sildenafil-citrate and Necrosis

This study aimed to demonstrate the efficacy of sildenafil citrate in order to improve the distal necrosis of randomized flaps in diabetic rats, and to explore new methods to reduce distal necrosis encountered in flap surgery.. This is an experimental study in rats. The rats were first divided into three groups: Control(C), Diabetes(D), and Sildenafil(S). Streptozotocin 40mg/kg was administered intraperitoneally to the rats in groups D and S that would develop diabetes. Two days after the procedure, blood glucose was measured from the tail vein of the rats, and the rats with a blood glucose level of 250mg/dL and above were considered diabetic. 7×3cm McFarlane flap was randomly planned on the back of the rats. In the flaps, ischemia was measured at the 30th minute with Na fluorescein, flap necrosis was measured on days 4 and 7, and specimens were collected from the critical zone and distal zone regions for histological examination.. The comparison of ischemia and necrosis regions, ischemia was found to be more significant in groups D and S compared to group C (P<0.05). In the comparison of necroses on days 4 and 7, it was determined that necrosis occurred significantly (P<0.05) less in group S compared to the other groups. It was determined that necrosis in group D was significantly (P<0.05) higher on days 4 and 7 compared to the other groups.. The distal circulation is affected worse in randomized flaps in diabetes. Sildenafil citrate significantly increased the flap viability (P<0.05).

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Graft Survival; Ischemia; Necrosis; Rats; Sildenafil Citrate

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

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

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cell Cycle; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Mice; Necrosis; Neovascularization, Pathologic; Signal Transduction; Sildenafil Citrate; Time Factors; Tumor Burden

Neuroprotective agents such as methylprednisolone and sildenafil may limit damage after spinal cord injury. We evaluated the effects of methylprednisolone and sildenafil on biochemical and histologic changes after spinal cord injury in a rabbit model. Female New Zealand rabbits (32 rabbits) were allocated to 4 equal groups: laminectomy only (sham control) or laminectomy and spinal trauma with no other treatment (trauma control) or treatment with either methylprednisolone or sildenafil. Gelsolin and caspase-3 levels in cerebrospinal fluid and plasma were determined, and spinal cord histology was evaluated at 24 hours after trauma. There were no differences in mean cerebrospinal fluid or plasma levels of caspase-3 between the groups or within the groups from 0 to 24 hours after injury. From 0 to 24 hours after trauma, mean cerebrospinal fluid gelsolin levels significantly increased in the sildenafil group and decreased in the sham control and the trauma control groups. Mean plasma gelsolin level was significantly higher at 8 and 24 hours after trauma in the sildenafil than other groups. Histologic examination indicated that general structural integrity was better in the methylprednisolone in comparison with the trauma control group. General structural integrity, leptomeninges, white and grey matter hematomas, and necrosis were significantly improved in the sildenafil compared with the trauma control group. Caspase-3 levels in the cerebrospinal fluid and blood were not increased but gelsolin levels were decreased after spinal cord injury in trauma control rabbits. Sildenafil caused an increase in gelsolin levels and may be more effective than methylprednisolone at decreasing secondary damage to the spinal cord. 

Topics: Animals; Caspase 3; Female; Gelsolin; Models, Animal; Necrosis; Neuroprotective Agents; Rabbits; Sildenafil Citrate; Spinal Cord; Spinal Cord Injuries

We report the case of a 37-year-old woman who developed critical upper limb ischemia caused by a cervical rib. Because the malformation was initially undiagnosed, a vascular bypass was performed, and failure occurred. Following a 6-month therapy with sildenafil, revascularization of the arm was successful and amputation was avoided. A 6-year follow-up shows a rich collateral network at the compression site and normal values of digital plethysmography. Because hand surgeons often see patients with digital ulcerations and other manifestations of peripheral vascular pathology, therapy of ischemia with sildenafil could be an effective treatment option in patients not responding to classic drugs.

Topics: Adult; Arm; Female; Humans; Ischemia; Necrosis; Peripheral Vascular Diseases; Sildenafil Citrate; Skin Ulcer; Thoracic Outlet Syndrome; Vasodilator Agents

Sildenafil is used for the treatment of erectile dysfunction and is helping millions of men around the world to achieve and maintain a long lasting erection. Fifty healthy male rabbits (Oryctolagus cuniculus) were used in the present study and exposed daily to sildenafil (0, 1, 3, 6, 9 mg/kg) for 5 days per week for 7 weeks to investigate the biochemical changes and alterations in the hepatic tissues induced by this drug overdosing. In comparison with respective control rabbits, sildenafil overdoses elevated significantly (p-value<0.05, ANOVA test) alanine aminotransferase (ALT), aspartate aminotransferase (AST), testosterone, follicular stimulating hormone and total protein, while creatinine and urea were lowered with no significant alteration was observed in uric acid and luteinizing hormone concentration. Also sildenafil provoked hepatocytes nuclear alterations, necrosis, hydropic degeneration, bile duct hyperplasia, Kupffer cells hyperplasia, inflammatory cells infiltration, hepatic vessels congestion and evident partial depletion of glycogen content. The results show that subchronic exposure to sildenafil overdoses exhibits significant biochemical and alterations in the hepatic tissues that might affect the functions of the liver and other vital organs.

Topics: Animals; Bile Ducts; Biomarkers; Chemical and Drug Induced Liver Injury; Drug Overdose; Hyperplasia; Kupffer Cells; Liver; Liver Function Tests; Male; Necrosis; Phosphodiesterase 5 Inhibitors; Rabbits; Risk Assessment; Sildenafil Citrate; Time Factors; Toxicity Tests

Nicotine causes ischemia and necrosis of skin flaps. Phosphodiesterase-5 (PDE-5) inhibition enhances blood flow and vasculogenesis. This study examines skin flap survival in rats exposed to nicotine that are treated with and without PDE-5 inhibition.. Eighty six rats were divided into five groups. Group 1 received saline subcutaneous (SC) once per day. Group 2 received nicotine SC 2 mg/kg day. Group 3 received sildenafil intraperitoneal (IP) 10 mg/kg day. Group 4 received nicotine SC 2 mg/kg and sildenafil IP 10 mg/kg day. Group 5 received nicotine SC 2 mg/kg day and sildenafil IP 10 mg/kg two times daily. After 28 days of treatment, modified McFarlane flaps were created, silicone sheets were interposed, and flaps were sutured. Photographs were taken on postoperative days 1, 3, and 7 and fluorescence angiography was used on day 7, both to evaluate for skin flap necrosis. Rats were euthanized and flaps were harvested for Vascular Endothelial Growth Factor (VEGF) Western blot analysis. Images were analyzed by three blinded observers using ImageJ, and necrotic indices were calculated.. The nicotine and PDE-5 inhibition twice-daily group showed a 46% reduction in flap necrosis when compared to saline only (P < 0.05) and a 54% reduction when compared to nicotine only (P < 0.01). Fluorescence angiographic image analysis revealed reductions in flap necrosis (P < 0.01). VEGF analysis trended toward increased VEGF for all sildenafil-treated groups (P > 0.05).. PDE-5 inhibition exhibits a dose-dependent reduction in skin flap necrosis in rats exposed to nicotine. This suggests that PDE-5 inhibition may mitigate the ill effects of smoking on skin flaps.

Topics: Animals; Fluorescein Angiography; Ischemia; Male; Necrosis; Nicotine; Nicotinic Agonists; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats, Wistar; Sildenafil Citrate; Skin; Sulfonamides; Surgical Flaps; Vascular Endothelial Growth Factor A

Thrombosis of vascular anastomosis in the field of reconstructive microsurgery is a clinical problem of extraordinary importance for the devastating consequences for affected patients. Sildenafil has been shown to be relaxing vascular action on the peripheral vascular system in vivo and have an ability to reduce platelet aggregation. There is no study up to date on the effect of sildenafil on microvascular anastomosis, neither experimental studies nor clinical settings.. A purposeful thrombotic back-wall stitch was performed in the groin flap pedicle to obtain an anastomosis with thrombotic potential where the drug effect was studied.. Data in the experimental group treated with papaverine or sildenafil indicate a considerable decrease in the percentage of necrotic flaps (20% necrotic flaps in papaverine group versus 30% necrotic flaps in sildenafil group) in comparison with control group (60% necrotic flaps). In papaverine group, in 100% cases, flap necrosis was established in the first 24 h, but in sildenafil group, 66% flap necrosis was established between the second and the seventh postoperative days.. The study did not demonstrate significant differences between the groups, but it does suggest a benefit in applying papaverine and sildenafil in the anastomosis with already thrombogenetic disease, compared to the nonapplication of antithrombotic drugs. The establishment of thrombosis in the necrotic flaps in the group treated with sildenafil was later than in the group treated with papaverine, with a statistical trend but without becoming significant.

Topics: Anastomosis, Surgical; Animals; Disease Models, Animal; Free Tissue Flaps; Humans; Male; Microsurgery; Necrosis; Piperazines; Postoperative Complications; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Sutures; Thrombosis; Vasodilator Agents

Sildenafil, the first drug for erectile dysfunction, has cardiopulmonary protective actions. A recent study has reported that sildenafil given intraperitoneally (i.p.) attenuated cisplatin (CP)-induced nephrotoxicity. Here, we evaluated whether sildenafil, given by two different routes and at two different doses, can attenuate CP-induced nephrotoxicity and would also affect renal haemodynamics in CP-treated rats. Six groups of rats were treated with saline (controls), CP [5 mg/kg, intraperitoneally (i.p.) once], sildenafil (0.4 mg/kg/day, i.p. for 5 days), sildenafil (0.4 mg/kg/day i.p. for 5 days) plus CP (5 mg/kg, i.p., once), sildenafil [10 mg/kg/day, subcutaneous (s.c.) for 5 days] or sildenafil (10 mg/kg/day, s.c. for 5 days) plus CP (5 mg/kg, i.p. once). Five days after the end of the treatments, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous (i.v.) injection of norepinephrine for the measurement of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several biochemical, functional and structural parameters. CP reduced body-weight and renal blood flow but did not affect norepinephrine-induced renal vasoconstriction. It increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. CP caused extensive renal tubular necrosis, increased urine volume and N-acetyl-β-D-glucosaminidase activity. When sildenafil (0.4 mg/kg/day, i.p. for 5 days) was combined with cisplatin, there was a dramatic improvement in renal histopathology, reduction in N-acetyl-β-D-glucosaminidase and increase in renal blood flow. However, sildenafil (10 mg/kg/day, s.c. for 5 days) did not affect CP nephrotoxicity, suggesting the importance of dose and route selection of sildenafil as a nephroprotectant.

Topics: Animals; Antineoplastic Agents; Cisplatin; Disease Models, Animal; Hemodynamics; Injections, Subcutaneous; Kidney; Kidney Diseases; Kidney Tubules; Male; Necrosis; Piperazines; Purines; Rats; Rats, Wistar; Renal Circulation; Sildenafil Citrate; Sulfones; Vasoconstriction; Vasodilator Agents

To assess the viability of McFarlane skin flaps in rats with administration of sildenafil.. Twenty Wistar rats were distributed into two groups: Control (dorsal skin flap, subdermal application of saline solution at 0.9%) and Study (dorsal skin flap, subdermal application of sildenafil). Seven days after the surgery, flaps were photographed and graphically rendered. Then, they were analyzed with AutoCAD software. Three biopsies (proximal, medial and distal) of each flap were collected for histological analysis.. Macroscopic analysis showed that animals of the study group had greater necrotic areas (p=0.003) in the dorsal skin flaps. Additionally, histological analysis of the distal third of these flaps showed a tendency to less granulated tissue formation in animals treated with sildenafil.. Sildenafil subdermally was associated with lower viability of the random skin flap in rats.

Topics: Animals; Biopsy; Dermatologic Surgical Procedures; Female; Necrosis; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Skin; Sulfones; Surgical Flaps; Tissue Survival; Wound Healing

We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 +/- 4.6%) compared with that in saline (69.6 +/- 4.1%, P < 0.05). NG-nitro-l-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 +/- 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 +/- 0.3% with saline to 1.2 +/- 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 +/- 0.2% with saline to 1.2 +/- 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 +/- 0.1 to 5.2 +/- 0.2 and to 5.5 +/- 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 +/- 0.2 and 4.4 +/- 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway.

Topics: Animals; Apoptosis; Blotting, Western; Cardiomegaly; Cardiomyopathy, Restrictive; Coronary Vessels; Echocardiography, Doppler; Enzyme Inhibitors; In Situ Nick-End Labeling; Ligation; Male; Mice; Mice, Inbred ICR; Myocardial Infarction; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperazines; Pulmonary Edema; Purines; Sildenafil Citrate; Sulfones; Survival Analysis; Vasodilator Agents; Ventricular Function, Left; Ventricular Remodeling

Distal ischemic necrosis of the flap remains an unsolved, challenging problem. Phosphodiesterase (PDE) inhibitors, which include the drug sildenafil, are a relatively new class of U.S. Food and Drug Administration-approved medications whose effect on tissue viability has not been widely explored. The vasodilatory effects of these drugs have the potential to enhance blood flow to flaps and increase their survivability. The purpose of this study was to examine the short- and long-term effects of sildenafil, administered intraperitoneally at a dose of 9 mg/kg per day, on the survival of surgical skin flaps in rats.. A McFarlane-type random pattern skin (3 x 10-cm) flap model was used to evaluate the effect of sildenafil on necrosis at multiple time points. Rats were assigned to sildenafil-treated (9 mg/kg per day intraperitoneally; n = 34), vehicle control (n = 35), or sham (no injection; n = 40) groups. In each group, caudally based, dorsal, rectangular (3 x 10-cm) flaps were created. Flap necrosis was determined using orthogonal polarization spectral imaging and digital photography analysis on days 1, 3, 5, and 7 postsurgery.. Orthogonal polarization spectral imaging results showed a significant decrease in necrosis and stasis in rats treated with sildenafil on days 1 and 3. Although reductions observed at days 5 and 7 were not as dramatic as days 1 and 3, digital photography analysis confirmed a decrease in the area of necrosis at all time points evaluated.. These results suggest that PDE 5 inhibitors may play a more important role in early postoperative skin flap viability rather than at later time points and may be beneficial for skin flap viability as shown in the rat model. PDE 5 inhibitors may reduce the extent of necrosis after reconstructive surgeries.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Flow Velocity; Dermatologic Surgical Procedures; Disease Models, Animal; Follow-Up Studies; Male; Microcirculation; Necrosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Surgical Flaps; Time Factors; Treatment Outcome

We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 microM) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible therapeutic potential in preventing myocyte cell death following ischemia/reperfusion.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Apoptosis; bcl-X Protein; Benzimidazoles; Blotting, Western; Carbocyanines; Caspase 3; Caspases; Cell Survival; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 5; DNA Primers; DNA, Complementary; Enzyme Activation; Enzyme Inhibitors; Immunohistochemistry; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mitochondria; Muscle Cells; Myocytes, Cardiac; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Proto-Oncogene Proteins c-bcl-2; Purines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sildenafil Citrate; Sulfones; Time Factors; Transcription, Genetic; Trypan Blue

Sildenafil is a cyclic guanosine-specific phosphodiesterase type 5 (PD-5) inhibitor that is widely used for erectile dysfunction. Potent and competitive inhibition of PD-5 enhances levels of cyclic guanosine monophosphate (cGMP). Fibrin glue-apart from tissue fixation-has been used for slow release of drugs. In this study, local delivery of Sildenafil citrate with fibrin glue was accomplished to improve random flap survival. Fifty Wistar rats were randomized into 5 groups, and a standardized dorsal random-pattern skin flap was elevated in each rat. In Group I (n = 10), the base of the flap was divided, making it a "graft" control to study the graft effect. In Group II (n = 10), a thin Silastic sheet was used to separate the flap from the underlying vascular bed, and no pharmacologic treatment was given. In Group III (n = 10), only 0.5 mL of fibrin glue was applied to the flap donor site. In Group IV (n = 10), 2.5 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied to donor site of the flap, whereas 10 mg of sildenafil citrate mixed in 0.5 mL of fibrin glue was applied in Group V (n = 10). Area of flap survival was evaluated on postoperative seventh day. Total necrosis of all of the flaps was observed in "graft" control group (Group I). Sildenafil and fibrin glue groups (Group IV and V) resulted in a statistically significant decrease in flap necrosis compared with Groups II and III (P < 0.0001). A statistically significant difference could not be documented between Group II and Group III (P > 0.0001). The decrease in skin necrosis was statistically significant in Group V compared with Group IV (P < 0.0001). Histologic examination revealed significantly increased vascular density in Groups IV and V compared with Groups II and III (P < 0.0001), whereas a significant difference could not be documented between Groups IV and V (P > 0.0001) and between Groups II and III (P > 0.0001). In view of these results, topical sildenafil application seems to improve flap survival in random-pattern skin flaps in dose-dependent manner.

Topics: Animals; Fibrin Tissue Adhesive; Necrosis; Piperazines; Postoperative Complications; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Surgical Flaps; Tissue Survival

Sildenafil (Viagra), a selective and specific inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterases (PDEs), is currently marketed for the treatment of erectile dysfunction. Sildenafil is a potent and highly selective PDE-V inhibitor and enhances smooth muscle relaxation in human. Systemic arterial and venous smooth muscle cells contain PDE-V and nitric oxide (NO) which is a major mediator of relaxation of the smooth muscle cell. The aim of the present study is to investigate, in a rat model, the potential effect of sildenafil on survival of random pattern skin flaps. For this purpose, 32 Sprague-Dawley rats were used and a McFarlane-type caudally based skin flap was designed on the dorsum of the rat (2.5 x 8 cm). Rats were divided into four groups: One control (Group D), and three treatment groups (Groups A, B, C). Sildenafil was administered orally to the experiment groups; Group A: 3 mg/kg/single dose a day, Group B: 10 mg/kg/single dose a day and Group C: 10 mg/kg/twice dose a day. The areas of flap necrosis were measured in each group. The extent of viable flap areas were expressed as a percentage of total flap area, and differences were studied by Completely Randomised Experimental design. The areas of necrosis of skin flaps decreased depending on sildenafil dose, but viability of the flaps treated with 3 mg/kg/day was not different than the control group. The flaps receiving 2 x 10 mg/kg/day sildenafil gave the highest (P < 0.01) survival rate. As a conclusion, sildenafil may have a dose dependent effect to increase flap survival in random skin flaps.

Topics: Animals; Graft Survival; Male; Necrosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Skin Transplantation; Sulfones; Surgical Flaps

Adverse cardiac events in patients treated with the phosphodiesterase-5 inhibitor sildenafil for erectile dysfunction raised concerns about its safety in ischemic heart disease.. In anesthetized open-chest rabbits, receiving 1.45 mg/kg sildenafil intravenously or saline 30 min prior to ischemia (n=12, each), infarct size (IS, triphenyltetrazolium), the area of no-reflow (ANR, thioflavin S) (% of the risk area, RA, blue dye), and regional myocardial blood flow (RMBF, radioactive microspheres) were measured after 30 min of coronary occlusion and 180 min of reperfusion. Left ventricular hemodynamics and dimensions (echocardiography) were determined in a separate series of animals (n=5, each).. Sildenafil significantly lowered arterial blood pressure before occlusion (-17 to -19 mmHg over 30 min), but during ischemia and reperfusion hemodynamics were comparable to controls. IS in treated animals (51+/-4%) did not significantly differ from control animals (47+/-4%). No major arrhythmias or lengthening of QT/QTc occurred. While sildenafil slightly increased RMBF and significantly reduced specific vascular resistance in the RA during reperfusion (51+/-7 versus 73+/-10 mmHg g min/ml, P<0.05), the ANR (46+/-3%) was similar to control animals (44+/-4%). Sildenafil reduced left ventricular dP/dt(max) (P<0.05) and dP/dt(min) (P<0.01) in non-ischemic conditions, and slightly during ischemia, along with a pronounced decrease in ischemic left ventricular end-diastolic pressure (9+/-2 versus 15+/-2 mmHg after saline, P<0.05), but did not attenuate acute ischemic left ventricular dilation.. Sildenafil reduced cardiac pre- and afterload, and parameters of left ventricular contractility. Myocardial necrosis and microvascular dysfunction were neither exacerbated nor attenuated.

Topics: Animals; Blood Pressure; Coronary Circulation; Echocardiography; Hypertrophy, Left Ventricular; Male; Microcirculation; Models, Animal; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Necrosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Vascular Resistance