Effects of the angiotensin-converting enzyme inhibitor quinapril on renal function in rats.
Angiotensin-converting enzyme inhibitors induce hypertrophy of renal juxtaglomerular cells in laboratory animals, and, in some studies, also produced renal tubular lesions. The objective of the present study was to evaluate the effects of the new angiotensin-converting enzyme inhibitor quinapril on renal function in normotensive rats. Male rats were dosed orally with quinapril at 0 (vehicle control) or 400 mg/kg for 1, 3, 8, 17 or 29 days. This dose of quinapril is more than 1000-fold greater than the effective antihypertensive dose in rats. Parameters of renal function were measured approximately 24 hours after dosing in order to minimize interference from acute pharmacologically mediated effects. Mean arterial blood pressure was only mildly affected at this time: 126.7 +/- 6.0 and 100.0 +/- 8.7 mm/Hg (mean +/- S.E.; day 29) for the control and quinapril-treated animals, respectively. Microscopic analysis of kidney tissue showed pronounced juxtaglomerular cell hypertrophy and hypergranularity in the quinapril-treated animals. These changes were first observed on day 7 and reached a maximum response by day 14. There were no morphologic changes in renal tubules. Quinapril had no significant effect on serum biochemistry parameters (electrolytes, urea nitrogen, creatinine). Urine output in quinapril-treated animals was increased 65% to 197% over controls during the course of the study and correlated with increased water consumption (r = 0.96). Urine osmolality was reduced 31% to 55% on days 8, 17 and 29. However, except for minimal reductions (< 15%) on day 8, there were no significant effects of quinapril on total (24 hour) urinary excretion of electrolytes or creatinine. There were also minimal effects of quinapril on direct measurements of renal function in anesthetized animals. Mean values (+/- S.E.) for control and quinapril-treated animals on day 29 were, respectively: glomerular filtration rate: 2.93 +/- 0.37 and 2.70 +/- 0.53 ml/min; effective renal plasma flow: 11.14 +/- 2.06 and 11.22 +/- 2.35 ml/min; effective renal tubular secretion: 267 +/- 63 and 261 +/- 106 micrograms/min; filtration fraction: 27.1 +/- 2.5 and 24.0 +/- 0.4%; and fractional sodium excretion: 0.25 +/- 0.04 and 0.34 +/- 0.04%. There were also no significant differences between control and quinapril-treated animals when the above parameters were measured following plasma volume expansion on day 29. The results show that quinapril had no adverse effects on renal function in rats when administered at a suprapharmacological dose for up to 4 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)
Graziano
M J
MJ
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Dethloff
L A
LA
Griffin
H E
HE
Pegg
D G
DG
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D010953:Plasma Volume / Q000187:drug effects; D000077583:Quinapril; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077583:Quinapril