ramipril and Liver-Cirrhosis

Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Female; Inflammation; Liver Cirrhosis; Oxidative Stress; Ramipril; Rats; Rats, Long-Evans

Chronic pancreatitis (CP) results in impairment of exocrine as well as endocrine functions and progressive fibrosis. Previous studies, have demonstrated the presence of renin-angiotensin system receptors within different pancreatic cells. The aim of the present study was to assess the effects of renin-angiotensin system (RAS) inhibitors on serum levels of fibrosis biomarkers (matrix metalloproteinase 2 and 9 (MMP-2, MMP-9), tissue inhibitor of MMP (TIMP- 1, TIMP-2), hyaluronic acid (HA)) and fasting glucose levels in patients with alcoholic CP. Seventy seven outpatients (mean age 43 years, 62 males) with diagnosed alcoholic CP were randomly enrolled into 5 study groups depending on the RAS inhibitors administered and their doses (2.5 or 5 mg and 12.5 or 25 mg for ramipril or losartan, respectively). Venous blood was sampled monthly for a period of one year to monitor serum drug levels. MMP-2, -9, TIMP-1, TIMP-2 and HA were measured with ELISA method on the onset and at the end of the study. Only forty five patients regularly participated in follow-up visits and completed the study. The fluctuations in serum HA levels observed among patients from the remaining groups also did not reach statistical significance. Serum MMP-2 levels (P = 0.06) and MMP-2/TIMP-1 ratio (P = 0.06) showed increasing tendency in the losartan 25 mg group. High doses of ramipril and losartan statistically significantly reduced fasting glucose levels. High doses of losartan can increase the MMP-2 activity in serum of alcoholic CP patients, which potentially is likely to affect turnover of extracellular matrix proteins within the pancreas. Moreover, high doses of both RAS inhibitors decrease the fasting glucose level.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Female; Humans; Liver Cirrhosis; Losartan; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Pancreatitis, Chronic; Ramipril; Renin-Angiotensin System; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

In an open trial, the pharmacokinetics of the angiotensin converting enzyme inhibitor ramipril and its active metabolite ramiprilat were studied in 12 patients with liver cirrhosis. After a single oral dose of 5 mg ramipril plasma levels of the parent compound reached peak concentrations of 48.6 +/- 39.8 ng/ml after 0.7 +/- 0.5 h and declined rapidly to 0.7 +/- 1.2 ng/ml after 8 h. Plasma levels of ramiprilat reached peak concentrations of 3.8 +/- 2.9 ng/ml after 3.0 +/- 2.2 h, thereafter declined slowly and could be detected up to 240 h. The total recovery of ramipril and metabolites in urine within 96 h was on average 46.0 +/- 10.9% of the administered dose. Major fractions were due to diketopiperazines and glucuronides of ramipril and ramiprilat. The overall ACE inhibition was still 92.0 +/- 8.6%. In conclusion, patients with liver cirrhosis had enough capacity to metabolize and excrete the parent compound ramipril, but had not enough capacity to form ramiprilat, although enough ramiprilat was formed for sufficient ACE inhibition of about 90%. This indicates that titration of the dose should start with 5 mg or even lower doses in patients with markedly impaired liver function.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Female; Humans; Liver; Liver Cirrhosis; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Ramipril