sildenafil-citrate and Hypertension--Portal

Portopulmonary hypertension (PoPH) is an underrecognized complication of portal hypertension, related to cirrhosis and noncirrhotic portal hypertension. PoPH has been found in 5-6% of patients with decompensated liver disease and may adversely affect outcome after liver transplantation. The prevalence of PoPH is unrelated to the severity of liver disease but associated with female sex and underlying autoimmune liver disease. Diagnosis of PoPH is based on screening with Doppler echocardiography and confirmation by right-heart catheterization. Treatment options with proven efficacy in idiopathic pulmonary hypertension include endothelin receptor antagonists, prostanoids, and sildenafil. In PoPH, such targeted treatment was found to be safe in small uncontrolled studies but randomized trials demonstrating its benefit are lacking.

Topics: Algorithms; Endothelin Receptor Antagonists; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Transplantation; Piperazines; Prostaglandins; Purines; Sex Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Porto-pulmonary hypertension (PoPH) is the association of pulmonary artery hypertension and portal hypertension. The diagnosis of PoPH is based on pulmonary haemodynamic criteria, obtained via right heart catheterisation, including an increase in mean pulmonary arterial pressure (> 25 mmHg) and in pulmonary vascular resistance (> 240 dyn.s.cm-5).. The exact pathophysiological mechanisms of PoPH are unknown. However, since PoPH has been reported in patients with non-hepatic portal hypertension, the factor that determines the development must be portal hypertension rather than liver disease per se. Moreover, no simple relationship has been identified between the degree of hepatic impairment and the severity of PoPH. The clinical presentation is non-specific with haemodynamic failure occurring at the end stage. As a consequence, screening by annual transthoracic echocardiography is highly recommended in potential liver transplant candidates. Therapy with prostacyclin analogues may partially relieve pulmonary arterial hypertension (PAH). Liver transplantation has an uncertain effect in PoPH and because PoPH is associated with a high perioperative mortality, moderate to severe PoPH remains a contraindication for liver transplantation.. Recent advances in the management of PoPH have improved the prognosis. The safety and efficacy of oral endothelin receptor antagonists and oral phosphodiesterase inhibitors is currently under evaluation. A therapeutic approach utilising combinations of drugs should provide better long-term results.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Therapy, Combination; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Oxygen Inhalation Therapy; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient (HVPG) in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown.. Ten patients with biopsy proven cirrhosis (five females/five males, mean age 54 +/- 8 years) and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick's principle, with correction for non-steady state.. The plasma concentration of sildenafil was 222 +/- 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 +/- 7 mmHg to 66 +/- 12 mmHg, P = 0.003, while the splanchnic blood flow and oxygen consumption remained unchanged at 1.14 +/- 0.71 L/min and 2.3 +/- 0.6 mmol/min, respectively. Also the HVPG remained unchanged (18 +/- 2 mmHg vs 16 +/- 2 mmHg) with individual changes ranging from -8 mmHg to +2 mmHg. In seven patients, HVPG decreased and in three it increased.. In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.

Topics: Administration, Oral; Adult; Female; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Splanchnic Circulation; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents; Venous Pressure

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (

Topics: Animals; Hemodynamics; Hypertension, Portal; Models, Animal; Norepinephrine; Portal Pressure; Rats; Sildenafil Citrate

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Patients with severe PPHTN are contraindicated for liver transplant because of the associated risk of intraoperative acute right heart failure during reperfusion phase or massive volume infusion. Therefore, it has been recommended that patients with moderate to severe PPHTN undergo medical treatment to lower the pulmonary artery pressure before undergoing transplant. Herein, we report 3 patients with severe PPHTN who underwent sildenafil monotherapy before living donor liver transplant. None of the patients experienced associated adverse effects during sildenafil treatment, and the pulmonary artery pressure was effectively reduced before transplant. The first patient was diagnosed during anesthesia prior to transplant, and the mean pulmonary artery pressure was reduced by 34% after treatment. The second and third patients were followed-up with echography, and the estimated pulmonary artery systolic pressure were reduced by 34% and 47%, respectively. Pretransplant right heart catheterization also confirmed the reduction of the mean pulmonary artery pressure. Intraoperative hemodynamic parameters were stable, and the 3 patients were discharged uneventfully. After transplant, sildenafil was discontinued, and all patients remained in a stable clinical and functional status during follow-up.

Topics: Antihypertensive Agents; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Sildenafil Citrate; Vasodilator Agents

To investigate the potential effect of inhibitors of phosphodiesterase-5 (PDE-5) for therapy of portal hypertension in liver cirrhosis.. In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase subunits α1 and β1 (sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil (0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers.. Hepatic gene expression of eNOS (2.2-fold;. Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanosine Monophosphate; Humans; Hypertension, Portal; Liver; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase 5 Inhibitors; Rats; Rats, Sprague-Dawley; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Thioacetamide; Treatment Outcome

Hepatopulmonary syndrome and portopulmonary hypertension are complications of portal hypertension with opposing mechanisms that can coexist. Moderate portopulmonary hypertension, which is a contraindication to a liver transplant, must be managed with pulmonary vasodilators to normalize pulmonary arterial pressures before a transplant listing. Concomitant hepatopulmonary syndrome complicates the management of portopulmonary hypertension, as pulmonary vasodilators can theoretically exacerbate the intrapulmonary dilatation believed to cause hepatopulmonary syndrome. We describe a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension safely treated with sildenafil.

Topics: Antihypertensive Agents; Female; Hemodynamics; Hepatopulmonary Syndrome; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Circulation; Liver Transplantation; Middle Aged; Pulmonary Circulation; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) that occurs in the setting of cirrhosis and portal hypertension is referred to as portopulmonary hypertension (PPHTN). Liver transplantation (LTx) is curative, but the presence of moderate-to-severe PPHTN may be a contraindication for transplantation because of the elevated risk of peri- and post-transplantation morbidity and mortality. We report a successful liver transplantation in a patient with liver cirrhosis after treatment of moderate-to-severe PPHTN with a combination of the dual endothelin receptor antagonist bosentan and the specific phosphodiesterase-5 inhibitor sildenafil.

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Transplantation; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm(-5) . There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Portal; Length of Stay; Liver Failure; Liver Transplantation; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Postoperative Complications; Pulmonary Circulation; Purines; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones

We documented the frequency of large spontaneous portosystemic shunts in patients with moderate or severe portopulmonary hypertension (POPH) and determined the association between large shunts and response to treatment.. We performed a retrospective case-control study of data from patients with mild (mean pulmonary artery pressure [MPAP], 25-35 mm Hg; n = 18), moderate (MPAP, 35-50 mm Hg; n = 45), and severe POPH (MPAP, >50 mm Hg; n = 16). Data were compared with those from controls (normal echocardiography with estimated right ventricular systolic pressure, <35 mm Hg; n = 122). Spontaneous portosystemic shunts greater than 10 mm in diameter, identified by computed tomography or magnetic resonance, were classified as large. Response to treatment at 6 months was defined by right ventricular systolic pressure or MPAP as significant (<35 mm Hg), partial (35-50 mm Hg), or no response (>50 mm Hg).. The frequency of spontaneous shunts did not differ significantly between groups of subjects with severe (n = 14 of 16), moderate (n = 38 of 45), or mild POPH (n = 11 of 18) or normal echocardiograms (controls, n = 86 of 122) (P = .77). Large shunts were associated with severe (14 of 16) and moderate POPH (32 of 45), compared with mild POPH (6 of 18) or controls (30 of 122) (P < .01). In 13 patients with severe POPH, large shunts were associated with lack of response to treatment in 90% (8 of 9) or partial response in 50% (2 of 4). Among 27 patients with moderate POPH, large shunts were associated with no response to treatment in 13 of 19 (68%) and a partial response in 2 of 6 (33%).. Large spontaneous portosystemic shunts are associated significantly with moderate and severe POPH, and with lack of response to treatment.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Case-Control Studies; Child; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Magnetic Resonance Imaging; Male; Mesentery; Middle Aged; Piperazines; Purines; Regional Blood Flow; Renal Veins; Retrospective Studies; Severity of Illness Index; Sildenafil Citrate; Splenic Vein; Sulfonamides; Sulfones; Tomography, Spiral Computed; Treatment Outcome; Vena Cava, Inferior

Increasing NO bioavailability improves hepatic endothelial dysfunction, which ameliorates intrahepatic resistance and portal hypertension. Acute administration of sildenafil increases hepatic production of NO with a reduction in hepatic sinusoid resistance in cirrhotic patients and enhances the vasorelaxation response to NO in cirrhotic rat livers. However, the mechanisms were still unclear. Therefore, our present study aims to evaluate the effects and mechanisms of administration of sildenafil for 1 week on the hepatic microcirculation of cirrhotic rats. Cirrhosis was induced by bile duct ligation with sham-operated rats serving as normal controls. Intrahepatic resistance was evaluated by in situ liver perfusion. Expression of phospho-eNOS (endothelial NO synthase), iNOS (inducible NO synthase), phospho-Akt, PDE-5 (phosphodiesterase-5) and sGC (soluble guanylate cyclase) were determined by Western blot analysis. Biosynthesis of BH4 (tetrahydrobiopterin) and GTPCH-I (GTP cyclohydrolase I) activity were examined by HPLC. Intravital microscopy was used to observe the direct change in hepatic microcirculation. In cirrhotic rat livers, sildenafil treatment increased hepatic sinusoid volumetric flow, NO bioavailability, BH4, GTPCH-I activity, and the protein expression of phospho-Akt, phospho-eNOS and sGC. These events were associated with reduced protein expression of PDE-5, portal perfusion pressure and portal vein pressure. In contrast, sham rats did not produce any significant change in these measurements. In conclusion, sildenafil treatment improves endothelial dysfunction by augmenting NO bioavailability in the hepatic microcirculation.

Topics: Animals; Biological Availability; Drug Administration Schedule; Drug Evaluation, Preclinical; Hemodynamics; Hypertension, Portal; Liver Circulation; Liver Cirrhosis, Biliary; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Portal Pressure; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vascular Resistance

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Transplantation; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Portopulmonary hypertension is a recognized but uncommon complication of cirrhosis. Liver transplantation may be contraindicated in patients with severe portopulmonary hypertension. In order to decrease the pulmonary arterial pressure, intravenous administration of epoprostenol has been shown to provide substantial beneficial results in these patients. Additionally, a recent case report demonstrated that long-term oral administration of sildenafil decreased pulmonary arterial pressure, but its effects on splanchnic hemodynamics were not measured. We report on a patient with cirrhosis and portopulmonary hypertension and the changes in the hemodynamic status after an oral administration of sildenafil. This case report clearly delineates that sildenafil decreases pulmonary arterial pressure but may exacerbate portal hypertension and hyperdynamic circulation in patients with cirrhosis and portopulmonary hypertension.

Topics: Adult; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Portopulmonary hypertension is a poorly understood and uncommon complication of advanced chronic liver disease. Current therapy is based largely on treatment options proven in idiopathic pulmonary hypertension. The severity of the portopulmonary hypertension should best be attenuated medically before attempting combined liver and lung transplantation to avoid increased peri-operative mortality. This case report describes the successful use of sildenafil to decrease the pulmonary vascular resistance in a patient with hepatitis-C cirrhosis who was preparing for liver transplantation.

Topics: Female; Follow-Up Studies; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilation; Vasodilator Agents

Sildenafil is a selective inhibitor of the cGMP-specific phosphodiesterase type V (PDE-V) in the corpus cavernosum. PDE-V is also present in the mesenteric artery. Cirrhosis is complicated by a splanchnic vasodilation attributed to a local overproduction of nitric oxide (NO). As sildenafil potentiates the effects of NO, it may further decrease mesenteric vascular tone and increase portal venous blood flow. The aim is to evaluate the effects of sildenafil on the systemic and splanchnic haemodynamics in an experimental model of cirrhosis.. Secondary biliary cirrhosis was induced in male Wistar rats by common bile duct ligation (CBDL, n=8); control rats were sham-operated (sham, n=7). The mean arterial pressure (MAP), portal venous pressure (PVP) and arterial mesenteric blood flow (MBF) were measured after intramesenteric (0.01-10 mg/kg) and after intravenous (i.v.) (0.01-10 mg/kg) administration of sildenafil.. Baseline PVP was significantly higher in CBDL than in sham rats, whereas baseline MAP tended to be lower and MBF tended to be higher in CBDL compared with sham rats. Both intramesenteric and i.v. injection of sildenafil significantly decreased MAP and increased MBF and PVP in a dose-dependent way. The decrease in MAP was significantly less important in CBDL than in sham rats. The increase in MBF was importantly lower in CBDL than in sham rats. PVP tended to increase more significantly in sham rats than in CBDL.. Sildenafil increases MBF and PVP and induces systemic hypotension. The effects are less pronounced in cirrhosis, suggesting vascular hyporesponsiveness to sildenafil. Although the rise in PVP in cirrhotic animals is smaller than in controls, it may present a risk for haemorrhagic complications. Further studies are necessary before prescribing sildenafil to patients with cirrhosis.

Topics: Animals; Blood Pressure; Fibrosis; Hemodynamics; Hypertension, Portal; Male; Models, Animal; Phosphodiesterase Inhibitors; Piperazines; Portal Pressure; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Splanchnic Circulation; Sulfones