sildenafil-citrate and Acute-Disease

After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Calcium Channel Blockers; Carbonic Anhydrase Inhibitors; Cytokines; Dexamethasone; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Nifedipine; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Sildenafil Citrate

Pharmacologic strategies to reduce pulmonary vascular tone and to treat pulmonary hypertension originally aimed to enrich vascular smooth muscle cyclic adenosine monophosphate levels. Alternatively, increasing cyclic guanosine monophosphate (cGMP) also reduces pulmonary vascular tone. Inhaled nitric oxide is extremely efficacious in increasing cGMP and selectively reducing mean pulmonary arterial pressure in pediatric cardiac patients. It is considered standard treatment in most centers. However, not all patients respond to inhaled nitric oxide and withdrawal is sometimes problematic. This has prompted investigation of alternative methods to increase intracellular vascular smooth muscle cGMP. Phosphodiesterase type 5 is particularly abundant in the lung vasculature of patients with severe pulmonary hypertension. Its inhibition with the sildenafil class of drugs is now commonplace. Drugs that affect cGMP metabolism in children with acute pulmonary hypertension are the subject of this review and consensus statement. Oral sildenafil is recommended in postoperative pulmonary hypertension after failed withdrawal of inhaled NO (class I, level of evidence B). The effectiveness of prolonged treatment with sildenafil in documented postoperative pulmonary hypertension is not well established (class IIb, level of evidence C). Sildenafil is indicated in idiopathic pulmonary hypertension, although data have been extrapolated mainly from adult trial (class I, level of evidence A, extrapolated). Recently, completed pediatric trials have seemed to support this recommendation. Longer-acting and intravenous forms of phosphodiesterase type 5 inhibitors, brain natriuretic peptides, and direct soluble guanylate cyclise activators all have appeal, but there is insufficient experience in children with acute pulmonary hypertensive disorders for recommendations on treatment.

Topics: Acute Disease; Administration, Inhalation; Administration, Oral; Child; Child, Preschool; Clinical Trials as Topic; Cyclic GMP; Endothelium-Dependent Relaxing Factors; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Antioxidants; Bolivia; Expeditions; Fatigue; Female; Headache; Humans; Male; Mountaineering; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sleep Wake Disorders; Sulfones; Surveys and Questionnaires; Syndrome; Tanzania; Vasodilator Agents; Visual Analog Scale; Young Adult

Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome measure.. Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria.. Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality.. In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures.

Topics: Acute Disease; Adult; Aged; Clinical Trials as Topic; Disease Progression; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Reproducibility of Results; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Treatment Outcome

We sought to determine the influence of sildenafil on the diffusing capacity of the lungs for carbon monoxide (DLCO) and the components of DLCO (pulmonary capillary blood volume VC, and alveolar-capillary membrane conductance DM) at rest and following exercise with normoxia and hypoxia. This double-blind placebo-controlled, cross-over study included 14 healthy subjects (age = 33 +/- 11 years, ht = 181 +/- 8 cm, weight = 85 +/- 14 kg, BMI = 26 +/- 3 kg/m2, peak normoxic VO2 = 36 +/- 6 ml/kg, mean +/- SD). Subjects were randomized to placebo or 100 mg sildenafil 1 h prior to entering a hypoxic tent with an FiO2 of 12.5% for 90 min. DLCO, VC, and DM were assessed at rest, every 3 min during exercise, at peak exercise, and 10 and 30 min post exercise. Sildenafil attenuated the elevation in PAP at rest and during recovery with exposure to hypoxia, but pulmonary arterial pressure immediately post exercise was not different between sildenafil and placebo. Systemic 02 saturation and VO2peak did not differ between the two conditions. DLCO was not different between groups at any time point. VC was higher with exercise in the placebo group, and the difference in DM between sildenafil and placebo was significant only when corrected for changes in VC (DM/VC = 0.57 +/- 0.29 vs. 0.41 +/- 0.16, P = 0.04). These results suggest no effect of sildenafil on DLCO, but an improvement in DM when corrected for changes in VC during short-term hypoxic exposure with exercise.

Topics: Acute Disease; Adult; Capillaries; Cross-Over Studies; Cyclic GMP; Double-Blind Method; Endothelin-1; Exercise; Female; Heart Rate; Humans; Hypoxia; Male; Natriuretic Peptide, Brain; Oxygen; Piperazines; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Gas Exchange; Purines; Rest; Sildenafil Citrate; Stroke Volume; Sulfones; Vasodilator Agents

We examined the effects of the 5-phosphodiesterase (5-PDE) inhibitor sildenafil on pulmonary arterial pressure and some oxygen transport and cardiopulmonary parameters in humans during exposure to hypobaric hypoxia at rest and after exercise. In a double-blind study, 100 mg sildenafil or placebo was administered orally to 14 healthy volunteers 45 min before exposure to 5,000 m of simulated altitude. Arterial oxygen saturation (SaO2), heart rate (HR), tidal volume (VT), respiratory rate (RR), left ventricular ejection fraction (EF), and pulmonary arterial pressure (PAP) were measured first at rest in normoxia, at rest and immediately after exercise during hypoxia, and after exercise in normoxia. The increase in systolic PAP produced by hypoxia was significantly decreased by sildenafil at rest from 40.9 +/- 2.6 to 34.9 +/- 3.0 mmHg (-14.8%; p = 0.0046); after exercise, from 49.0 +/- 3.9 to 42.9 +/- 2.6 mmHg (-12.6%; p = 0.003). No significant changes were found in normoxia either at rest or after exercise. Measurements of the effect of sildenafil on exercise capacity during hypoxia did not provide conclusive data: a slight increase in SaO2 was observed with exercise during hypoxia, and sildenafil did not cause significant changes in ventilatory parameters under any condition. Sildenafil diminishes the pulmonary hypertension induced by acute exposure to hypobaric hypoxia at rest and after exercise. Further studies are needed to determine the benefit from this treatment and to further understand the effects of sildenafil on exercise capacity at altitude.

Topics: Acute Disease; Adult; Altitude; Blood Pressure; Cardiac Output; Cross-Over Studies; Double-Blind Method; Exercise; Exercise Tolerance; Heart Rate; Hemodynamics; Humans; Hypoxia; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Reference Values; Sildenafil Citrate; Sulfones; Tidal Volume; Vasodilator Agents; Ventricular Function, Left

Endothelial dysfunction is a key early event in the process of atherosclerosis and a risk factor for cardiovascular events. Sildenafil, an effective oral treatment for patients with erectile dysfunction, inhibits cGMP degradation by specific type 5 phosphodiesterase (PDE) inhibition. Sildenafil has been shown to improve vascular function, however, the effect of type 5 PDE inhibition on acute smoking-induced endothelial dysfunction is unknown.. We studied the effect of 50 mg of sildenafil on acute smoking-induced endothelial dysfunction in 14 male smokers according to a randomized, placebo-controlled, cross-over design. Endothelial function was evaluated with flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasonography.. Sildenafil abolishes the decrease in FMD of the brachial artery that is induced acutely by smoking (placebo/smoking session: from 4.56% +/- 0.60% to 2.80% +/- 0.43%, sildenafil/smoking session: from 3.83% +/- 0.64% to 4.33% +/- 0.47%, ie, improvement of 51%, P < .05). This was associated with no reversal effect of sildenafil on smoking-induced decrease in resting brachial artery diameter and with a partial reversal of the smoking-induced decrease in hyperemic brachial artery diameter (placebo/smoking session: from 4.68 +/- 0.13 mm to 4.53 +/- 0.15 mm, sildenafil/smoking session: from 4.72 +/- 0.12 mm to 4.64 +/- 0.13 mm, ie, improvement of 1.5%, P < .005).. The present study shows, for the first time, that type 5 PDE inhibition with sildenafil abrogates the smoking-induced acute decrease in FMD of the brachial artery. These findings may have clinical implications given the detrimental consequences of smoking and the strategic role of normal endothelial function.

Topics: Acute Disease; Adult; Cross-Over Studies; Dilatation, Pathologic; Double-Blind Method; Endothelium, Vascular; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Smoking; Sulfones; Vascular Diseases; Vasodilation

The current study aimed to investigate the effects of sildenafil and N-acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (APT). We developed an APT model using healthy male China big-ear rabbits (2.7 ± 0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis-associated molecules, FoxO1, Bad and Bcl-2, in the lung tissue. Gelatine zymography was used to detect matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N-acetylcysteine potentiated the haemodynamic-improving effect of sildenafil and significantly inhibited the oxidative stress response. N-acetylcysteine combined with sildenafil decreased MMP-2 and MMP-9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP-1 and p-p38 MAPK. Thus, NAC potentiates the haemodynamic-improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP-1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT.

Topics: Acetylcysteine; Acute Disease; Animals; Apoptosis; Cell Count; Chemokine CCL2; Disease Models, Animal; Drug Synergism; Endothelial Cells; Hemodynamics; Lipid Peroxidation; Lung; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Neutrophils; Nitric Oxide; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Pulmonary Embolism; Rabbits; Sildenafil Citrate

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof.

Topics: Acute Disease; Administration, Inhalation; Bronchopulmonary Dysplasia; Cardiac Catheterization; Chronic Disease; Consensus; Constriction, Pathologic; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Lung Diseases; Nitric Oxide; Persistent Fetal Circulation Syndrome; Phosphodiesterase 5 Inhibitors; Pulmonary Veins; Sildenafil Citrate; Tomography, X-Ray Computed

Acute pulmonary hypertension (PH) complicates the course of several cardiovascular, pulmonary and other systemic diseases in children. An acute rise of RV afterload, either as exacerbating chronic PH of different aetiologies (eg, idiopathic pulmonary arterial hypertension (PAH), chronic lung or congenital heart disease), or pulmonary hypertensive crisis after corrective surgery for congenital heart disease, may lead to severe circulatory compromise. Only few clinical studies provide evidence on how to best treat children with acute severe PH and decompensated RV function, that is, acute RV failure. The specific treatment in the intensive care unit should be based on the underlying pathophysiology and not only be focused on so-called 'specific' or 'tailored' drug therapy to lower RV afterload. In addition therapeutic efforts should aim to optimise RV preload, and to achieve adequate myocardial perfusion, and cardiac output. Early recognition of patients at high risk and timely initiation of appropriate therapeutic measures may prevent the development of severe cardiac dysfunction and low cardiac output. In patients not responding adequately to pharmacotherapy, (1) novel surgical and interventional techniques, temporary mechanical circulatory support with extracorporeal membrane oxygenation, (2) pumpless lung assist devices (3) and/or lung or heart-lung transplantation should be timely considered. The invasive therapeutic measures can be applied in a bridge-to-recovery or bridge-to-lung transplant strategy. This consensus statement focuses on the management of acute severe PH in the paediatric intensive care unit and provides an according treatment algorithm for clinical practice.

Topics: Acute Disease; Administration, Inhalation; Administration, Intravenous; Adolescent; Cardiac Output; Child; Consensus; Critical Care; Disease Management; Disease Progression; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Intensive Care Units, Pediatric; Lung Transplantation; Nitric Oxide; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right

There are contradictory results about the effects of exercise and sildenafil on cognitive functions.. To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions.. Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6 weeks, 5 days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis.. Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage.

Topics: Acute Disease; Animals; Anxiety Disorders; Cognition; Disease Models, Animal; Exercise Therapy; Exploratory Behavior; Hippocampus; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Physical Conditioning, Animal; Psychotropic Drugs; Random Allocation; Rats, Wistar; Recognition, Psychology; Sildenafil Citrate; Stress, Psychological; Swimming; Treatment Outcome

Recent research suggests that priapism in sickle cell disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if subacute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the subacute setting.. The aim of this study was to investigate the effects of subacute hemolysis (3-month exposure) on priapism and NO pathway regulation.. Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild-type (WT) bone marrow. BM-SS mice were treated with sildenafil 100 mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernous nerve stimulation following bone marrow transplantation to assess for priapism.. ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, protein kinase G (PKG), PDE5, and ROS activities.. BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections per hour, P < 0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared with that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, P < 0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, P < 0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, P < 0.05) compared with non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, P < 0.05).. Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, because of restored NO balance with decreased ROS generation and increased PDE5 activity.

Topics: Acute Disease; Anemia, Sickle Cell; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Hemolysis; Male; Mice; Mice, Transgenic; Nitric Oxide Synthase; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Signal Transduction; Sildenafil Citrate

We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant, after a therapeutic course with sildenafil, a phosphodiesterase type 5 inhibitors (PDE5i). The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago. After 2 months of recurring chylothorax, a course of oral sildenafil was administered, with the hypothesis that pulmonary vascular resistances were increased. Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION. Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids, no visual recovery was noticed at 2-year follow-up. NAION has been associated with PDE5i therapy in adults, but to the best of our knowledge it is almost unheard of in children. We suggest close monitoring of visual function in children undergoing treatment with sildenafil.

Topics: Acute Disease; Blindness; Diagnosis, Differential; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Infant; Magnetic Resonance Imaging; Optic Neuropathy, Ischemic; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Visual Acuity

We investigated whether atorvastatin has beneficial hemodynamic effects during acute pulmonary thromboembolism (APT) and whether sildenafil improves these effects. We studied the involvement of oxidative stress, matrix metalloproteinases (MMPs), and neutrophil activation. APT was induced with autologous blood clots (500 mg/kg) in anesthetized male lambs pretreated with atorvastatin (10 mg/kg/day, subcutaneously; 1 week) or vehicle (dimethyl sulfoxide 10% subcutaneously). Sildenafil (0.7 mg/kg intravenously) or saline infusions were performed 60 min after APT induction. Non-embolized control animals received saline. APT significantly increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) by approximately 310% and 258% respectively. While atorvastatin pretreatment attenuated these increases (~150% and 153%, respectively; P < 0.05), its combination with sildenafil was associated with lower increases in PVRI and MPAP (~32% and 36%, respectively). Gelatin zymography showed increased MMP-9 and MMP-2 levels in the bronchoalveolar lavage, and increased MMP-9 levels in plasma from embolized animals. Atorvastatin pretreatment attenuated bronchoalveolar lavage MMP-2 increases. The combination of drugs blunted the MMPs increases in bronchoalveolar lavage and plasma (P < 0.05). Neutrophils accumulated in bronchoalveolar lavage after APT, and atorvastatin pretreatment combined with sildenafil (but not atorvastatin alone) attenuated this effect (P < 0.05). APT increased lung lipid peroxidation and total protein concentrations in bronchoalveolar lavage, thus indicating oxidative stress and alveolar-capillary barrier damage, respectively. Both increases were attenuated by atorvastatin pretreatment alone or combined with sildenafil (P < 0.05). We conclude that pretreatment with atorvastatin protects against the pulmonary hypertension associated with APT and that sildenafil improves this response. These findings may reflect antioxidant effects and inhibited neutrophils/MMPs activation.

Topics: Acute Disease; Animals; Atorvastatin; Bronchoalveolar Lavage; Drug Synergism; Enzyme Activation; Heart Ventricles; Hemodynamics; Heptanoic Acids; Lipid Peroxidation; Lung; Male; Matrix Metalloproteinases; Myocytes, Cardiac; Neutrophils; Oxidative Stress; Piperazines; Pulmonary Embolism; Purines; Pyrroles; Sildenafil Citrate; Sulfones

Topics: Acute Disease; Adult; Cardiac Output, Low; Catheterization; Critical Care; Electrocardiography; Female; Femoral Artery; Gastrectomy; Humans; Multiple Sclerosis; Peptic Ulcer Perforation; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Thrombolytic Therapy; Vasodilator Agents; Vena Cava Filters

To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the prevention and treatment of acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). These guidelines present the main prophylactic and therapeutic modalities for each disorder and provide recommendations for their roles in disease management. Recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches to the prevention and management of each disorder that incorporate these recommendations.

Topics: Acetazolamide; Acute Disease; Albuterol; Altitude Sickness; Brain Edema; Carbolines; Dexamethasone; Humans; Mountaineering; Nifedipine; Piperazines; Pulmonary Edema; Purines; Salmeterol Xinafoate; Sildenafil Citrate; Societies; Sulfones; Tadalafil; Wilderness Medicine

While endogenous nitric oxide (NO) may be relevant to the beneficial hemodynamic effects produced by sildenafil during acute pulmonary embolism (APE), huge amounts of inducible NO synthase (iNOS)-derived NO may contribute to lung injury. We hypothesized that iNOS inhibition with S-methylisothiourea could attenuate APE-induced increases in oxidative stress and pulmonary hypertension and, therefore, could improve the beneficial hemodynamic and antioxidant effects produced by sildenafil during APE. Hemodynamic evaluations were performed in non-embolized dogs treated with saline (n=4), S-methylisothiourea (0.01 mg/kg followed by 0.5 mg/kg/h, n=4), sildenafil (0.3 mg/kg, n=4), or S-methylisothiourea followed by sildenafil (n=4), and in dogs that received the same drugs and were embolized with silicon microspheres (n=8 for each group). Plasma nitrite/nitrate (NOx) and thiobarbituric acid reactive substances (TBARS) concentrations were determined by Griess and a fluorometric assay, respectively. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 25±1.7 mm Hg and by 941±34 dyn s cm(-5) m(-2), respectively. S-methylisothiourea neither attenuated APE-induced pulmonary hypertension, nor enhanced the beneficial hemodynamic effects produced by sildenafil after APE (>50% reduction in pulmonary vascular resistance). While sildenafil produced no change in plasma NOx concentrations, S-methylisothiourea alone or combined with sildenafil blunted APE-induced increases in NOx concentrations. Both drugs, either alone or combined, produced antioxidant effects. In conclusion, although iNOS-derived NO may play a key role in APE-induced oxidative stress, our results suggest that the iNOS inhibitor S-methylisothiourea neither attenuates APE-induced pulmonary hypertension, nor enhances the beneficial hemodynamic effects produced by sildenafil.

Topics: Acute Disease; Animals; Dogs; Female; Hemodynamics; Isothiuronium; Male; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Thiobarbituric Acid Reactive Substances

Inhibition of matrix metalloproteinases (MMPs) improves the hemodynamics during acute pulmonary embolism (APE) and oxidative stress upregulates MMPs. We compared the effects of different NO-cGMP pathway activators on APE-induced increases in MMPs.. Hemodynamic and biochemical evaluations were performed in non-embolized dogs treated with saline (N=5), and in microspheres embolized dogs receiving saline (n=9), or nitrite (6.75 micromol/kg i.v. over 15 min followed by 0.28 micromol/kg/min; n=5), or sildenafil (0.25 mg/kg; n=5), or BAY 41-2272 (0.03, 0.1, 0.3, and 1 mg/kg/h; n=5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations were determined. Zymograms of plasma samples were performed, and in vitro antioxidant effects or inhibition of MMPs by these drugs were examined.. APE increased mean pulmonary artery pressure by ~25 mmHg. Nitrite, BAY 41-2272, or sildenafil reversed this increase by ~40% (P<0.05). Similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the highest dose of BAY 41-2272 produced systemic hypotension (P<0.05). While nitrite and sildenafil blunted the increases in plasma pro-MMP-9 levels and TBARS (all P<0.05), BAY 41-2272 produced no such effects. Nitrite and sildenafil produced in vitro antioxidant effects and inhibited MMPs only at high concentrations. BAY 41-2272 produced no such effects.. Activation of the NO-cGMP pathway with nitrite or sildenafil, but not with BAY 41-2272, attenuates APE-induced oxidative stress and increased MMP-9 levels. These findings are consistent with the idea that NO-cGMP pathway activators with antioxidant effects prevent the release of MMP-9 during APE.

Topics: Acute Disease; Animals; Disease Models, Animal; Dogs; Female; Humans; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Nitrites; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyridines; Sildenafil Citrate; Sulfones

Topics: Acute Disease; Adult; Arthritis, Gouty; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Acute pulmonary embolism produces acute pulmonary hypertension, which can be counteracted by activating the nitric oxide-cyclic guanosine 3',5'-monophosphate (cGMP) pathway. While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 micromol/kg intravenously over 15 min. followed by 0.28 micromol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by approximately 24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by approximately 42% (both P < 0.05), the combined infusion of both drugs reversed this increase by approximately 58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both drugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism.

Topics: Acute Disease; Animals; Blood Pressure; Disease Models, Animal; Dogs; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Lipid Peroxides; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sodium Nitrite; Sulfones; Vascular Resistance

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

Sildenafil, a potent inhibitor of phosphodiesterase type 5, has recently been investigated in animal models of myocardial ischemia-reperfusion (MI/R) injury. Previous studies have suggested that the protective effects of sildenafil are mediated via activation of endothelial nitric oxide (NO) synthesis (eNOS) and inducible NOS (iNOS). To further investigate the protective mechanism of sildenafil, we subjected wild-type, eNOS, and iNOS null animals to 30 min of myocardial ischemia and 24 h of reperfusion. Treatment with 0.06 mg/kg sildenafil 5 min before reperfusion significantly reduced myocardial infarct size in wild-type, eNOS null mice (eNOS(-/-)), and iNOS(-/-) animals. Additionally, the low dose utilized in this study did not alter myocardial cGMP. These results suggest that acute low-dose sildenafil-mediated cardioprotection is independent of eNOS, iNOS, and cGMP. In a second series of experiments, we investigated sildenafil in db/db diabetic mice subjected to MI/R. We found that sildenafil failed to protect diabetic mice against MI/R. However, NO(.) donor therapy was found to significantly protect against MI/R injury in both nondiabetic and diabetic mice, suggesting that protection could be conferred in diabetic mice and that the upstream modulator of soluble guanylyl cyclase, NO(.), may mediate protection independent of cGMP signaling. The present study suggests that further research is needed to delineate the precise mechanisms by which sildenafil exerts cardioprotection.

Topics: Acute Disease; Animals; Cardiotonic Agents; Cyclic GMP; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Nitric Oxide; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sulfones; Treatment Outcome

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Aged; Antihypertensive Agents; Coitus; Combined Modality Therapy; Erectile Dysfunction; Glaucoma, Angle-Closure; Humans; Intraocular Pressure; Iridectomy; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Canada; Dexamethasone; Humans; Methazolamide; Nifedipine; Piperazines; Purines; Sildenafil Citrate; Sleep Wake Disorders; Sulfones; Travel

To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension.. Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube.. Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil.. Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Drug Evaluation; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Milrinone; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Swine; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Oral sildenafil has been demonstrated to be an effective treatment for pulmonary hypertension, and is increasingly used in children. We report an infant with pulmonary hypertension, stable on regular treatment with oral sildenafil, who presented in acute respiratory failure after aspiration, requiring ventilation and intensive care. The course of the stay in intensive care was difficult, with recurrent pulmonary hypertensive crises despite use of oral sildenafil, use of 100% oxygen, high frequency oscillatory ventilation, and inhaled nitric oxide. In view of his instability, and the presumed inability to absorb the sildenafil orally due to gastrointestinal malabsorption, sildenafil was administered as a continuous intravenous infusion. With this therapy, it proved possible to wean from oxygen, nitric oxide, and ventilatory support. Intravenous sildenafil, therefore, might be an effective alternative for children with pulmonary hypertension during episodes of acute deterioration and malabsorption, preventing life-threatening pulmonary hypertensive crises. Its pharmacokinetics, efficacy, and safety, nonetheless, need to be validated in randomized controlled trials.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Malabsorption Syndromes; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Acute Disease; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Acute pulmonary embolism (APE) is a major cause of pulmonary hypertension and death. We examined the effects of sildenafil on the hemodynamic changes caused by APE in anesthetized dogs. Sham-operated dogs (n = 3) received only saline. APE was induced by stepwise IV injections of 300 mum microspheres in amounts adjusted to increase mean pulmonary artery pressures by 20 mm Hg. Hemodynamic evaluation was performed at baseline, after APE was induced, and then after sildenafil 0.25 mg/kg (n = 8), or sildenafil 1 mg/kg + 0.3 mg . kg(-1) . h(-1) (n = 8) or saline (n = 9) infusions were started. Similar experiments were conducted to examine the effects of sildenafil in rat isolated perfused lung preparation. Plasma thiobarbituric acid reactive species were also determined in both studies to measure oxidative stress. Both doses of sildenafil reduced mean pulmonary artery pressures in dogs by approximately 8 to 16 mm Hg (both P < 0.05) and attenuated the increase in oxidative stress after APE. Mean arterial blood pressure remained unaltered after both doses of sildenafil. Sildenafil produced similar effects after APE in rat isolated perfused lung preparation. These findings indicate that IV sildenafil can selectively attenuate the increases in mean pulmonary artery pressures after APE, possibly through antioxidant mechanisms.

Topics: Acute Disease; Animals; Blood Pressure; Dogs; Female; Hemodynamics; Hypertension, Pulmonary; Male; Malondialdehyde; Oxidative Stress; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

Sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during acute pulmonary embolism have not been examined yet. In the present study, we examined the hemodynamic effects of combined sildenafil (0.25 mg/kg, i.v.) and L-arginine (100, 200, 500, and 1000 mg/kg/h, i.v.) in an anesthetized dog model of acute pulmonary embolism. Plasma nitrite/nitrate (NO(x)) and cGMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that L-arginine alone did not attenuate acute pulmonary embolism-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 30, 45, 60, and 75 min after the administration of sildenafil alone or after the combined administration of sildenafil and L-arginine (all P < 0.05). No significant differences among groups were observed in the respiratory parameters. While L-arginine significantly increased NO(x) concentrations, cGMP concentrations increased only when sildenafil was administered (all P < 0.05). These results suggest that while sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension, L-arginine does not enhance the beneficial hemodynamic effects of sildenafil. In addition, these findings suggest that stimulation of NO synthesis with L-arginine during acute pulmonary embolism does not produce beneficial effects.

Topics: Acute Disease; Analysis of Variance; Animals; Arginine; Blood Pressure; Cyclic GMP; Dogs; Female; Heart Rate; Hypertension, Pulmonary; Infusions, Intravenous; Male; Nitrates; Nitrites; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension.. Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound.. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05).. The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Topics: Acute Disease; Animals; Disease Models, Animal; Hypertension, Pulmonary; Piperazines; Purines; Pyrimidinones; Random Allocation; Sildenafil Citrate; Sulfones; Swine; Vasodilator Agents

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.

Topics: Acute Disease; Animals; Atrial Natriuretic Factor; Cyclic GMP; Drug Synergism; Humans; Hypertension, Pulmonary; Hypoxia; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Acute Disease; Aged; Erectile Dysfunction; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Male; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

To determine whether inhalation of aerosolized sildenafil with and without inhaled nitric oxide (NO) causes selective pulmonary vasodilation in a sheep model of pulmonary hypertension.. A controlled laboratory study in instrumented, awake, spontaneously breathing lambs.. Animal research laboratory affiliated with a university hospital.. Twenty Suffolk lambs.. Lambs were instrumented with a carotid artery catheter, a pulmonary artery catheter, and a tracheostomy tube and studied awake. After baseline measurements, pulmonary hypertension was induced by the continuous infusion of U46619, a thromboxane A2 analog. After breathing three concentrations of inhaled NO (2, 5, and 20 ppm), lambs were divided into two groups. Group 1 (n = 7) breathed aerosols containing 1, 10, and 30 mg of sildenafil alone, and group 2 (n = 4) simultaneously breathed NO (2 and 5 ppm) and aerosols containing 10 mg of sildenafil. Hemodynamic measurements were obtained before and at the end of each drug administration. Venous admixture was calculated, and plasma cyclic guanosine monophosphate and sildenafil concentrations were measured.. Aerosols containing 10 mg and 30 mg of sildenafil selectively decreased the pulmonary artery pressure by 21% +/- 3% and 26% +/- 3%, respectively (p < .05 vs. baseline pulmonary hypertension). When 10 mg of sildenafil was inhaled while simultaneously breathing 2 ppm and 5 ppm NO, the pulmonary artery pressure decreased by 35% +/- 3% and 43% +/- 2% (p < .05 vs. baseline pulmonary hypertension). Inhaled sildenafil did not impair systemic oxygenation, increase right-to-left intrapulmonary shunting, or impair the ability of inhaled NO to reduce right-to-left shunting.. Nebulized sildenafil is a selective pulmonary vasodilator that can potentiate the pulmonary vasodilating effects of inhaled NO.

Topics: Acute Disease; Administration, Inhalation; Aerosols; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Drug Synergism; Hemodynamics; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Gas Exchange; Purines; Sheep; Sildenafil Citrate; Sulfones; Vasodilation

Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction.. In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6).. Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation.. Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Hypertension, Pulmonary; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Artery; Pulmonary Circulation; Purines; Purinones; Sheep; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Wakefulness

This case report describes a patient with hypertrophic cardiomyopathy who developed symptomatic atrial fibrillation on two occasions after ingesting sildenafil citrate (Viagra). Sildenafil citrate should be withheld or used with extreme caution in persons with hypertrophic obstructive cardiomyopathy.

Topics: Acute Disease; Atrial Fibrillation; Cardiomyopathy, Hypertrophic; Humans; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Aged; Coitus; Cystitis; Erectile Dysfunction; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Arteriovenous Shunt, Surgical; Enzyme Inhibitors; Erectile Dysfunction; Humans; Kidney Failure, Chronic; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thrombosis