Role of nitric oxide in the autoregulation of renal blood flow and glomerular filtration rate in aging spontaneously hypertensive rats.

Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) is well maintained in the spontaneously hypertensive rat (SHR). In old SHR, the RBF autoregulation is dependent upon prostaglandins as well as the sympathetic nervous system. The purpose of this study was to examine the role of nitric oxide (NO) in the autoregulation of RBF and GFR in aging SHR (70 weeks) as compared with young SHR (10 weeks) and age-matched Wistar-Kyoto (WKY) rats using NO synthase (NOS) inhibition that has a minimal effect on the RBF. The autoregulation of RBF was examined using an adjustable aortic clamp above the renal arteries and an ultrasound Doppler flow probe on the left renal artery. The lower pressure limit of RBF autoregulation was examined before and after infusion of the NOS inhibitor N(G)-monometyl-L-arginine (L-NMMA; 500 microg. kg(-1).min(-1)). Separate groups were given a coinfusion of L-NMMA and L-arginine (5 mg.kg(-1).min(-1)) or Ringer solution. The autoregulation of the GFR was studied in continuously infused animals using the (125)I-iothalamate clearance. Measurements of the GFR were done at control blood pressure, at a renal arterial pressure 10 mmHg above the lower pressure limit of RBF autoregulation and at a renal arterial pressure of about 60-65 mmHg. In both SHR and WKY rats, infusion of L-NMMA increased the mean arterial blood pressure, and the RBF decreased in young SHR, while the RBF was unchanged in the WKY groups and aged SHR. The autoregulation of RBF was maintained in all animals. The GFR was unchanged in all groups after infusion of L-NMMA, and the autoregulation of GFR was well maintained in all groups except in the 70-week-old SHR. In these animals, the fractional compensation of GFR decreased from 0.95 to approximately 0 after infusion of L-NMMA, indicating that autoregulation of the GFR was lost during NOS inhibition. Coinfusion of L-NMMA and L-arginine normalized the GFR autoregulation in this group. The results indicate that in hypertensive rats with renal hypertensive damage, the GFR autoregulation is strongly NO dependent, as doses of L-NMMA that do not interfere with the RBF have an effect on the GFR autoregulation. As the GFR was unchanged during L-NMMA infusion, these observations suggest that postglomerular contraction during NOS inhibition may be involved in the regulation of GFR in 70-week-old SHR.

Effects of antihypertensive drugs on autoregulation of RBF and glomerular capillary pressure in SHR.

The relationship between systemic blood pressure and glomerular capillary pressure (Pgc) in spontaneously hypertensive rats (SHR) during treatment with antihypertensive drugs is still unclear. The effects of an angiotensin-converting enzyme inhibitor (enalapril), two calcium channel antagonists (nifedipine and verapamil), and an alpha1-receptor blocker (doxazosin) on renal blood flow (RBF) autoregulation, Pgc, and renal segmental resistances were therefore studied in SHR. Recordings of RBF autoregulation were done before and 30 min after intravenous infusion of the different drugs, and Pgc was thereafter measured with the stop-flow technique. When the mean arterial pressure (MAP) was reduced to approximately 120 mmHg by infusions of doxazosin or enalapril, the lower pressure limit of RBF autoregulation was reduced significantly. Nifedipine or verapamil abolished RBF autoregulation. Doxazosin did not change Pgc (43.6 +/- 1.4 vs. 46.7 +/- 1.5 mmHg in controls, P > 0.5), enalapril lowered (41.3 +/- 0.8 mmHg, P < 0.01), and the calcium channel antagonists increased Pgc [53.7 +/- 1.4 mmHg (nifedipine) and 54.8 +/- 1.2 mmHg (verapamil), P < 0.01]. When MAP was reduced to approximately 85 mmHg by drugs, Pgc was reduced to 43.3 +/- 1.7 mmHg after nifedipine (P > 0.2 vs. control), whereas Pgc after enalapril was 38.5 +/- 0.5 mmHg (P < 0.05 vs. control). Enalapril reduced Pgc mainly by reducing efferent resistance. During treatment with calcium channel antagonists, Pgc became strictly dependent on MAP. Monotherapy with nifedipine may increase Pgc and by this mechanism accelerate glomerulosclerosis if a strict blood pressure control is not obtained.

Resetting of renal blood autoregulation during acute blood pressure reduction in hypertensive rats.

Decrease in systemic blood pressure, duration of pressure decrease, and change in the activity of the renin or the sympathetic nervous system may represent mechanisms involved in resetting the renal blood flow (RBF) autoregulation found in hypertensive rats. Autoregulation of RBF, plasma renin concentration (PRC), and the time needed for resetting to take place were studied in the nonclipped kidney before and after removal of the clipped kidney of two- kidney, one-clip (2K1C) hypertensive rats and before and after mechanical reduction of the renal arterial pressure (RAP) for 10 min in the spontaneously hypertensive rat (SHR) and in the nonclipped kidney of 2K1C hypertensive rats with and without renal denervation. Mean arterial pressure (MAP) fell from 147 to 107 mmHg 30 min after removal of the clipped kidney, and the lower pressure limit of RBF autoregulation decreased from 113 to 90 mmHg (P < 0.01); PRC fell. Mechanical reductions of RAP from 161 to 120 mmHg in the nonclipped kidney for 10 min did not change RBF, but at 120 mmHg, the lower pressure limit of RBF autoregulation was reduced from 115 mmHg before pressure reduction to 96 mmHg afterwards (P < 0.02). In SHR, similar pressure reduction for 10 min decreased the lower pressure limit of RBF autoregulation from 106 to 86 mmHg (P < 0.01). PRC was unchanged in both models, and denervation did not change RBF autoregulation. When RAP was reduced below the lower pressure limit of RBF autoregulation, RBF decreased approximately 20%; the lower pressure limit of RBF autoregulation remained unchanged. In normotensive Wistar-Kyoto rats, pressure reduction did not change the range of RBF autoregulation. These results indicate that acute normalization of the pressure range of RBF autoregulation in hypertensive rats is dependent on the degree of pressure reduction of RAP, whereas renal innervation and PRC do not play a major role. We propose that the mechanism of resetting is due to afterstretch of noncontractile elements of the vessel wall or is caused by pure myogenic mechanisms. An effect of intrarenal angiotensin cannot be excluded.

Increased glomerular capillary pressure and size mediate glomerulosclerosis in SHR juxtamedullary cortex.

To gain insight into the mechanisms in the development of glomerulosclerosis in juxtamedullary cortex, the degree of glomerulosclerosis, glomerular tuft diameter, glomerular capillary pressure (Pgc), and local renal blood flow (RBF) autoregulation were measured in superficial and juxtamedullary cortex of 10- and 70-wk-old spontaneously hypertensive rat (SHR), using aged matched Wistar-Kyoto (WKY) rats as controls. Pgc was measured after corticotomy by direct micropuncture of glomeruli in superficial and juxtamedullary cortex. Total RBF was measured by a transit-time flowmeter (Transonic) and local blood flow by use of laser-Doppler flowmetry. The degree of glomerulosclerosis measured by a semiquantitative histological technique was significantly increased in juxtamedullary compared with superficial cortex in all groups. The difference was most pronounced in the juxtamedullary cortex of 70-wk-old SHR. Pgc was significantly increased in juxtamedullary cortex compared with superficial cortex in 70-wk SHR (57.1 +/- 2.7 vs. 46.5 +/- 0.5 mmHg, P < 0.01). The corresponding data set from 70-wk WKY was 45.5 +/- 0.43 vs. 41.6 +/- 1.5 (P < 0.05). The Pgc in juxtamedullary cortex of 10-wk SHR was slightly higher than in superficial cortex (45.1 +/- 2.3 vs. 50.1 +/- 1.2 mmHg, P = 0.05), whereas there was no difference in 10-wk WKY. Glomerular diameter was larger in juxtamedullary cortex in old animals but not significantly different in 10-wk WKY rats and 10-wk SHR. Total RBF was reset to higher perfusion pressures in hypertensive rats. Juxtamedullary and superficial blood flow autoregulation were not significantly different from total RBF autoregulation in all groups. These results suggest that hypertrophy as well as increased Pgc might contribute to the development of manifest glomerulosclerosis. Changes in local blood flow autoregulation do not seem to play a major role in the development of glomerulosclerosis.

[Treatment of hypertension in renal parenchymal diseases]. / Behandling av hypertensjon ved parenkymatøse nyresykdommer.

Hypertension is a common finding in patients with renal parenchymatous diseases. Development of hypertension causes increased proteinuria, decline in glomerular filtration rate and reduced life span in experimental models of glomerulonephritis. Hypertension has been shown to reduce glomerular filtration rate in man. It is therefore important to treat hypertension. The blood pressure should be reduced to about 140/80 mm Hg. Reduction of glomerular capillary pressure, inhibition of glomerular permeability, renal hypertrophy and inhibition of mesangial metabolism are the main mechanisms of renal protection during antihypertensive therapy. Autoregulation of the renal blood flow probably has an impact on these mechanisms. Impaired autoregulation is found in kidneys with low glomerular filtration rate and during treatment with calcium channel blockers. Alpha receptor blockers, angiotensin converting enzyme inhibitors (ACE-) and angiotensin II receptor blockers do not interfere with autoregulation. All types of antihypertensive drugs provide similar renal protection when the glomerular filtration rate is reduced. When calcium channel blockers are used in kidneys with normal or slightly reduced function, either blood pressure should be kept strictly at normal levels or these type of drugs should be combined with ACE inhibitors or angiotensin II receptor blockers.

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.

Effect of mesangiolysis on autoregulation of renal blood flow and glomerular filtration rate in rats.

Interlobular arteries and afferent arterioles are involved in autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR). The question of whether the contractile mesangial cells are also involved in autoregulation was investigated in Wistar rats. Autoregulation of RBF was examined before and 1 h after infusion of antithymocyte (anti-Thy 1-1) antibodies, and both RBF and GFR autoregulation were examined 30 h after the infusion of antibodies. Mesangial cell destruction was present 30 h after the infusion of antibodies. The angiotensin II-induced contraction of isolated glomeruli (70% of control volume, P less than 0.001) was abolished after the glomeruli had been exposed to anti-Thy 1-1 in vitro. RBF, as well as the lower limit of RBF autoregulation, were not different from control 30 h after the infusion (82 +/- 5 vs. 79 +/- 4 mmHg, P greater than 0.10). Autoregulation of GFR was maintained in the control group but was restricted in the experimental group (autoregulatory index: 0.71 +/- 0.42 for left kidney, 0.02 +/- 0.35 for control; P less than 0.05). The afferent arteriolar diameter was unchanged 30 h after the infusion of antibodies (17.8 +/- 0.8 vs. 17.6 +/- 0.4 microns, P greater than 0.10). One hour after infusion of the antibodies, RBF autoregulation was normal. It is concluded that mesangial cells do not seem to be involved in RBF autoregulation, but may in part influence autoregulation of GFR during pressure reduction.