The hydrolysis of bradykinin (BK) by human placental subcellular fractions and pregnancy sera was studied in the presence of inhibitors by measuring amino acids liberated from BK by high-performance liquid chromatography. The effects of the inhibitors DL-2- mercaptomethyl-3-guanidinoethylthiopropionic acid (MGTA, for kininase I), phosphoramidon (for endopeptidase 24.11) and captopril and rentiapril (for angiotensin-converting enzyme [ACE, kininase II]) suggested the essential roles of the above three proteases in BK degradation: among the three proteases, kininase I and endopeptidase 24.11 appeared to be the most important in kininase action in the placenta microsomes, whereas kininase I and ACE appeared to be the most important in kininase action in the placental cytosol, lysosome and pregnancy serum. Measurements of BK concentrations in the umbilical arterial blood, umbilical venous blood and maternal plasma revealed higher concentrations in the mother than in the fetus. The present data suggest that degradation of BK in the placenta and pregnancy serum might contribute to the gradient of BK between mother and fetus.

01 Jan 1995·Arzneimittel-Forschung

Toxicity study of the angiotensin converting enzyme inhibitor rentiapril in rats.

Article

Author: Ikuse, T ; Aono, H ; Okahara, A ; Takase, K

A three-months toxicity study of an angiotensin converting enzyme (ACE) inhibitor, rentiapril (CAS 80830-42-8), was performed in Sprague-Dawley rats by oral administration. The dose levels of 0, 30, 125, 500 and 1000 mg/kg were tested in both sexes, in which each experimental group comprised 10 rats. Another ACE inhibitor, captopril, was used as a reference compound. Rentiapril at the highest dose of 1000 mg/kg caused low food consumption and death of some animals with signs of bloody feces and anemia. In males and females receiving 500 and 1000 mg/kg, there were low body weight gain, increases in water intake, urine volume and serum BUN level, and decreases in levels of various erythrocytic parameters. Kidney weight was increased dose-dependently in both sexes. Histopathologically, renal changes in the 500 and 1000 mg/kg groups consisted of proximal tubular degeneration, juxtaglomerular cell hyperplasia and interstitial cell infiltration. Similar, but mild, changes in proximal tubules were present in the female 125 mg/kg group. Dead animals from the highest dose groups further showed gastrointestinal hemorrhagic erosion and/or ulcer, decreased bone marrow erythropoiesis and hepatocytic vacuolar degeneration. There was no pathological alteration in rats from other rentiapril-treated groups, as well as in controls. These results indicate that the no-effect dose of rentiapril in rats by three months oral administration is 30 mg/kg in female and 125 mg/kg in male, and suggest that, like other ACE-inhibitors, this compound also has a toxic potential to affect renal tissues.

01 Jul 1994·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

The assessment of the HO· scavenging action of therapeutic agents

Q3 · MEDICINE

Article

Author: J. Ness ; W.E. Smith ; J. Russell ; J. McMurray ; M. Chopra

A new method is reported for the assessment of the HO. scavenging action of therapeutic agents. It is based on the photolysis of zinc oxide and has a detection limit of 3.3%. The scavenging order of the compounds tested was penicillamine > rentiapril > ascorbic acid > cysteine > glutathione > thiomalic acid > N-acetylcysteine > myocrysin > methionine. None were as effective as DMSO. It is argued that these compounds can have an in vivo protective effect where HO. is produced from oxidant producing cells, thus limiting radical induced damage.

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