Acute but not chronic angiotensin-converting enzyme inhibition induces enzyme synthesis in the glomerulus of the spontaneously hypertensive rat.
1. Treatment with angiotensin-converting enzyme (ACE) inhibitors slows the rate of progression of nephropathy in the spontaneously hypertensive rat (SHR) with streptozotocin-induced diabetes. Paradoxically, however, chronic ACE inhibitor therapy has been reported to be associated with induction of ACE in the plasma. We sought to determine whether induction also occurred in the glomerulus. 2. Seven days after induction of diabetes rats were randomized to receive perindopril (4 mg/kg per day) in the drinking water or water alone. Blood glucoses were maintained 6-10 mmol/L by daily ultralente insulin. Rats were killed after 1 and 12 weeks of ACE inhibitor therapy and the kidneys were harvested. Angiotensin-converting enzyme activity was determined in isolated glomeruli before and after removal of perindopril and reconstitution with zinc sulphate. 3. After 1 week of ACE inhibitor therapy, glomerular ACE was significantly greater after removal of perindopril than either before its removal (P < 0.025) or in the untreated controls (P < 0.025). After 12 weeks of therapy, ACE activity was significantly lower in the perindopril-treated group than in the untreated controls (P < 0.025). There was no increase in ACE activity following removal of perindopril. 4. These studies suggest that short-term ACE inhibition is associated with induction of ACE in the glomerulus. However, there was no increase in ACE activity after removal of perindopril, suggesting that induction of synthesis of this enzyme in the glomerulus does not occur during chronic ACE inhibition.
Hodge
G
G
Hypertension Laboratory, Liverpool Hospital, New South Wales, Australia.
Makarious
M M
MM
Charlesworth
J A
JA
Duggan
K A
KA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000201:enzymology; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000187:drug effects; D020913:Perindopril; D051381:Rats; D011918:Rats, Inbred SHR
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril