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The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

The nephrotoxicity of gentamicin and amikacin was evaluated comparatively in young and adult rats. The aminoglycosides were administered once daily for 14 days, gentamicin in a dose of either 20 or 60 mg/kg, and amikacin in a dose of either 60 or 180 mg/kg. Renal function was measured during and after treatment. In adult rats there was a dose dependent fall in the glomerular filtration rate which was preceded by histopathological changes in the proximal tubules. The nephrotoxicity of gentamicin was more severe than that of amikacin. The nephrotoxicity of either aminoglycoside was less severe in young rats than in adult rats. In the proximal tubules there were less histopathological changes in young rats than in the adult rats. The mechanism underlying this difference in nephrotoxicity was investigated by measuring the renal accumulation of gentamicin and amikacin. The renal uptake after the first dose of either aminoglycoside was similar in young and adult rats. Expressed as a percentage of the injected amount, the uptake decreased as the aminoglycoside dosage increased. The uptake of gentamicin was somewhat greater than that of amikacin. In young rats, the aminoglycoside concentration in total kidney as well as in renal cortex, was significantly less than in adult rats. This difference was due to the larger wet kidney weight relative to body weight in the young rats. The lower renal aminoglycoside levels in the young rats provide an explanation for the difference observed in aminoglycoside nephrotoxicity when comparing young and adult rats.

The effect of Cis-platin on the glomerular filtration rate and effective renal plasma flow was determined using a radioisotope clearance technique in young (3 wk old) and adult (more than 12 wk old) rats. Cis-platin was administered intravenously in dosages ranging from 2.5 to 10 mg/kg body weight, either as a single dose or fractionated over 5 consecutive days. Following either dose regimen, identical total doses of Cis-platin caused less severe nephrotoxicity in young rats than in adult ones. In adult rats fractionated dosage significantly reduced nephrotoxicity. This was not observed in young rats. The difference in nephrotoxicity between young and adult rats was due to the renal handling of Cis-platin. After a single dose of 5 and 7.5 mg/kg body weight, platinum concentrations were measured in urine and renal tissue. During the first 2 days after Cis-platin administration, up to 60% of the amount of platinum injected was excreted in the urine of both age groups. There was a marked difference, however, in renal platinum concentration between the two groups. In young rats renal platinum concentration was only 63 and 49% of that in adult rats after 5 and 7.5 mg/kg body weight, respectively. We believe that this is due to the comparatively larger renal mass in relation to body weight in the young animals. Relatively more renal tissue provides at least partial protection against nephrotoxic drugs in these young rats.

Renal function was measured during the first 4 postnatal days in 9 preterm neonates (gestational age 26.2 to 31 wk) exposed to indomethacin during the last 2 days of pregnancy (group I). The data were compared to those obtained from nine control neonates (gestational age 28 to 34.5 wk) (group II). Five of the nine neonates in group I were markedly edematous at birth, none of group II were edematous. Urine production in group I was low (32.2 +/- 16.8 ml/kg.day on day 1 increasing to 68.6 +/- 21.4 ml/kg.day on day 4) and differed significantly from group II [75.2 +/- 26.8 ml/kg.day on day 1 increasing to 84.8 +/- 20.9 ml/kg.day on day 4 (p less than 0.001)]. Fluid intake was adapted to urine production when necessary. A continuous inulin infusion was started directly after admission and continued for 5 days. Renal function was evaluated for 3 consecutive days after at least 48 h of insulin infusion. The values of the inulin clearance, serum creatinine, urine osmolarity, osmolar clearance, and free water clearance were stable in both groups during the study period. Inulin clearance was lower in group I than in group II (p less than 0.001), whereas serum creatinine was higher in group I than in group II (p less than 0.0001). Urine osmolarity was higher in group I (p less than 0.01), whereas osmolar clearance and free water clearance were lower in group I (p less than 0.02, respectively, p less than 0.01). There was no difference in fractional sodium excretion between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)