Effect of cyclooxygenase inhibition on renal blood flow autoregulation in SHR.

The effect of acute and chronic indomethacin treatment on renal blood flow (RBF) autoregulation was studied in 10- and 40-wk-old spontaneously hypertensive rats (SHR). RBF autoregulation was substantially reduced in 40-wk-old SHR both during acute and chronic indomethacin treatment, whereas no effect was seen in the young SHR. The pressure range of autoregulation was 169 +/- 9 to 130 +/- 5 mmHg in the untreated 40-wk-old SHR, and 154 +/- 14 to 146 +/- 6 mmHg in indomethacin-treated 40-wk-old SHR (P less than 0.001). Indomethacin treatment had no effect on control RBF, mean arterial pressure, or renal vascular resistance in the 40-wk-old SHR. After removal of the renal nerves, RBF autoregulation during indomethacin treatment was restored in 40-wk-old SHR. The pressure range of RBF autoregulation was 158 +/- 7 to 142 +/- 7 mmHg in sham-operated animals, significantly different from the denervated 40-wk-old SHR, where RBF was autoregulated from 150 +/- 5 to 118 +/- 6 mmHg (P less than 0.01) during indomethacin treatment. The afferent arteriolar diameter (DAA) was studied by the microsphere method in 10-wk-old SHR and in untreated and indomethacin-treated 40-wk-old SHR. DAA was significantly greater in 40-wk-old compared with 10-wk-old SHR (22.1 +/- 0.4 vs. 17.9 +/- 0.5 microns) (P less than 0.01), whereas indomethacin treatment in 40-wk-old SHR did not influence the DAA significantly (21.5 +/- 0.3 microns, P greater than 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular hemodynamics in progressive renal disease.

A descriptive survey of renal hemodynamics in the major experimental models of progressive renal disorders (primary loss of renal tissue, primary glomerular injury and primary hypertension) is given. Although the pathogenesis in the different models differs in several respects, increases in glomerular capillary pressure and renal growth factors are important for the development of progressive renal disorders. In primary glomerular disorders, interstitial immune reactions seem to be critical. In glomerular nephritis with increased capillary wall thickness, the increase in glomerular capillary pressure may be of less importance than in other models. A third important factor for progression of renal disorders is a gradual breakdown of autoregulation of renal blood flow and glomerular filtration rate exposing the glomerulus to the variations in systemic blood pressure.

Acute effect of passive Heymann nephritis on renal blood flow and glomerular filtration rate in the rat: role of the anaphylatoxin C5a and the alpha-adrenergic nervous system.

In earlier studies, we have shown that induction of passive Heymann nephritis (PHN) by intrarenal infusion of anti-Fx1A antibodies provokes an immediate fall in renal blood flow (RBF) and glomerular filtration rate (GFR). This was probably mediated via the complement system, as infusion of the F(ab')2 fraction of anti-Fx1A did not reduce RBF and GFR. In the present study, the effects of alpha-adrenergic blockade upon the acute hemodynamic changes during induction of PHN and of C5a infusion were studied. Group 1 was infused with anti-Fx1A antibodies during blockade of the sympathetic nervous system with the alpha-blocker phentolamine; control animals were treated similarly, but infused with normal rat IgG. Group 2 was infused with the anaphylatoxin C5a, normally produced during complement activation, and compared with control animals infused with saline. In group 1, RBF did not differ from control animals after the infusion of anti-Fx1A antibodies (6.6 +/- 0.5 compared to 7.3 +/- 1.0 ml/min/g in the controls). GFR in the left, antibody-infused kidney fell compared to controls, and was 0.25 +/- 0.08 ml/min/g at the end of the experiment compared to 0.60 +/- 0.13 ml/min/g (p less than 0.05 with Student's t test, p = 0.07 with two-way analysis of variance (ANOVA). GFR in the right kidney remained unchanged compared to controls. In group 2, C5a induced a significant fall in RBF (from 7.9 +/- 0.9 to 3.1 +/- 0.4 ml/min/g kidney weight), significantly different from control animals where it fell from 8.1 +/- 0.5 to 6.8 +/- 0.7 ml/min/g (p less than 0.0001 with two-way ANOVA, p less than 0.001 with t test).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effect of passive Heymann nephritis on renal blood flow and glomerular filtration rate in rat: the effect of infusion of F(ab')2 fraction of anti-FX1(A) antibody.

We have earlier shown that there is an immediate fall in renal blood flow (RBF) and glomerular filtration rate (GFR) during induction of passive Heymann nephritis (PHN) by infusion of rabbit antibodies towards rat renal brush-border antigens (anti-Fx1A). To investigate the role of complement activation in this stage of the disease, we infused the F(ab')2 fraction of anti-Fx1A (aFFab) in one group of rats and the F(ab')2 fraction of normal rabbit IgG in another group (controls). aFFab produced no hemodynamic changes when compared to controls. Sixty minutes after infusion of aFFab, RBF was 5.7 +/- 0.4 ml/min/g kidney weight (control 7.3 +/- 1.0, NS), after anti-Fx1A RBF was 3.2 +/- 0.7, p less than 0.05 compared to control. GFR after infusion of aFFab was 1.0 +/- 0.1 ml/min/g (control 0.8 +/- 0.1, NS), after infusion of anti-Fx1A 0.2 +/- 0.1 (p less than 0.02 compared to control). The blood pressure was unaffected by aFFab infusion, while there was a temporary fall in blood pressure to a minimal value of 76 +/- 4 mm Hg 10-20 min after infusion of anti-Fx1A (p less than 0.01 compared to control). Immunofluorescence studies showed granular immune deposits in the subepithelial region of the glomerular basement membrane as shown after infusion of anti-Fx1A antibodies. In addition, fluorescence was seen in the brush-border of proximal tubuli. The results indicate that the immediate fall in RBF and GFR during induction of PHN in mediated via activation of the complement system.

Renal blood flow and glomerular filtration rate during the heterologous phase in passive Heymann nephritis in rats.

When passive Heymann nephritis (PHN) is induced by infusion of antibodies (anti-Fx1A), an acute fall in renal blood flow (RBF) and glomerular filtration rate (GFR) has been reported. Activation of the complement cascade by the local antigen-antibody reaction might be involved in this reaction. We therefore studied RBF and GFR during acute infusion of anti-Fx1A and after 3 days when heterologous antibodies are no longer present in the circulation. Two groups of rats were infused with 2 mg anti-Fx1A antibodies into the left renal artery; RBF was measured by the microsphere method and GFR by 125I-Na-iothalamate clearance. In the first group, the measurements were made 40 min after the infusion, and in the second group after 3 days. A third group was studied 3 days after infusion of 1 mg anti-Fx1A. Animals infused with normal IgG were used as controls. Forty minutes after infusion of 2 mg anti-Fx1A, GFR in the left kidney was reduced from 1.16 +/- 0.07 to 0.41 +/- 0.16 ml/min/g in the controls (p less than 0.05). Three days after the infusion, GFR was 1.04 +/- 0.07, not significantly different from control. RBF was reduced to 3.97 +/- 1.11 ml/min/g after 40 min, compared to 7.53 +/- 0.73 in controls (p less than 0.05), and was normalized after 3 days. The effect of 1 and 2 mg anti-Fx1A antibodies was not significantly different after 3 days. Anti-Fx1A antibodies were detected in serum in the acute stage, but not after 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

The acute effect of passive Heymann nephritis on renal blood flow and glomerular filtration rate in rats.

The acute renal hemodynamic changes during induction of passive Heymann nephritis (PHN) may be of importance for the understanding of the pathogenesis of this model. We studied the renal blood flow (RBF) and glomerular filtration rate (GFR) during and after infusion of anti-FxlA into the left renal artery of rats for 10 min. 3 control groups were given 0.9% NaCl, 1 and 2 mg of normal rabbit IgG, respectively. The experimental groups were given 1 and 2 mg IgG fraction of anti-FxlA. Compared to controls, both RBF and GFR were substantially reduced during the first 20-30 min after infusion and remained unaltered for the rest of the observation period. After 20-30 min, RBF in the 1-mg group was 4.8 +/- 0.77 ml/min/g kidney weight versus control, 6.4 +/- 1.23 (NS), and in the 2-mg group, 3.5 +/- 0.65 ml/min/g versus control, 6.4 +/- 1.07 (p less than 0.05). Similarly, in the 1-mg group, GFR was 0.40 +/- 0.08 ml/min/g versus control, 0.76 +/- 0.11 (p less than 0.05), and in the 2-mg group, 0.14 +/- 0.05 versus control, 0.77 +/- 0.12 (p less than 0.0001). The reductions were greater in the 2-mg than in the 1-mg infused experimental groups, but this difference did not reach statistical significance. Immunofluorescence showed typical granular fluorescence of rabbit IgG along the glomerular basement membrane, and electron microscopy showed subepithelial immune deposits. This indicates that in the initial phase of PHN, corresponding with the formation of immune complexes, a pronounced fall in RBF and GFR occurs.

Autoregulation of renal blood flow (RBF) with and without participation of afferent arterioles.

The participation of the afferent arterioles (AA) in RBF autoregulation was studied in two groups of rats (groups A and B) by measurement of the afferent arteriolar diameters (dAA) by the microsphere method at control pressure (groups A and B), at the lower pressure limit of RBF autoregulation (group A) and at a perfusion pressure half-way between these pressures (intermediate pressure) (group B). The RBF was autoregulated from 109 +/- 7 (control pressure) to 80 +/- 7 mmHg (lower pressure limit) in group A, and from 101 +/- 4 (control pressure) to 77 +/- 3 mmHg in group B. In group A, dAA was significantly lower (17.2 +/- 0.3 micron) at control pressure than at the lower pressure limit of RBF autoregulation (20.3 +/- 0.03 micron) (P less than 0.005). In group B, dAA was 17.3 +/- 0.3 micron at control pressure and 17.1 +/- 0.4 micron at the intermediate pressure (89 +/- 3 mmHg) (P greater than 0.10). The results indicate that dilation of the afferent arterioles occurs only in the lower part of the autoregulatory pressure range. Possibly, RBF autoregulation at minor pressure reductions is achieved by dilation of the interlobular artery. Participation of the glomerular hilar branches of the afferent arterioles in RBF autoregulation cannot be excluded.

Resetting of renal blood flow autoregulation in spontaneously hypertensive rats.

Renal blood flow (RBF) autoregulation was examined in untreated 10- and 40-wk-old spontaneously hypertensive rats (SHR) [mean arterial pressure (MAP) 125 +/- 4 and 167 +/- 7 mmHg] and in captopril-treated (7 days) 10- and 40-wk-old SHR (88 +/- 7 and 112 +/- 5 mmHg). Age-matched Wistar-Kyoto rats (WKY) were used as controls (MAP 91 +/- 3 and 104 +/- 2 mmHg). The study was carried out in rats with and without acute uninephrectomy. In 10-wk-old acutely uninephrectomized animals, the lower pressure limit of autoregulation was 78 +/- 4 mmHg in WKY, 102 +/- 5 mmHg in SHR (P less than 0.02), and 78 +/- 7 mmHg in captopril-treated SHR (P greater than 0.10). The renal vascular resistance (RVR) was significantly elevated at the lower pressure limit of RBF autoregulation in untreated SHR (P less than 0.02) but became normal after treatment (P greater than 0.10). Neither uninephrectomy nor variation of RBF between different batches seemed to influence the lower pressure limit of RBF autoregulation. In 40-wk-old acutely nephrectomized animals, the lower pressure limit of RBF autoregulation in WKY was 85 +/- 4 mmHg, 128 +/- 3 mmHg in SHR (P less than 0.001), and 101 +/- 5 mmHg in captopril-treated SHR (P less than 0.01). RVR at the lower pressure limit was increased in untreated SHR (P less than 0.01), but fell to normal values during captopril treatment. Neither the uninephrectomy nor variation of RBF between different batches of rats seemed to influence the lower pressure limit of RBF autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoregulation of renal blood flow in two-kidney, one-clip hypertensive rats.

Renal blood flow (RBF) autoregulation was examined in the clipped and nonclipped kidneys in two groups of two-kidney, one-clip (2K-1C) hypertensive rats 10 wk after clipping. The arterial pressure distal to the clip and the renin secretion rate (RSR) were also examined. The blood pressure (BP) was 149 +/- 4 and 162 +/- 6 mmHg in the two hypertensive groups vs. 114 +/- 3 mmHg in the controls (P less than 0.02). The RBF (in ml X min-1 X kidney-1) was 4.27 +/- 0.41 in the nonclipped and 2.18 +/- 0.23 in the clipped kidneys (P less than 0.001). The pressure distal to the clip was 104 +/- 7 mmHg. The renal vascular resistance (RVR) (in mmHg X ml-1 X min-1 X g-1) was 25.0 +/- 1.4 in the control kidneys vs. 58.4 +/- 4.5 in the nonclipped (P less than 0.001) and 39.9 +/- 6.6 in the clipped kidneys (P less than 0.01). The RBF autoregulation was well preserved in the nonclipped kidneys but reset to a higher lower pressure limit of autoregulation of 106 +/- 4 mmHg, which was significantly higher than in the normotensive controls (84 +/- 6 mmHg) (P less than 0.01). In the clipped kidneys there was complete loss of RBF autoregulation. RSR decreased with reduction of the perfusion pressure in the clipped kidneys. The increased RVR might have been due to a combination of structural and functional changes in both kidneys.