Jarle Ofstad

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.

Cadmium and Zinc in Human Liver and Kidney

Liver and kidney samples obtained from 76 autopsies were analyzed for cadmium and zinc content. The patients had died of various internal diseases. None of them had any known occupational exposure to cadmium. A record was made of age, sex, place of residence, diagnosis, and smoking habits of each patient. The results showed no significant correlation between cadmium accumulation and hypertension or cardiovascular disease. There was, however, a significantly higher kidney cadmium level in smokers than in nonsmokers.

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.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 α1-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 Pgcwas thereafter measured with the stop-flow technique. When the mean arterial pressure (MAP) was reduced to ∼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 ∼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 ∼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.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.

Diameter of the afferent arteriole in the dog kidney estimated by the microsphere method.

Microspheres with diameters of from 10 to 30 mum were injected into the renal arteries of three anesthetized dogs. The six kidneys were studied by light microscopy. The diameters of the spheres trapped in the afferent arterioles and of all spheres recovered in the kidneys were recorded. On the basis of the distribution of diameters in these two populations of spheres, the average diameter of the afferent arteriole and the distribution of the afferent arteriolar diameters were estimated. The average diameter of the afferent arterioles was 16.3 mum (S.D. 2.2 mum), without any difference between three cortical layers of equal thickness. The mean diameter of spheres trapped in the interlobular arteries was 25.7 mum (S.D. 2.6). It is suggested that the pressure drop along some interlobular arteries may be of physiological importance, affecting the autoregulation of blood flow in the renal cortex.

Effect of light exercise on renal hemodynamics in patients with hypertension and chronic renal disease.

Objective : Increased physical activity is followed by a stimulation of the sympathetic nervous system and this effect is probably more pronounced in patients with chronic renal failure and hypertension than in healthy controls. The role of sustained exercise in hypertensive patients with chronic renal failure, with and without antihypertensive therapy, is unclear, as is hormonal regulation of the renal hemodynamics. We hypothesized that prolonged low-intensity bicycle exercise would have a greater effect in patients with chronic renal failure than in controls, and that antihypertensive treatment would ameliorate these effects. Material and Methods : Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), mean arterial blood pressure (MAP), norepinephrine (NE) and atrial natriuretic peptide (ANP) were measured in the upright position before and during low-intensity exercise for 2 h in healthy controls ( n = 8) and in hypertensive patients with moderately reduced renal function who were not taking antihypertensives ( n = 7) or who were receiving treatment with captopril ( n = 10), enalapril ( n = 6) or verapamil ( n = 9). Results : GFR tended to decrease and ERPF decreased significantly in healthy individuals when exercise duration was prolonged from 1 to 2 h. An earlier decline in GFR and ERPF was seen in the renal failure patients compared with the controls. Filtration fraction (FF) increased during exercise in all groups except the group taking enalapril. MAP increased in the captopril group during exercise but was unchanged in the other groups. Treatment with captopril produced a more pronounced and earlier fall in exercise-induced GFR than in untreated controls, while verapamil treatment completely blunted the decline in GFR, with a concomitant increase in plasma ANP. No significant changes were seen in plasma NE levels, but urinary NE excretion increased in controls and captopril-treated patients during exercise. Conclusions : The results suggest that prolonged low-intensity exercise has a substantially greater effect on renal hemodynamics in hypertensive renal failure patients than in healthy controls, with negligible changes in plasma NE levels. Verapamil treatment seems to ameliorate the renal effects of exercise on GFR in these patients, and this may in part be mediated via a stimulatory effect on ANP.

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 NG–monometyl–L–arginine (L–NMMA; 500 μg·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 125I–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 ∼ 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.

Intrarenal venous and cortical catheter pressures in the dog kidney.

To examine the validity of intrarenal venous pressure (IRVP) as a measure of peritubular capillary pressure when obtained with a method applicable in man, IRVP was measured with a 0.9 mm o.d. catheter introduced retrograde into interlobar veins of anesthetized dogs and was compared with a modified needle pressure (cortical catheter pressure = RCCP) measured simultaneously in the same kidneys. In twelve dogs with a mean experimental kidney control sodium excretion of 91 +/- 15 (SEM) micronmol/min IRVP averaged 16.0 +/- 1.1 mmHg and was significantly lower than the average RCCP of 22.6 +/- 1.1 mmHg (P less than 0.001). These pressures compare well with the reported micropuncture pressures in the peritubular capillaries and proximal tubules, respectively, at comparable levels of sodium excretion. IRVP fell significantly during reduction of renal perfusion pressure within the range of autoregulation of renal blood flow and increased during elevation of renal pelvic pressure (PP). At at PP of 60 mmHg, when urine flow had stopped, the PP-IRVP gradient was 22.7 +/- 3.1 and increased to 36.7 +/- 3.8 (P less than 0.001) at a PP of 80. Acute renal vein constriction always increased IRVP before renal vein pressure reached the preceeding control level of IRVP. Increased urine flow during saline volume expansion and furosemid infusion was associated with increased IRVP. The results when compared with micropuncture data indicate that IRVP is a satisfactory expression of peritubular capillary pressure in the experimental conditions included in the study.

Distribution of Radioisotope-Labeled Microparticles in the Renal Cortex of Dogs in Hemorrhagic Hypotension

Isotope-labeled microspheres with an average diameter of 15 μ and 25 μ, and isotope-labeled macroalbumin (131MA) were injected into the aorta of 26 dogs before or after the animals were bled to hemorrhagic hypotension. The localization of the microspheres was studied by microscopical examination and the intrarenal distribution of the radioactivity was measured. No significant effect of the hemorrhagic hypotension upon the distribution of radioactivity or the number of microspheres in different cortical layers was observed in normal kidneys. In surgically manipulated kidneys the hypotension provoked a relative increase of the radioactivity in the middle and juxta-medullar parts of the renal cortex. In the early phase of hemorrhagic hypotension the fraction of spheres with a diameter greater than 20 μ recovered in the glomeruli increased from zero to 6.3% when compared with normotensive animals; this indicates a dilatation of the afferent arterioles in this phase of hemorrhagic hypotension.

Dye Dilution Measurement of the Renal Blood Flow: Observations of the Down Slope of the Dye Dilution Curve

The dye dilution curves from twelve human kidneys were compared with systemic curves from the same individuals recorded at the same time. The recirculation distance was the same for both types of recording.The renal curves were constantly influenced by recirculating dye. The initial deviation from the linear semilogarithmic extrapolation of the down slope of the renal curves occurred before the minimal re-circulation time and could be caused by inadequate mixing of dye in the renal artery, leakage of dye into the extravascular space or by the medullary circulation.