sildenafil-citrate and Ischemia

Ischemic priapism is a rare occurrence which can cause severe erectile dysfunction (ED) without timely treatment. This retrospective study reports our experience in treating prolonged ischemic priapism and proposes our further considerations. In this paper, a total of nine patients with prolonged ischemic priapism underwent one to three types of surgical shunts, including nine Winter shunts, two Al-Ghorab shunts and one Grayhack shunt. During the follow-up visit (after a mean of 21.11 months), all patients' postoperative characters were recorded, except one patient lost for death. Six postoperative patients accepted a 25-mg oral administration of sildenafil citrate. The erectile function of the patients was evaluated by their postoperative 5-item version of International Index of Erectile Function Questionnaire (IIEF-5), which were later compared with their premorbid scores. All patients had complete resolutions, and none relapsed. The resolution rate was 100%. Seven patients were resolved with Winter shunts, one with an Al-Ghorab shunt and one with a Grayhack shunt. The mean hospital stay was 8.22 days. There was only one urethral fistula, and the incidence of postoperative ED was 66.67%. Four patients with more than a 72-h duration of priapism had no response to the long-term phosphodiesterase type 5 (PDE-5) inhibitor treatment. These results suggest that surgical shunts are an efficient approach to make the penis flaccid after prolonged priapism. However, the severe ED caused by prolonged duration is irreversible, and long-term PDE-5 inhibitor treatments are ineffective. Thus, we recommend early penile prosthesis surgeries for these patients.

Topics: Adult; Aged; Erectile Dysfunction; Humans; Ischemia; Male; Middle Aged; Penile Prosthesis; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Sildenafil Citrate; Sulfones; Ultrasonography; Vascular Surgical Procedures

To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).. Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).. Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).. The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.. NCT01295736.

Topics: Adult; Double-Blind Method; Female; Fingers; Humans; Intention to Treat Analysis; Ischemia; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Time Factors; Treatment Outcome; Vasodilator Agents

Successful preventive therapy for ischemic priapism, a disorder of penile erection with major physical and psychologic consequences, is limited. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of sildenafil by a systematic dosing protocol to prevent recurrent ischemic priapism associated with sickle cell disease.. Thirteen patients with sickle cell disease reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily, unassociated with sleep or sexual activity, for 8 weeks, followed by open-label use of this sildenafil regimen for an additional 8 weeks.. Priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per protocol analyses (P = 1.0). However, during open-label assessment, 5 of 8 patients (62.5%) by intention-to-treat analysis and 2 of 3 patients (66.7%) by per protocol analysis met this primary efficacy outcome. No significant differences were found between study groups in rates of adverse effects, although major priapism episodes were decreased 4-fold in patients monitored "on-treatment.". Sildenafil use by systematic dosing may offer a strategy to prevent recurrent ischemic priapism in patients with sickle cell disease.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Double-Blind Method; Humans; Ischemia; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Prospective Studies; Purines; Recurrence; Sildenafil Citrate; Sulfones; Young Adult

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD).. In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil.. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD.. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD.. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.

Topics: Adolescent; Carbolines; Child; Exercise; Forearm; Humans; Ischemia; Male; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Spectroscopy, Near-Infrared; Sulfones; Sympathetic Nervous System; Tadalafil; Ultrasonography; Vasoconstriction

Endothelial dysfunction of precapillary arterioles impairs nutritional microcirculation at rest as well as during post-ischemic reactive hyperemia. In this monocentric, prospective, double-blind, placebo-controlled, randomized cross-over study we investigated the acute effect of 50 mg sildenafil, a selective PDE-5 inhibitor, on resting and post-ischemic capillary circulation in twenty patients with angiographically confirmed coronary artery disease not taking nitrates or NO-donors. Mean erythrocyte velocity in digital nail-fold capillaries was determined before and after sildenafil and placebo, both baseline and after a three-minutes supra-systolic occlusion of the upper arm. Primary efficacy parameter was the drug effect on peak velocity during reactive hyperemia (peak velocity: V(max)). Post ischemic maximal capillary erythrocyte velocity V(max) significantly increased by 47% one hour after 50 mg sildenafil (mean value+/-standard deviation: 0.85+/-0.42 mm/s vs. 0.58+/-0.18 mm/s at baseline, p=0.0023), whereas placebo had no effect (p=0.5248). The difference between sildenafil and placebo was significant (p=0.0129) and sildenafil's effect can be regarded as biometrically highly relevant with standardized difference according to Cohen of 0.81. In spite a small decrease of both systolic and diastolic blood pressure after sildenafil, sildenafil significantly increased capillary erythrocyte velocity at rest.. A single oral dose of sildenafil significantly increased resting and post-ischemic cutaneous capillary circulation in patients with coronary artery disease. Future studies should assess whether sildenafil also improves nutritional capillary blood flow in other organs and in other diseases with impaired endothelial function and microcirculation, for example in diabetic microangiopathy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Aged; Blood Flow Velocity; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Humans; Ischemia; Male; Microcirculation; Microscopy, Video; Middle Aged; Piperazines; Placebos; Purines; Sildenafil Citrate; Skin; Sulfones

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

Hypoxia and inflammation play a major role in revascularization following ischemia. Sildenafil inhibits phosphodiesterase-5, increases intracellular cGMP and induces revascularization through a pathway which remains incompletely understood. Thus, we investigated the effect of sildenafil on post-ischemic revascularization. The left femoral artery was ligated in control and sildenafil-treated (25 mg/kg per day) rats. Vascular density was evaluated and expressed as the left/right leg (L/R) ratio. In control rats, L/R ratio was 33 ± 2% and 54 ± 9%, at 7- and 21-days post-ligation, respectively, and was significantly increased in sildenafil-treated rats to 47 ± 4% and 128 ± 11%, respectively. A neutralizing anti-VEGF antibody significantly decreased vascular density (by 0.48-fold) in control without effect in sildenafil-treated animals. Blood flow and arteriolar density followed the same pattern. In the ischemic leg, HIF-1α and VEGF expression levels increased in control, but not in sildenafil-treated rats, suggesting that sildenafil did not induce angiogenesis. PI3-kinase, Akt and eNOS increased after 7 days, with down-regulation after 21 days. Sildenafil induced outward remodeling or arteriogenesis in mesenteric resistance arteries in association with eNOS protein activation. We conclude that sildenafil treatment increased tissue blood flow and arteriogenesis independently of VEGF, but in association with PI3-kinase, Akt and eNOS activation.

Topics: Animals; Hindlimb; Ischemia; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Sildenafil Citrate; Vascular Endothelial Growth Factor A

There is a lack of effective therapeutic interventions for preeclampsia. A central factor in the etiology of the disease is the development of placental hypoxia due to abnormal vascular remodeling. However, methods to assess the impact of potential therapies on placental growth and remodeling are currently lacking. Here, we develop and validate ultrasound-guided photoacoustic imaging methods to monitor the placental response to therapeutic intervention. Establishing non-invasive tools to image placental function opens up previously unachievable understandings of placental therapeutic response.. Studies were performed in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. Preclinical research has identified tempol, a superoxide dismutase mimetic, and the phosphodiesterase inhibitor sildenafil as potential therapeutics for preeclampsia, as both improve in vivo maternal outcomes. PA images of the placental environment were acquired in RUPP rats receiving tempol (n = 8) or sildenafil (n = 8) to assess the longitudinal effects of treatment on placental oxygenation and vascular remodeling. Imaging measurements were validated with ex vivo histological analysis.. Spectral photoacoustic imaging non-invasively measured placental hypoxia and impaired vascular growth two days after the RUPP procedure was implemented. Sildenafil significantly improved (p < 0.05) placental oxygenation and promoted vascular remodeling in RUPP animals, while RUPP animals treated with tempol had a diminished placental therapeutic response.. We demonstrate that photoacoustic imaging provides in vivo measures of placental oxygenation and vascular remodeling, a previously unobtainable assessment of preeclamptic therapeutic response. These imaging tools have tremendous potential to accelerate the search for effective therapies for preeclampsia.

Topics: Animals; Disease Models, Animal; Female; Humans; Hypoxia; Ischemia; Photoacoustic Techniques; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling

Acute mesenteric ischemia (AMI) is a condition that results from a sudden decline in blood flow through the mesenteric vessels that has a high morbidity and mortality. Non-occlusive AMI often presents in critically ill, hypotensive patients that suffer from decreased organ perfusion. Here we describe a case of non-occlusive acute mesenteric ischemia in the setting of transient hypotension precipitated by sildenafil. The patient required rapid fluid resuscitation in the emergency department. He did not require surgical intervention and was able to be discharged home with resolution of symptoms after a 7-day inpatient stay.

Topics: Emergency Service, Hospital; Humans; Ischemia; Male; Mesenteric Ischemia; Mesenteric Vascular Occlusion; Sildenafil Citrate

Posttraumatic osteonecrosis of the femoral head (ONFH) affects patients at different ages and may lead to functional limitation and joint replacement, with total hip arthroplasty, which is a costly procedure. Proposed methods to optimize ischemic tissue regeneration have been reported. Phosphodiesterase-5 inhibitors act by inhibiting the degradation of guanosine 3',5'-cyclic monophosphate in the nitric oxide pathway, increasing its bioavailability and promoting vascular endothelial growth factor (VEGF)-mediated neovascular recruitment and the induction of tissue regeneration in the traumatized bone. Thirty male Sprague-Dawley rats (6 months old) were subjected to an experimental model of traumatic ONFH divided into two groups, according to the administration of 5 mg/kg sildenafil or water (control group). Rats were then killed at 7, 14, and 21 days. Histological (Goldner's trichrome), histochemical (periodic acid-Schiff [PAS]), and immunohistochemical (VEGF and osteopontin [OPN]) techniques were used to quantify bone and vascular responses. Higher levels of VEGF (p < 0.01) and OPN (p < 0.01) immunostaining in the epiphysis, the greater formation of osteoid tissue (p < 0.01 on Day 7; p < 0.05 on Day 14), and higher levels of PAS staining (p < 0.01 on Day 7) were observed in the sildenafil-treated group. The present study demonstrated that sildenafil optimized bone tissue regeneration by increasing VEGF signaling and OPN expression, with increased bone formation (osteoid and carbohydrate macromolecule deposition) in the early stages following traumatic ischemic insult. Thus, sildenafil treatment may improve the prognosis of patients with osteonecrosis.

Topics: Animals; Bone Regeneration; Cyclic Nucleotide Phosphodiesterases, Type 5; Femur Head; Femur Head Necrosis; Humans; Ischemia; Male; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Endothelial Growth Factor A

Smoking aggravates skin necrosis as a complication of random-pattern flap ischaemia. Sildenafil and nitroglycerin (NTG) are vasodilator agents that may affect skin flap survival. Fifty rats were subjected to a dorsal random-pattern flap operation and randomly divided into 5 groups. The control group received no treatment. The ischaemic group were administered local nicotine injections. The sildenafil group were administered oral sildenafil treatment in addition to the same intervention as the ischaemic group. The NTG group received topical NTG ointment application instead of sildenafil. The combined group were given both sildenafil and NTG treatments. After 7 days, all rats were sacrificed for flap assessment. Flap survival percentages at the 3

Topics: Animals; Apoptosis; Cell Proliferation; Drug Design; Ischemia; Male; Microscopy, Electron, Transmission; Nicotine; Nitroglycerin; Ointments; Random Allocation; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Skin; Skin Transplantation; Surgical Flaps; Vasodilator Agents

Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has endothelium protective and angiogenic effects.. To test if sildenafil improves tissue perfusion and neovascularization and downregulates proinflammatory molecules following limb ischemia.. 30 ApoE-/- male mice, bred with cholesterol rich diet for 4 weeks, were anesthetized and underwent unilateral hind-limb ischemia with ligation of the left femoral artery. Mice were randomized in 2 groups: sildenafil (1 mg/Kg for 7 days intraperitoneally, i.p.) or normal saline (0.4 ml for 7 days, i.p.). Bilateral hind-limb perfusion was estimated by laser Doppler imaging after surgery on days 0, 7 and 28.. Sildenafil significantly reduced at day 28 compared with day 0 levels of soluble intracellular adhesion molecule-1(sICAM-1) [2.24(1.81-2.41) vs. 1.29(0.87-1.45) ng/ml, p=0,01], soluble E-selectin (sE-Selectin) [5.52 (3.67-6.14) vs 1.71 (1.42-2.86) ng/ml, p=0.02] and tissue plasminogen activator inhibitor- 1 (tPAI-1) [0.13(0.07-0.21) vs 0.08 (0.04-0.10) ng/ml, p=0.01] while normal saline had no effect on the levels of sICAM-1, sE-Selectin and tPAI-1. Treatment with sildenafil was associated with increased perfusion in the ischemic limb compared with controls.. Sildenafil exerts significant beneficial effects on tissue perfusion and inflammatory status after limb ischemia, a finding implying neovascularization and potential vascular protective properties of sildenafil.

Topics: Angiogenesis Inducing Agents; Animals; Anti-Inflammatory Agents; Atherosclerosis; Blood Flow Velocity; Disease Models, Animal; E-Selectin; Hindlimb; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Ischemia; Male; Mice, Knockout, ApoE; Muscle, Skeletal; Neovascularization, Physiologic; Plasminogen Activator Inhibitor 1; Regional Blood Flow; Sildenafil Citrate; Time Factors

Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment.

Topics: Antirheumatic Agents; Cardiomyopathies; Fingers; Humans; Ischemia; Male; Middle Aged; Myocardium; Raynaud Disease; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Substance Withdrawal Syndrome; Time Factors

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

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

Phosphodiesterase-5 is an enzyme that inactivates cyclic guanosine monophosphate and regulates the balance of nitric oxide (NO). NO is an important molecule synthesized during wound repair. An in vivo study was conducted to evaluate the effect of sildenafil, known to have a role in regulating the effect of NO in perfusion, on the wound healing process under ischemic conditions in rats. Reepithelialization, neovascularization, inflammatory cells, and amount and maturation of granulation tissue were scored on a scale of 0-3 (none, partial, complete but immature/thin, complete and mature, respectively). Data were analyzed using ANOVA one-way test, with statistical significance determined at P < 0.05. Forty-two (42) Sprague-Dawley rats were anesthetized, wounded with H-shaped flaps, and randomized into 2 groups: 1 group received 10 mg/kg sildenafil (dissolved in 1 mL distilled water) orally via orogastric tubes and the other group received a 0.9% NaCl solution via intraperitoneal injection (0.1 mL). On days 3, 5, and 10, 7 rats from each group were sacrificed. Blinded investigators analyzed skin samples for the wound healing evaluating criteria using from hematoxylin/eosin staining under an optical microscope at 10X and 40X magnification. Histopathological analysis showed sildenafil significantly reduced reepithelialization, neovascularization, amount of granulation tissue, and number of inflammatory cells on day 3 and increased inflammatory cells on day 10 (P < 0.05). Further research is needed to clarify the potential role of oral or topically applied different doses of sildenafil for ischemic wound healing as well to evaluate its safety and efficacy when administered alone or in combination with other therapies.

Topics: Animals; Ischemia; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Wound Healing

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

Preeclampsia is a complication of pregnancy that is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of placental hypoxia/ischemia, which releases pathogenic soluble factors. There is currently no effective treatment for preeclampsia, but the phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been suggested, as PDE-5 is enriched in the uterus, and its antagonism could improve uteroplacental function. Here, we report in the reduced uterine perfusion pressure (RUPP) rat model that administration of oral sildenafil is effective in attenuating placental ischemia-induced hypertension during gestation. RUPP animals have significantly elevated arterial pressure compared with control animals (132 ± 3 vs. 100 ± 2 mmHg; P < 0.05). Administration of oral sildenafil (45 mg·kg⁻¹·day⁻¹) had no effect on blood pressure in control rats but decreased pressure in RUPP rats (115 ± 1 mmHg; P < 0.05). RUPP induced changes in placental sFlt-1, and vascular endothelial growth factor (VEGF) was unaffected by sildenafil administration, as was the decrease in free plasma VEGF. RUPP animals had a significant increase in medullary PDE-5/β-actin ratio (1 ± 0.14 vs. 1.63 ± 0.18; P < 0.05) expression with a resulting reduction in renal medullary cGMP (1.5 ± 0.15 vs. 0.99 ± 0.1 pmol/μg protein, P < 0.05) compared with controls. Although sildenafil had no effect on renal medullary cGMP in control animals, it significantly increased cGMP in RUPP animals (1.3 ± 0.1 pmol/μg protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.

Topics: Actins; Administration, Oral; Animals; Antihypertensive Agents; Arterial Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Ischemia; Kidney Medulla; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vasodilator Agents

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

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 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

Topics: Anastomosis, Surgical; Animals; Colon; Intestinal Mucosa; Ischemia; Nitric Oxide; Oxidative Stress; Piperazines; Purines; Rats; Sildenafil Citrate; Sulfones; Vasodilator Agents; Wound Healing

Sildenafil may lead an improvement in anastomotic healing of ischemic left colon anastomosis.. Thirty-six male Wistar albino rats were randomized into four experimental groups (n=9 in each group). In group 1, a well-perfused left colonic segment was transected, and free ends were anatomosed. In groups 2, 3 and 4 animals underwent a standardized surgical procedure to induce ischemic left colon anastomosis. Group 2 animals received only tap water. In groups 3 and 4 animals received 10mg/kg/body-weight and 20mg/kg/body-weight sildenafil, single dose a day during 4 days, respectively. Rats were sacrificed on day 4 following operation. Anastomotic integrity, intra-peritoneal adhesion scores, anastomotic bursting pressures and tissue hydroxyproline levels were recorded. Histopathological examination of the anastomosis was also performed.. There was no statistically significant difference among groups with respect to anastomotic integrity (p=0.142) but ischemia decreased the anastomotic bursting pressure. The mean bursting pressure values were 78.8+/-24.1, 43.3+/-26, 55.1+/-32.4, and 43.3+/-20.4 in groups 1, 2, 3, and 4, respectively. Group 1 had the highest values whereas; there was no statistically significant difference between groups 1 and 3. There was no statistically significant difference among groups 2, 3, and 4 with respect to tissue hydroxyproline levels, adhesion scores and the Chiu scores. The highest inflammatory cell presence in the granulation tissue was detected in group 2, whereas the lowest was detected in group 4 (p=0.0001). The highest fibroblast infiltration in the granulation tissue was detected in group 1 (p=0.045).. Our results showed that 10mg/kg sildenafil decreased the adverse effects of ischemia on the healing of ischemic left colon anastomosis. Additional investigations are needed to confirm the effects of phosphodiesterase-5 inhibitors in ischemic colon anastomosis models.

Topics: Anastomosis, Surgical; Animals; Colon; Ischemia; Male; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Suture Techniques; Tissue Adhesions; Vasodilator Agents; Wound Healing

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions. Apolipoprotein E-deficient (ApoE(-/-)) mice were treated (or not treated) with sildenafil (40 mg/kg per day in water), and hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to an improved blood flow recovery, an increased capillary density, and a reduction of oxidative stress levels in ischemic muscles at day 7 after surgery. Sildenafil therapy is associated with an increased activation of angiogenic transduction pathways, including Akt, p44/42 mitogen-activated protein kinase, and p38. In vitro, sildenafil increases cellular migration and tubule formation of mature endothelial cells (human umbilical vascular endothelial cells) in a cGMP-dependent manner. In vivo, ApoE(-/-) mice treated with sildenafil exhibit a significant increase in the number of bone marrow-derived EPCs. Moreover, the angiogenic activities of EPCs (migration and adhesion) are significantly improved in ApoE(-/-) mice treated with sildenafil. In summary, this study demonstrates that sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic ApoE(-/-) mice. The mechanisms involve beneficial effects on angiogenic transduction pathways together with an increase in the number and the functional activity of EPCs. Sildenafil could constitute a novel therapeutic strategy to reduce tissue ischemia in atherosclerotic diseases.

Topics: Analysis of Variance; Animals; Apolipoproteins E; Blotting, Western; C-Reactive Protein; Cell Movement; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Hindlimb; Hypercholesterolemia; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Piperazines; Probability; Purines; Random Allocation; Sildenafil Citrate; Stem Cells; Sulfones

Topics: Amputation, Surgical; Female; Fingers; Hand Dermatoses; Humans; Ischemia; Microcirculation; Middle Aged; Piperazines; Postoperative Complications; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Vasodilator Agents

The purpose of this study was to examine the effects of sildenafil citrate on normal and ischemic colon anastomosis in the rat model by measuring the levels of blood and colonic tissues nitric oxide, thiobarbituric acid reactive substrates (as a marker of lipid peroxidation), and glutathione (as an antioxidant).. Normal (group 1 and 3) and ischemic anastomosis (group 2 and 4) were performed in four equal rat groups (n = 14). Orally 10 mg/kg per day of sildenafil citrate therapy were applied in group 3 and group 4 after operation. Seven rats of the each group were killed on postoperative days 3 and 7.. Sildenafil citrate therapy was resulted in elevated nitric oxide levels in both normal and ischemic anastomotic tissues (p < 0.0001 and p < 0.03) at postoperative day 3. Tissue thiobarbituric acid reactive substrate levels were elevated in rats with normal anastomosis by sildenafil therapy (p < 0.001) at postoperative days 3 and 7 (p < 0.05). Sildenafil therapy given to the normal anastomosis group has significantly higher tissue nitric oxide levels than the normal anastomosis group without therapy at postoperative day 7 (p < 0.001). On postoperative day 7, plasma nitric oxide levels were decreased by sildenafil citrate in rats with normal (p < 0.01) and ischemic anastomosis (p < 0.05). The beneficial effect of sildenafil citrate also was seen for erythrocyte glutathione levels in rats with normal anastomosis at postoperative day 7 and in rats with ischemic anastomosis at postoperative day 3.. Our results suggest that sildenafil citrate may affect ischemic anastomotic healing due to its possible effects on nitric oxide metabolism and lipid peroxidation. However, functional implication of this agent further needs to be elucidated.

Topics: Anastomosis, Surgical; Animals; Biomarkers; Colon; Glutathione; Ischemia; Male; Nitric Oxide; Oxidative Stress; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Statistics, Nonparametric; Sulfones; Thiobarbituric Acid Reactive Substances; Wound Healing

Since the launch in 1998 of the anti-impotence drug sildenafil (viagra), the American food and drug administration has identified 50 cases of drug-related blindness, the so-called nonarteritic anterior ischemic optic neuropathy. This, very serious, side effect frequently leads to sudden, mostly irreversible loss of vision, and there is no proven effective treatment to cure patients or to prevent recurrence. The mechanism of ischemic optic neuropathy is not clear, but it could be related to the fact that the ophthalmic and central retinal arteries have an autoregulation of their own blood flow without any autonomic nerve supply; vasoreactivity could be lower albeit efficient, and therefore more vulnerable to systemic modifications of the circulation. But decreased visual acuity and loss of visual ability also are, although uncommon, anesthesiological and surgical complications. These data are consistent with the hypothesis that sildenafil, surgery and anesthesia, taken together, could be a potentially dangerous cocktail of risk factors for sudden irreversible loss of vision. To reduce the risk, sildenafil use should be avoided at least one week before surgical operations, since the reported cases of blindness developed 36h after drug ingestion.

Topics: Anesthesia; Blindness; Carbon Dioxide; Humans; Hypertension; Ischemia; Male; Optic Nerve; Optic Nerve Diseases; Optic Neuropathy, Ischemic; Piperazines; Postoperative Complications; Purines; Risk; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate in an experimental model the effects of the PDE5 inhibitor sildenafil on kidney grafts autotransplanted after a period of 45 minutes of warm ischemia and 60 minutes of hypothermic pump perfusion.. Nine laboratory large-white pigs were divided into two groups. Group A (n = 4): oral dose of 100 mg sildenafil was administered 1 hour before the surgery. Group B (n = 5): no sildenafil given. Right single nephrectomy was completed after a 45-minute period of warm ischemia by complete vascular clamping. Before the autotransplant, all kidneys were submitted to a 60-minute period of hypothermic pulsatile perfusion. Renal flow, arterial pressure, and renal vascular resistance were recorded in real time for 60 minutes after autotransplant. Nitric oxide levels were determined in blood samples of the renal vein at predefined intervals. Optical and electronic microscopy was performed on all organs at the end of the procedure.. Renal vascular flow was significantly higher and renal vascular resistance significantly lower in the sildenafil group compared with the non-sildenafil group. No significant differences were observed in systemic arterial pressure values between both groups. Nitric oxide levels were significantly higher for all periods in the sildenafil group. No differences were observed in histological studies.. Our experimental work suggested a positive effect of sildenafil on the immediate posttransplant outcome of warm-ischemic kidneys without systemic secondary effects.

Topics: Animals; Ischemia; Kidney Transplantation; Models, Animal; Piperazines; Postoperative Period; Purines; Renal Circulation; Sildenafil Citrate; Sulfones; Swine; Vasodilator Agents

Peripheral artery disease (PAD) is a prevalent cardiovascular disorder that results in tissue ischemia which can progress to critical limb ischemia. Restoration of tissue perfusion in the setting of chronic ischemia through stimulation of arteriogenesis and angiogenesis remains a key therapeutic target for PAD. However, experimental therapeutics, including growth factor and gene therapy, have had little clinical success indicating the need for a better understanding of molecular pathways required for therapeutic angiogenesis.. Here we report that phosphodiesterase-5 inhibition by sildenafil significantly increases vascular perfusion, tissue blood flow, and vascular density during chronic ischemia of the mouse hind limb. Importantly, sildenafil therapy did not alter any of these parameters in nonischemic limbs. Sildenafil increased tissue cGMP levels independently of increases in nitric oxide production, and sildenafil therapy stimulated angiogenesis in ischemic limbs of eNOS-/- and iNOS-/- mice. Lastly, sildenafil-mediated angiogenic activity was blocked by inhibition of protein kinase G using the PKG antagonist DT-3.. These data demonstrate that sildenafil therapy results in increased angiogenic activity through a PKG-dependent pathway that is independent of nitric oxide production or NOS activity and identify the angiogenic therapeutic potential of sildenafil for critical limb ischemia.

Topics: Animals; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Hindlimb; Ischemia; Male; Mice; Neovascularization, Physiologic; Peripheral Vascular Diseases; Phosphodiesterase Inhibitors; Piperazines; Purines; Regional Blood Flow; Signal Transduction; Sildenafil Citrate; Sulfones

Rats fed with ethanol and a nutritious diet intragastrically develop liver pathologic changes associated with cyclic elevation of blood and urinary ethanol levels (BAL and UAL cycle). At the peaks of the UAL cycle, the livers are hypoxic. When the liver portal hepatic blood flow is temporarily clamped for 2 min and then released, the livers at the peak UAL fail to recover completely compared to the control livers and the livers at the UAL cycle troughs. Viagra was fed to the ethanol-fed rats to enhance the effects of nitric oxide. Since nitric oxide is known to increase hepatic blood flow, it was anticipated that Viagra would prevent the liver hypoxia at the UAL cycle peaks and also improve the post-clamp recovery from the post-clamp ischemia challenge. Viagra tended to improve the post-clamp recovery of the liver surface pO2 levels of the ethanol-fed rats probably by slowing O2 consumption as result of NO inhibition of mitochondrial cytochrome c oxidase activity. However, Viagra increased the pathology score when fed with ethanol. For this reason, Viagra is a two-edged sword. On the one hand, it tended to be protective in the post-ischemic injury in the ethanol-fed rats and on the other hand, it enhanced the liver injury caused by ethanol. Viagra did not affect the UAL cycle.

Topics: Animals; Ethanol; Ischemia; Liver; Liver Diseases, Alcoholic; Male; Nitric Oxide; Oxygen; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Aged; Female; Fingers; Humans; Hypertension, Pulmonary; Ischemia; Phosphodiesterase Inhibitors; Piperazines; Purines; Raynaud Disease; Sildenafil Citrate; Sulfones; Toes

We studied the effect of chronic ischemia on prostatic smooth muscle contraction in the rabbit.. New Zealand male rabbits weighing 3 to 3.5 kg were assigned to 2 groups. Group 1 (10 rabbits) underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet for 4 weeks and then a regular diet for 8 weeks. Control group 2 (10 rabbits) received a regular diet. After 12 weeks the animals were anesthetized. Iliac artery and prostate blood flow was recorded. Prostate tissues were prepared for isometric tension measurement, enzyme immunoassay to determine cyclic guanosine monophosphate (cGMP) release and histological examination.. In group 1 atherosclerosis as well as a significant decrease in iliac artery and prostate blood flow were observed. Ischemia significantly increased prostatic tissue contraction, decreased cGMP release and led to capsular and stromal thickening, and epithelial atrophy. The alpha1-adrenoceptor blocker doxazosin and the phosphodiesterase-5 inhibitor sildenafil citrate significantly decreased the contraction of control and ischemic tissues. Doxazosin was more effective in decreasing contractions when it was combined with sildenafil or the nitric oxide (NO) precursor L-arginine. In contrast, doxazosin was less effective when it was combined with the NO synthase inhibitor N omega-nitro-L-arginine or with the guanylate cyclase inhibitor methylene blue. Doxazosin significantly increased cGMP release in control tissues but not in ischemic tissues. Sildenafil significantly increased cGMP release in control and ischemic tissues.. Ischemia increased prostatic smooth muscle contraction and led to marked structural damage. Stimulators of NO synthesis and cGMP production enhanced the efficacy of doxazosin in decreasing prostatic tissue contraction. Sildenafil decreased contractility and increased cGMP release. Increased smooth muscle tone and structural changes in the ischemic prostate may suggest a role for prostate ischemia in resistance to urinary flow independent of prostate size.

Topics: Adrenergic alpha-Antagonists; Animals; Arginine; Arteriosclerosis; Blood Flow Velocity; Cyclic GMP; Doxazosin; Electric Stimulation; Iliac Artery; In Vitro Techniques; Ischemia; Laser-Doppler Flowmetry; Male; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prostate; Purines; Rabbits; Sildenafil Citrate; Sulfones