EFFECTS OF THE ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR QUINAPRIL ON RENAL-FUNCTION IN RATS

Angiotensin-converting enzyme inhibitors induce hypertrophy of renal j uxtaglomerular cells in laboratory animals, and, in some studies, also produced renal tubular lesions. The objective of the present study wa s to evaluate the effects of the new angiotensin-converting enzyme inh ibitor quinapril on renal function in normotensive rats. Male rats wer e 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 o f renal function were measured approximately 24 hours after dosing in order to minimize interference from acute pharmacologically mediated e ffects. Mean arterial blood pressure was only mildly affected at this time: 126.7 +/- 6.0 and 100.0 +/- 8.7 mm/Hg (XBAR +/- S.E.; day 29) fo r the control and quinapril-treated animals, respectively. Microscopic analysis of kidney tissue showed pronounced juxtaglomerular cell hype rtrophy and hypergranularity in the quinapril-treated animals. These c hanges 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 (electrolyt es, urea nitrogen, creatinine). Urine output in quinapril-treated anim als was increased 65 % to 197 % over controls during the course of the study and correlated with increased water consumption (r = 0.96). Uri ne osmolality was reduced 31 % to 55 % on days 8, 17 and 29. However, except for minimal reductions (< 15 %) on day 8, there were no signifi cant effects of quinapril on total (24 hour) urinary excretion of elec trolytes or creatinine. There were also minimal effects of quinapril o n 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 11.2 2 +/- 2.35 ml/min; effective renal tubular secretion: 267 +/- 63 and 2 61 +/- 106 mug/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 quina pril-treated animals when the above parameters were measured following plasma volume expansion on day 29. The results show that quinapril ha d no adverse effects on renal function in rats when administered at a suprapharmacological dose for up to 4 weeks.