; Microelectrodes; Muscle Contraction; Neutrophils; Perfusion; Peroxidase; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blood Urea Nitrogen; Caspase 3; Creatinine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Drug Administration Schedule; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Kidney Diseases; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Time Factors

The aim of the present study was to evaluate the effects of sildenafil on endothelium-dependent mesenteric artery vasorelaxation and nonadrenergic noncholinergic (NANC) ileal responses in an experimental rat intestinal ischemia-reperfusion (I/R) model. The superior mesenteric artery was occluded for 45 min of ischemia and then the clamp was removed for 60 min of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to surgery in the I/R and sham-operated groups. Acetylcholine-induced relaxation of the mesenteric arteries, which were precontracted via submaximal phenylephrine, decreased markedly after I/R. Sildenafil pretreatment reversed the acetylcholine-induced relaxation. In the ileum, NANC responses were significantly attenuated following I/R, which were increased by sildenafil pretreatment. These results indicate that pretreatment with sildenafil prevented both endothelial dysfunction in the mesenteric artery and impairment of ileal NANC responses in a rat intestinal I/R model.

Topics: Acetylcholine; Animals; Disease Models, Animal; Endothelium, Vascular; Ileum; Intestinal Mucosa; Male; Mesenteric Artery, Superior; Phenylephrine; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sildenafil Citrate; Sulfones; Vasodilator Agents

In an experimental model we studied the protective effects of the phosphodiesterase-5 inhibitor sildenafil on kidney grafts autotransplanted after 45 minutes of warm ischemia by vascular clamping, nephrectomy and 60 minutes of isolated hypothermic pump perfusion.. A total of 14 laboratory minipigs were divided into group 1-7 administered 100 mg sildenafil orally 1.5 hours preoperatively and group 2-7 in which no sildenafil was given. Right single nephrectomy was completed after 45 minutes of warm ischemia by complete vascular clamping. Before autotransplantation all kidneys underwent 60 minutes of hypothermic pulsatile perfusion. Renal flow, arterial pressure and renal vascular resistance were recorded in real time for 60 minutes after autotransplantation. Nitric oxide levels were determined in blood samples from the renal vein at predefined intervals. Optical and electronic microscopy was done in all organs at the end of the procedure.. In group 1 vs 2 renal vascular flow was significantly higher (155.30 vs 29.04 ml per minute per 100 gm) and renal vascular resistance was significantly lower (0.59 vs 3.10 mm Hg/ml per minute, each p <0.01). No significant differences were observed in systemic arterial pressure between groups 1 and 2 (84.08 and 84.65 mm Hg, respectively, p >0.05). Nitric oxide levels were significantly higher for all periods in group 1 (49.94 vs 16.85 muM, p <0.01). No significant differences were observed in histological studies, although endothelial cell structure was better preserved in the sildenafil group.. To our knowledge our study suggests for the first time in the literature a positive effect of sildenafil in the immediate posttransplantation outcome of warm ischemic kidneys without secondary systemic effects.

Topics: Animals; Disease Models, Animal; Kidney; Kidney Transplantation; Organ Preservation; Piperazines; Purines; Reperfusion Injury; Sildenafil Citrate; Sulfones; Swine; Transplants; Vasodilator Agents; Warm Ischemia

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 microg/kg; sildenafil-analog (n=5) 500 microg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes . cm . sec(-5) at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Topics: Acute Disease; Animals; Blood Pressure; Cardiopulmonary Bypass; Hypertension, Pulmonary; Milrinone; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Reperfusion Injury; Sildenafil Citrate; Sulfones; Sus scrofa; Vascular Resistance

We assessed the effectiveness of sildenafil administration during ischemic period in a rat model of testicular torsion/detorsion (T/D).. Sprague-Dawley rats were divided into four groups (n = 10). In those animals that underwent T/D, right testes were rotated 720 degrees for 1 h. Base line group was for basal normal values. Sham operated group was served as a control group. T/D group underwent 1 h testicular torsion. Sildenafil group received sildenafil (0.7 mg/kg) intraperitoneally 30 min after initiation of ischemic period. For measurement of lipid peroxidation and antioxidant enzyme activities, right testes of five animals in each group were excised after 4-h reperfusion. Germ cell apoptosis indices were determined 24 h following detorsion in right testes of remaining five animals in each group.. Malondialdehyde (MDA) levels in T/D group were significantly higher versus control and base line groups. Moreover, testicular MDA values in sildenafil group were significantly lower than T/D. There were also significant decreases in catalase and superxide dismutase activities in T/D group compared with control and base line groups. These values were significantly higher in sildenafil group versus T/D. Germ cell apoptosis indices were significantly higher in both groups that experienced T/D in comparison to control and base line groups; however, sildenafil treatment significantly reduced the apoptosis in sildenafil group compared with T/D group.. Sildenafil administration during testicular torsion decreased ischemia/reperfusion cellular damage. The results of biochemical studies suggest that, reduction of oxidative stress by sildenafil may have a major role in its cytoprotective effects.

Topics: Animals; Apoptosis; Catalase; Disease Models, Animal; Male; Malondialdehyde; Oxidative Stress; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury; Sildenafil Citrate; Spermatic Cord Torsion; Spermatozoa; Sulfones; Superoxide Dismutase; Testis; Vasodilator Agents

Improvement of preservation is still a major research objective in lung transplantation. The effects of phosphodiesterase-5 (PDE-5) inhibitors during procurement are still not clear. It was the aim of this study to investigate the effect of sildenafil on post-transplanted lung function in a porcine model using different application procedures.. In control group lungs were flushed with buffered low-potassium dextran (LPD) solution (I) and compared to LPD solution with supplementation of 0.15 mg/kg body weight (BW) sildenafil (II), whereas in a third group 0.15 mg/kg BW sildenafil was administered intravenously 20 min prior to LPD flushing (III). All grafts were stored for 24 h at 4-6 degrees C. Hemodynamics and blood gases were monitored until 6 h after reperfusion. Lung tissue was taken for wet/dry ratio assessment.. All animals of groups I and III survived the entire observation period in contrast to four animals of group II which died within 4 h after reperfusion due to severe reperfusion injury. Group II showed a lower mean PAP and a reduced pulmonary vascular resistance (PVR) throughout the observation period, but did not reach significance due to low number of surviving animals. Group III achieved significantly improved PO2/FiO2 fraction at all timepoints and a significant reduced PVR [434+/-98 vs 594+/-184 dyn s cm(-5), II vs I; mean+/-SD, p<0.01] at 6 h. Wet/dry ratio was significantly higher in group II throughout the experiment.. Sildenafil allows for a better graft function after 24 h ischemia when given prior to standard flushing and preservation. This effect can be explained by a complete/homogenous preservation achieved by selective pulmonal vasodilatation. However, this effect seems to persist when sildenafil remains in the storage solution, leading to severe pulmonary edema.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Extravascular Lung Water; Graft Survival; Lung Transplantation; Male; Organ Preservation; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Edema; Purines; Reperfusion Injury; Sildenafil Citrate; Sulfones; Swine; Transplantation Conditioning; Vascular Resistance

Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia.. Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (I) (n=5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 degrees C in the perfusion solution. After 24h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6h. Except for the sildenafil application, the control group (II) (n=4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5h, cardiopulmonary parameters (systemic atrial, PA, central venous, left atrial pressure, pCO(2), pO(2)) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run.. All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dynescm(-5)), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dynescm(-5) vs endpoint: 1000 dynescm(-5)). EVLW in group I did not increase during reperfusion (baseline: 6.75+/-1.4 mg/kg vs endpoint: 6.7+/-1.0mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7+/-0.1mg/kg vs group II: 6.48+/-1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8+/-1.6 pmol/g vs group II: 18.5+/-3.0 pmol/g, p<0.05).. Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Drug Evaluation, Preclinical; Extravascular Lung Water; Graft Survival; Lipid Peroxidation; Lung Transplantation; Peroxidase; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Circulation; Purines; Reperfusion Injury; Sildenafil Citrate; Sulfones; Swine; Vascular Resistance

Infants undergoing surgery for congenital heart disease are at risk for myocardial ischemia during cardiopulmonary bypass, circulatory arrest, or low-flow states. The purpose of this study was to demonstrate the effects of sildenafil, a selective phosphodiesterase-5 (PDE-5) inhibitor on myocardial functional improvement and infarct size reduction during ischemia/reperfusion injury in infant rabbits. Infant rabbits (aged 8 wk) were treated with sildenafil citrate (0.7 mg/kg i.v.) or normal saline 30 min before sustained ischemia for 30 min and reperfusion for 3 h. Transesophageal echocardiography (TEE) was used to assess left ventricular cardiac output (LVCO) and aortic velocity time integral (VTI). After ischemia/reperfusion, risk area was demarcated by Evan's blue dye and infarct size determined by computer morphometry of triphenyltetrazolium chloride-stained sections. The sildenafil-treated group had preservation and elevation in LVCO (143% of baseline, p < 0.05) and an elevated aortic VTI (145% of baseline, p < 0.05) after 30 min of ischemia compared with the control group LVCO (72% of baseline, p < 0.05) and aortic VTI (73% of baseline, p < 0.05). This is a statistically significant increase in LVCO and aortic VTI in the sildenafil group compared with controls (n = 6/group, p < 0.05). The sildenafil-treated group had significant reduction in infarct size (15.5 +/- 1.2 versus 33 +/- 2.3 in the saline group, % risk area, mean +/- SEM, n = 10-15/group, p < 0.05). For the first time, we have shown that sildenafil citrate promotes myocardial protection in infant rabbits as evidenced by postischemic preservation and elevation in LVCO and aortic VTI and reduction in infarct size.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Aorta; Cardiac Output; Cyclic Nucleotide Phosphodiesterases, Type 5; Echocardiography; Evans Blue; Heart; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rabbits; Reperfusion Injury; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents; Ventricular Function, Left