Studies on mechanisms of antinephritic action of SA-446 an angiotensin I converting enzyme inhibitor (1). A comparison with actions of spironolactone, kallidinogenase and saralasin.
The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. However, saralasin (72 micrograms/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D000450:Aldosterone / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D007610:Kallikreins / Q000494:pharmacology* / Q000652:urine; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009393:Nephritis / Q000188:drug therapy*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012504:Saralasin / Q000494:pharmacology*; D013148:Spironolactone / Q000494:pharmacology*; D013438:Sulfhydryl Compounds; D053778:Thiazolidines
D000806:Angiotensin-Converting Enzyme Inhibitors; D011453:Prostaglandins; D013438:Sulfhydryl Compounds; D053778:Thiazolidines; D013148:Spironolactone; D000450:Aldosterone; D015097:3-Mercaptopropionic Acid; C033437:rentiapril; D007610:Kallikreins; D012083:Renin; D012504:Saralasin