Serum cystatin C concentration correlates negatively with glomerular filtration rate as well as or better than that of serum creatinine, suggesting a constant formation, and elimination from extracellular fluid mainly by glomerular filtration. It is not known, however, how well the renal plasma clearance of this 13-kDa basic polypeptide matches the glomerular filtration rate. This was investigated in rats during control conditions and after reduced renal perfusion pressure. 125I-cystatin C and an indicator for glomerular filtration (51Cr-EDTA or 131I-aprotinin) were injected intravenously. The renal accumulation and urinary excretion of the tracers were recorded in periods of 2.5 to 20.0 min. The renal plasma clearance of 125I-cystatin C (Ccy) based on the renal content of 125I correlated well with the glomerular filtration rate (CCr-EDTA) in periods up to 6 min; i.e. Ccy = 0.94 x CCr-EDTA, r = 0.99. Less than 0.5% of the filtered amount appeared in the urine. During more prolonged periods, Ccy increasingly underestimated glomerular filtration rate, reaching about 0.4 x CCr-EDTA in a 20-min period. Free 125I relative to total plasma 125I activity increased from about 2% at 5 min to about 70% at 20 min. In nephrectomized rats, free 125I accumulated in plasma at a slower rate, accounting for about 15% of the total activity 20 min after injection of 125I-cystatin C. We conclude that cystatin C is (a) mainly removed from the extracellular fluid by the kidneys, (b) practically freely filtered in the glomeruli, and (c) completely absorbed and rapidly broken down by the proximal tubular cells.

Renal tissue damage is substantially more pronounced in the juxtamedullary than in the superficial cortex in hypertensive rats, and the pathogenesis of the morphological changes are only partly understood. Glomerular capillary pressure (PGC) is increased, and steady-state autoregulation is normal in the deep renal cortex. We tested the hypothesis that the transient period from one pressure level to another may induce greater variation in local perfusion before stable autoregulation is established. An acute increase in local perfusion was compared in the superficial and juxtamedullary cortex of spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) after an abrupt increase in perfusion pressure. Total renal blood flow (RBF) was measured by a Transonic flow probe and local renal perfusion by laser Doppler flowmetry. Renal perfusion pressure was lowered to 50% of initial values and released abruptly. The maximal RBF increased from 6.3 ± 0.4 to a maximal value of 7.6 ± 0.3 ml/min ( P < 0.001) in SHR and from 7.3 ± 0.3 to 8.2 ± 0.6 ml/min ( P < 0.001) in WKY. These changes were not significantly different from each other. The change in superficial cortical perfusion was also not different between SHR and WKY. Pressure release increased juxtamedullary perfusion in SHR from 146 ± 8 to a maximal value of 228 ± 17 units ( P < 0.001) and in WKY from 160 ± 13 to 179 ± 11 units ( P < 0.001). The results were significantly different from each other ( P < 0.001). The time for maximal flow response was shorter in the deep cortex of SHR, and the time for normalization was longer than in WKY. These data indicate that the buffering of perfusion pressure variation is significantly attenuated in the juxtamedullary cortex, and significantly more so in SHR than in WKY, assuming a covariation of RBF and PGC, and this finding may explain the extensive morphological damage in the juxtamedullary cortex of SHR.

The effect of AVP-V2 receptor agonist desmopressin, dDAVP, its non-peptide antagonist OPC-31260 and vehicle infusion on glomerular filtration rate (GFR) in the outer, middle and inner cortex was studied in both hydropenic and water diuretic Inactin anaesthetized female Sprague-Dawley rats using the aprotinin method. Two subsequent GFR measurements were carried out in the same kidney by injection of 125I- and 131I-labelled aprotinin before and after i.v. infusion of dDAVP, OPC-31260 or the vehicle. Acute infusion of dDAVP in hydropenic rats increased total GFR by 14% relative to vehicle infusion, whereas in water diuretic rats it had no effect relative to vehicle. No significant changes in arterial pressure (Pa) or renal blood flow (RBF) were recorded. Infusion of OPC-31260 reduced total GFR by 11% compared with vehicle. These results are consistent with the findings that a presensitization of the vasculature by high plasma levels of AVP is necessary for the renal vascular effects mediated by the V2 or V2-like receptors to occur. The ratio between inner and outer cortex GFR remained unchanged from control to experimental condition as follows: dDAVP infusion in hydropenic rats, 0.504 vs. 0.494 in control; vehicle infusion in hydropenic rats, 0. 393 vs. 0.392; OPC-31260 infusion in hydropenic rats, 0.517 vs. 0. 523; dDAVP in water diuretic rats, 0.547 vs. 0.543; vehicle in water diuretic rats, 0.413 vs. 0.417. Thus no significant difference in the GFR response was observed between superficial and deep cortical layers of the rat kidney.

Exogenous angiotensin II (AngII) has a marked vasoconstrictor effect on most vascular beds, including the kidney. More important, a constant intrarenal formation of AngII, regulated mainly through renin release by the juxtaglomerular apparatus, provides a sustained contribution to vascular tone and resistance. A large number of studies have shown that AngII infusion causes relatively greater reduction of renal blood flow (RBF) than of glomerular filtration rate (GFR) and an increase in the filtration fraction, suggesting a preferential vasoconstriction in postglomerular resistance vessels (Navar et al. 1996). More conflicting results have been obtained on a possible preferential reduction of RBF in deep or superficial cortical layers, possibly due to a variable counter-regulation by prostaglandins or nitric oxide (NO) formation (Aiken & Vane, 1973;Aukland, 1976;Mattson & Roman, 1991;Hura & Stein, 1992;Pallone, 1994;Navar et al. 1996).In the 1970s many GFR distribution studies were performed using the Hanssen ferrocyanide technique (Hanssen, 1963) to test the hypothesis that renal sodium chloride excretion could be determined by the relative filtration rate in deep and superficial cortex. As summarized by Lameire et al. (1977) the results obtained in rats on varying salt intake Different changes in glomerular filtration rates (GFR) in deep and superficial glomeruli have been suggested to influence renal NaCl excretion and concentrating ability. Angiotensin II (AngII) has been implicated in such changes, but the experimental evidence has been conflicting, probably because of the methodological limitation of just one 'snapshot' measurement of local GFR per kidney. We have therefore studied the effect of AngII and AT 1 -receptor blockade on glomerular filtration in outer, middle and inner cortex (OC, MC and IC, respectively) in pentobarbitoneanaesthetised rats using the aprotinin (Ap) method, providing control and experimental measurements in the same kidney. Glomerular filtration rate per gram cortical tissue was measured based on 'free' glomerular filtration of Ap followed by complete tubular uptake and a 20 min sojourn in the proximal tubular cells before breakdown and incipient return to the plasma. Effect of exogenous and endogenous angiotensin II on intrarenal distribution of glomerular filtration rate in rats 125I-labelled Ap was injected I.V. to determine control Ap clearance, followed after 13 min by injection of AngII or the A1 type AngII receptor blocker losartan and 2 min thereafter by 131 Ilabelled Ap to determine clearance in the experimental period. Tracer activity in frequent blood samples and in tissue samples allowed calculation of GFR in the two periods. Mean GFR control values were: 1.13 ml min _1 in whole kidney and 1.44, 1.27 and 0.76 ml min _1 per gram cortical tissue in OC, MC and IC, respectively. The most sensitive and comprehensive measure of altered GFR distribution is the ratio between the relative filtration change in inner versus that in outer cortex, F = (IC E /IC C )/(OC E /OC C ), w...

Background/Aims: Cross-transplantation studies between animals with genetic hypertension and normotensive animals indicate a key role of the kidney in development of hypertension, and studies in young spontaneously hypertensive rats (SHR) have shown reduced glomerular filtration rate (GFR) and renal blood flow (RBF) for a short period at the age of 4–6 weeks during blood pressure increase. We tested the hypothesis that a decline in GFR during development of hypertension in SHR might be more pronounced in juxtamedullary cortex than other cortical zones. Methods: By use of the aprotinin method, total and zonal cortical GFR was measured in anaesthetized Wistar-Kyoto (WKY) rats and SHR at the ages of 2, 4, 6, 8 and 10 weeks. RBF was measured by a transit time flowmeter. Results: Body and kidney weights in SHR and WKY were not significantly different in any age group (p >0.05). Mean arterial blood pressure (MAP) was not different at the age of 2 weeks (79 ± 6 mm Hg in SHR and 74 ± 5 mm Hg in WKY, p > 0.05), but was significantly higher in 4-week-old SHR (104 ± 1 mm Hg) compared to 4-week-old WKY (77 ± 3 mm Hg) (p < 0.01). The difference in blood pressure increased with age from 4 to 10 weeks. RBF, total GFR, and outer, middle, and inner cortical GFR increased with age but were not different in SHR and WKY in any age group (p >0.05). Renal vascular resistance was increased from 4 weeks of age in SHR (21.5 ± 1.8), significantly higher than WKY (14.4 ± 0.9 mm Hg·ml^–1·min·g) (p < 0.01) and stayed at higher values in older age groups (p ≤ 0.01). Conclusion: RBF, total and zonal GFR are not significantly different in anaesthetized SHR compared to WKY at ages from 2 to 10 weeks and GFR in juxtamedullary cortex is not decreased in SHR during onset of hypertension. The results from the present study indicate that development of hypertension cannot be explained by a temporary decline in RBF or total or zonal GFR.