Effect of angiotensin converting enzyme inhibitors on the vasoconstrictor action of angiotensin I on isolated rat kidney.
On the isolated perfused rat kidney, the angiotensin converting enzyme (ACE) activity was evaluated with two approaches: one, pharmacological, through the vasoconstrictor response to angiotensin I (ANG I), and the other, biochemical, through the measurements of the enzymatic activity on renal homogenate. ANG I and angiotensin II (ANG II) induced a concentration-dependent renal vasoconstriction (EC50 = 10.5 +/- 1.8 X 10(-9) and 1.1 +/- 0.5 X 10(-9) M, respectively). Both responses were competitively antagonized by an ANG II receptor antagonist, saralasin (pA2 = 8.65 +/- 0.63 and 8.94 +/- 0.28, respectively). The effects of ACE inhibitors were studied in vitro after addition of captopril and ramiprilat (10(-5) M) directly to the perfusion medium, and ex vivo, after pretreatment of the rats with ramipril (50 mg/kg, i.p. the day before or 10 mg/kg/day, per os, over 3 weeks). In spite of the high doses of ACE inhibitors used, the ANG I concentration-response curve was only shifted to the right by a factor of 4, although renal tissue ACE activity was completely inhibited. Saralasin (10(-5) M) totally abolished the ANG I-induced vasoconstriction elicited in the presence of ACE inhibitors, this response being therefore linked to a generation of ANG II from ANG I. Our results suggest that, on the isolated perfused rat kidney, ANG II may be formed from ANG I by a peptidyl dipeptidase different from the ACE.
D000803:Angiotensin I / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D007700:Kinetics; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D017257:Ramipril / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D014662:Vasoconstrictor Agents
D000806:Angiotensin-Converting Enzyme Inhibitors; D011758:Pyrroles; D014662:Vasoconstrictor Agents; C052549:ramiprilat; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D017257:Ramipril