sildenafil-citrate and Hepatopulmonary-Syndrome

Hepatopulmonary syndrome (HPS) is a severe complication of hepatic cirrhosis, which is characterized by hypoxia, intrapulmonary vasodilation, inflammation, and angiogenesis. In this study, we aimed to investigate the regulatory effects of diosmin (DS) on selected phosphodiesterase inhibitors against chronic bile duct ligation (CBDL)-induced HPS. Experimentally, Wistar Albino rats were used and HPS was induced by CBDL for 28 days. DS (100 mg/kg, daily, P.O.), sildenafil (Sild; 10 mg/kg, twice daily, P.O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for their anti-angiogenic activity. CBDL significantly altered oxidative stress biomarkers and up-regulated pulmonary mRNA expressions of VEGF, IGF-1, ET-1, iNOS, eNOS, and ANG-2 as well as the protein expressions of vWF, FGF-1, PI3K, AKT, p-AKT, TGF-β, HYP, MPO activity and circulating TNF-α. Treatment with DS, Sild, PTX, and their combinations significantly attenuated molecular and cellular changes due to CBDL. Improvement of histopathological changes was also observed after drug treatment which further supported our results. Furthermore, DS combination with Sild or PTX exhibited an improvement in HPS in comparison to each drug alone. Collectively, DS can augment the anti-angiogenic activity of Sild and PTX during HPS through regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.

Topics: Angiogenesis Inhibitors; Angiotensin II; Animals; Diosmin; Drug Synergism; Fibroblast Growth Factor 1; Hepatopulmonary Syndrome; Insulin-Like Growth Factor I; Male; Pentoxifylline; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

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