INTRODUCTION

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INCREASED GLOMERULAR capillary pressure is frequently associated with glomerular sclerosis in many models of renal disorders. Together with increased plasma flow, it is considered to be a major pathogenic factor in the progression of glomerular degeneration (20). In rats with genetic or renal hypertension, the tissue damage caused by the increased systemic pressure is not homogeneously distributed throughout the renal cortex. Arterial lesions, tubular atrophy, and interstitial fibrosis are typical findings in the juxtamedullary cortex, whereas these structures may remain normal in the superficial cortex (21). Collectively, these observations indicate first that the glomerular capillary pressure in hypertensive animals is increased in juxtamedullary cortex and second that autoregulation of the glomerular capillary pressure is different in juxtamedullary compared to the superficial cortical layers.

In the normotensive animal, glomerular capillary pressure, renal blood flow (RBF) and glomerular filtration rate (GFR) are kept constant within a wide range of systemic pressures by renal autoregulation (19). Autoregulation is mainly localized to the afferent arterioles, and in hypertensive animals, the inflection point of total RBF autoregulation is reversibly reset to the right (17). As the feeding pressure of the arterioles from the intralobular artery has been shown to be substantially greater in the juxtamedullary than in the superficial cortex (13), resetting of autoregulation might be different among cortical regions. One possible explanation of an increase in the glomerular capillary pressure in juxtamedullary glomeruli is that there is insufficient resetting or loss of autoregulation in these glomeruli when the systemic pressure is chronically elevated.

In the present study, we tested the hypothesis that the increased glomerulosclerosis in juxtamedullary glomeruli in hypertensive rats is due to increased glomerular capillary pressure. The glomerular capillary pressure was measured by direct micropuncture in superficial and juxtamedullary cortical glomeruli during development of glomerulosclerosis (3). Glomerular capillary pressures were related to the range of local RBF autoregulation and also to the size and sclerosis of glomeruli in the superficial and juxtamedullary cortical layers.

All measurements were performed in 10- and 70-wk-old spontaneously hypertensive rat (SHR), using age-matched Wistar-Kyoto (WKY) rats as controls. The results suggest that the development of glomerulosclerosis in juxtamedullary cortex correlates with both glomerular diameter and glomerular hydrostatic pressure, whereas local RBF autoregulation in superficial and juxtamedullary cortex was not significantly different.

	MATERIALS AND METHODS

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A total of 42 male SHR and 25 male WKY rats were used in this study. The rats had free access to water and were fed ordinary rat chow (B & K Universal), containing 0.30% sodium, 0.70% potassium, 0.88% calcium, and 18% crude protein. All experiments were performed in accordance with and under the approval of the Norwegian State Board for Biological Experiments with Living Animals.

Hemodynamic study. The measurements were carried out in fasted rats under pentobarbital sodium anesthesia (50-60 mg/kg). They were tracheostomized by polyethylene PE-260 tube, and a PE-50 catheter was introduced into the aorta through the left femoral artery. The left femoral vein was cannulated for infusion of 5% bovine serum albumin in 0.9% sodium chloride solution at a rate 1.0 ml · 100 g body wt¹ · h¹ to keep the hematocrit constant. The kidneys were exposed through a midline abdominal incision and dissected free with no attempts to denervate the kidney. It was placed in a plastic cup with its dorsal aspect facing upward and immobilized by cotton moistened in saline. The ureters were cannulated by a PE-10 catheter to ensure the urine excretion from the kidneys. RBF was measured by a 2-mm-diameter flow probe connected to a transit-time flowmeter (Transonic) and a Gould recorder. The probe was calibrated in vitro (15). A screw clamp was placed on the aorta above the renal arteries for reduction of the renal perfusion pressure. After surgery, the rats were allowed to recover for 30 min. Thereafter, arterial blood pressure was reduced in steps of 10-15 mmHg, and RBF was recorded continuously. In each case, RBF autoregulation was examined before and after corticotomy to ensure a normal flow/pressure relationship in each kidney. If this was not the case, then the animal was not used.

Corticotomy. After the left kidney was placed in the cup and immobilized, a corticotomy was performed, i.e., a lens-shaped slice with a diameter of ~5 mm was cut off from the dorsal part of the kidney using a sharp scalpel (3). The depth of the slice was 3-4 mm, exposing the juxtamedullary renal cortex. The bleeding stopped regularly after 2-4 min, and blood in the corticotomy was removed by repeatedly flushing with isotonic saline and suction with microsponges. Fluid that accumulated in the corticotomy was drained off during the micropuncture procedure. Maintenance of flow in the exposed glomeruli in the corticotomy was tested by injecting Evans blue and directly observing the capillaries in the glomeruli. Care was taken not to cut an arcuate artery; if this was done, then the animals were not used.

Micropuncture measurements of glomerular capillary pressure. Micropuncture was performed done with glass pipettes with sharpened tips of 3-5 µm in diameter, filled with 0.5 M NaCl colored with Evans blue under microscopic control (Wild model M5 stereomicroscope with a magnification of ×60), as previously described (3, 28) The micropipettes were connected to a servo-controlled counter pressure system, with a setup slightly modified from that described by Wiederhjelm et al. (28) and Intaglietta et al. (14). Pump pressure and aortic pressure were recorded continuously with Hewlett-Packard transducers (model 1280C) connected to a Gould model TA 4000 recorder. Illumination was provided by a two-armed fiber-optic lamp. The transducers were calibrated before each experiment. Zero pressure was checked repeatedly by placing the micropipette in a saline-filled cup at the level or in a drop of saline in the corticotomy. Since the localization of the micropipette within the glomerular capillary cannot be definitely ascertained visually, indirect criteria were employed for acceptance of pressure measurements as described by Aukland et al. (3). In short, the recorded pressure should not change when the feedback gain of the servo-controlled counter pressure system was varied. The systolic pressure peak should coincide with the arterial pressure curve, the pulse-to-pulse variation of the arterial pressure should be paralleled in the glomerular capillary pressure recordings, and the glomerular pulse pressure should demonstrate a dicrotic notch. When injecting Evans blue, the dye should not appear in Bowman's capsule, tubules, or interstitium.

Selection of glomeruli for micropuncture. In the corticotomy, as many as 50 glomeruli were exposed, some of which were loose and protruded into the corticotomy. These glomeruli were difficult to micropuncture, and most glomeruli at depth of 50-100 µm from the surface of the corticotomy were used for measurements. Glomeruli less than 600 µm from the surface of the kidney were defined as superficial glomeruli, and glomeruli in the bottom of the corticotomy, i.e., ~2,500-3,500 µm from the kidney surface, were defined as juxtamedullary glomeruli. As the density of glomeruli is lower in the deep cortex, fewer punctures were done in deep than in superficial glomeruli.

Laser-Doppler flowmetry and autoregulation of local renal perfusion. Local renal cortical perfusion was measured by laser-Doppler technique (Periflux 4001; Perimed). During the measurements, the kidneys were placed in a plastic cup and immobilized. The superficial probe was placed on the surface of the kidney, and the needle probe was 3-4 mm from the surface of the kidney to measure juxtamedullary cortical perfusion. Cortical blood flow was expressed a percentage of the respective laser-Doppler flux signals during the control period. The renal arterial pressure (RAP) was reduced in steps of 10-15 mmHg, and RAP, laser-Doppler flux signals, and total RBF were stored on a floppy disk until analysis.

View larger version (15K): [in this window] [in a new window]   Fig. 1.   Index of glomerular sclerosis in 10-wk and 70-wk Wistar-Kyoto (WKY; n = 13) and spontaneously hypertensive rats (SHR; n = 14). * P < 0.05, significant difference between superficial and juxtamedullary cortical glomeruli.

Measurement of GFR. Total GFR was measured in all groups of animals. GFR in cortical zones was studied in two groups of rats to assess the possible effect of corticotomy on total as well as local GFR. Total and local GFR values were measured by the method of tubular uptake of radiolabeled aprotinin (24, 26). Bolus of 10 µl ¹²⁵I-labeled aprotinin was injected during 5-7 s in the jugular vein. Arterial blood samples were collected at 15 s and 1, 3, 5, 10, and 15 min after starting the injection of ¹²⁵I-aprotinin. The kidneys were removed after 15 min, frozen in isopentane, prechilled to 20°C, put into preweighed counting glass tubes, reweighed, immediately counted in a gamma counter (Cobra II, Auto-Gamma) for 1 min, and thereafter frozen again. The total protein concentration and radioactivity were measured in each blood sample. Three pieces of tissue of equal thickness were obtained from outer, middle, and inner cortex. The radioactivity was counted in each piece (4-5 mg). Calculation of total and local GFR was by the amount of ¹²⁵I-aprotinin accumulated in the kidney or in the tissue sample (Q) divided by the time-integrated plasma concentration of aprotinin (pap), i.e., concentration of aprotinin (C_ap) = Q/(pap)dt. To obtain GFR, the clearance was corrected for plasma binding (P_b) of 7% aprotinin and for a glomerular Gibbs-Donnan distribution (r) across the glomerular membrane of 0.65 depending on the plasma concentration. GFR was calculated as follows: GFR = C_ap/(1  P_b) × r.

Corticotomy was done in the left kidney. In one group of 10-wk-old SHR (n = 7) and one group of 70-wk-old SHR (n = 7), total GFR was measured in both left and right kidney 30 min after corticotomy. In addition, local GFR was measured close to the corticotomy in the central surface of the left kidney and at the upper pole of the same kidney. The right kidney, where there was no corticotomy, served as control, and local GFR was measured in the middle part and in the upper pole. Zonal GFR was obtained by the average local GFR of five samples in one zone.

Measurements of sclerosis index. After the hemodynamic measurements were done, the kidneys were perfused with 4% formaldehyde with a perfusion pressure corresponding to the animal's arterial pressure. The kidneys were embedded in paraffin, and sections at 3-4 µm thickness were cut and stained with eosin and hematoxylin or periodic acid-Schiff (PAS). Sclerosis index as parameter of glomerular damage was determined in at least 100 superficial and 75 juxtamedullary glomeruli per animal using a modification of Raij et al. (22) on PAS-stained paraffin sections at a magnification of ×400. The degree of sclerosis was scored as follows: 0, no changes; 1, lesions involving less than 25% of the capillary tuft; 2, lesions affecting 25 to 49% of the capillary tuft; 3, lesion involving 50-75% of the capillary tuft; and 4, lesions involving more than 75% of the capillary tuft. The resulting index in each animal was expressed as a mean of all scores obtained.

Measurement of glomerular diameter. Standard stereological techniques were used to measure glomerular diameter in juxtamedullary and superficial cortex of all four groups (27). The diameter of the glomerular tuft was measured in four to six sections of total renal cortex after staining with hematoxylin and eosin and examined at a magnification of ×320.

Statistical analysis. The results are presented as means ± SE. Differences between groups were assessed by one-way analysis of variance in groups to be compared. Where significant difference was found, the groups were compared by Student's t-test. Differences between cortical layers were analyzed by paired comparisons.

View larger version (32K): [in this window] [in a new window]   Fig. 2.   A: relative frequency (%) of glomerulosclerosis index (GSI: 0-4) in superficial cortex in all groups showing increased relative frequency (%) of GSI 3-4 in 70-wk SHR. B: relative frequency (%) of GSI (0-4) in juxtamedullary cortex in all groups showing increased relative frequency (%) of GSI 3-4 in 70-wk SHR.

View larger version (17K): [in this window] [in a new window]   Fig. 3.   Glomerular tuft diameter in 10-wk and 70-wk WKY rats (n = 13) and SHR (n = 14). * P < 0.05 and ** P < 0.01, significant difference between superficial and juxtamedullary cortical glomerular diameter.

	RESULTS

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The mean arterial pressure (MAP) was significantly higher in SHR than in WKY rats (P < 0.001), but there was no significant increase in MAP between 10-wk and 70-wk in SHR (Table 1). The old animals had higher body and kidney weights. There was no significant difference in total RBF and free-flow proximal tubular pressure among the groups. GFR was significantly less in SHR than in WKY in both age. GFR declined with age (Table 1).

In all groups the sclerosis index was greater in the juxtamedullary than in the superficial cortex (Fig. 1). The sclerosis index was significantly greater in 70-wk than in 10-wk SHR both in superficial and juxtamedullary cortex (P < 0.01). In the corresponding cortical layers and age groups the index was greater in SHR than in WKY rats (P < 0.01).

The relative frequencies, in percent of glomerulosclerosis index (GSI, 0-4), in each group of animals are given in Fig 2, A and B. In 10-wk WKY and 10-wk SHR, GSI 0-1 was the dominant observation, whereas in 70-wk WKY, GSI 3 is found in juxtamedullary cortex in addition to GSI 0-2. In 70-wk SHR, GSI 3-4 is found and is more pronounced in juxtamedullary cortex than in the superficial layer.

The average diameter of the glomerular tuft was similar in superficial and juxtamedullary glomeruli in 10-wk WKY and 10-wk SHR (Fig. 3). The diameter in both cortical regions was larger in the old than in the young animals. In the old animals, the mean glomerular tuft diameter was greater in the juxtamedullary than in the superficial cortex (Fig. 4). In the corresponding cortical layers and age groups, the glomerular tuft diameter was significantly greater in old SHR than in the old WKY (P < 0.001).

View larger version (24K): [in this window] [in a new window]   Fig. 4.   Distribution of glomerular tuft diameters in 10- and 70-wk WKY (n = 13) and SHR (n = 14), showing a subpopulation of lager glomeruli in WKY 10-wk and 10-wk SHR. This subpopulation is not found in the old animals.

The distribution of glomerular diameters showed a biphasic distribution in the superficial cortex of the young rats with a small population of glomeruli with diameters >130 µm (Fig. 4). In the old SHR, there seemed to be a population of diameters greater than the mean value in the juxtamedullary cortex and a corresponding subpopulation of glomeruli with diameters less than the mean values in the superficial cortex (Fig. 4).

In SHR, glomerular capillary pressure in superficial cortex was not different in young and old animals (Fig. 5). In contrast, glomerular capillary pressure in the juxtamedullary glomeruli increased from 50.1 mmHg at 10-wk to 57.2 mmHg in the old SHR (P < 0.01). In WKY, the glomerular capillary pressures in juxtamedullary cortex were not different in young and old animals, whereas these pressures in the superficial glomeruli were significantly different as a result of a reduction of the glomerular capillary pressure from 45.1 to 41.6 mmHg (P < 0.05) in the old animals (Fig. 5).

View larger version (18K): [in this window] [in a new window]   Fig. 5.   Glomerular capillary pressure in superficial and juxtamedullary glomeruli in 10-wk and 70-wk WKY rats (n = 13) and SHR (n = 14). * P < 0.05, ** P < 0.01, and + P < 0.05, significant difference between superficial and juxtamedullary glomerular capillary pressures.

The glomerular capillary pressure in superficial glomeruli was similar (P > 0.2) in both SHR groups and in young WKY. The glomerular capillary pressure in the juxtamedullary glomeruli was greater in SHR than in WKY in both age groups (50.1 ± 2.3 vs. 45.2 ± 1.3 mmHg in young, P < 0.05; and 57.0 ± 2.7 vs. 46.5 ± 0.5 mmHg in old animals, P < 0.01) (Fig. 5). The distribution of the glomerular capillary pressure in juxtamedullary cortex was biphasic in old SHR. One fraction of the pressures overlapped the pressure distribution in the young SHR, whereas another population distributed around a value of ~62 mmHg (Fig. 6).

View larger version (16K): [in this window] [in a new window]   Fig. 6.   Distribution of glomerular capillary pressures in superficial and juxtamedullary cortex in 10- and 70-wk WKY rats and SHR showing two populations of glomerular capillary pressures in juxtamedullary cortex of 70-wk SHR.

The ratio between local GFR close to the corticotomy and in the upper pole in the left kidney was calculated in all three cortical layers. Local measurements were also performed in the right kidney, where there was no corticotomy. In the left kidney, the ratios of local GFR at upper kidney pole vs. local GFR close the corticotomy in the outer, middle, and inner cortex were 1.00 ± 0.03, 0.99 ± 0.02, and 0.95 ± 0.04, respectively. None of these values was significantly different from the ratios from the right kidney: outer cortex, 0.95 ± 0.04; middle cortex, 0.94 ± 0.04; inner cortex, 0.89 ± 0.03; P > 0.2. Similar measurements were performed in 70-wk SHR, and the ratios (upper kidney pole vs. local GFR close to the corticotomy) were 0.98 ± 0.04 in inner cortex, 0.96 ± 0.05 in middle cortex, and 0.95 ± 0.05 in inner cortex. These results were not significantly different from the data obtained in the right kidney where no corticotomy was done (0.98 ± 0.02 in outer cortex, 0.94 ± 0.04 in middle cortex, and 0.92 ± 0.03 in inner cortex; P > 0.2). There was no significant difference between total GFR in the right and the left kidney of either 10-wk or 70-wk SHR after corticotomy.

Total and local blood flow autoregulation. RBF autoregulation was seen in all groups (Fig 6). In the 10-wk WKY rats, the lower pressure limit of total blood flow as 79 ± 2 mmHg. In terms of general shape and lower pressure limit of autoregulations, this curve was not significantly different from what was obtained by laser-Doppler flowmetry in superficial and juxtamedullary cortex during pressure reduction. In 70-wk WKY rats, the lower pressure limit of total RBF autoregulation was 80 ± 3 mmHg. The relationships between changes in RAP and laser-Doppler flowmetry in superficial and juxtamedullary cortex were not significantly different (P > 0.2).

In the SHR, RBF autoregulation was reset to higher perfusion pressures. The lower pressure limit of total RBF autoregulation was 107 ± 2 mmHg in 10-wk SHR, and the corresponding value in 70-wk SHR was 110 ± 3 mmHg (not significant). Relationship between changes in perfusion pressure and superficial and juxtamedullary renal laser-Doppler flowmetry was not significantly different from total RBF in 10- and 70-wk SHR (Fig. 7).

View larger version (25K): [in this window] [in a new window]   Fig. 7.   Autoregulation of total renal blood flow (RBF) and blood flow in superficial and juxtamedullary cortex of 10- and 70-wk-old WKY rats (n = 12) and SHR (n = 14).

	DISCUSSION

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The main new finding in this study was the increased glomerular capillary pressure in the juxtamedullary cortex in 70-wk-old SHR. A corresponding increase was not observed in WKY and was not present in the superficial glomeruli either in SHR or in WKY. On the contrary, the glomerular capillary pressure decreased in the superficial glomeruli in WKY with age.

Previous studies of Heyeraas and Aukland (25) have validated the corticotomy method. The authors observed no difference between the glomerular capillary pressure in the area subjected to corticotomy compared with undisturbed areas on the surface of the cortex. In the present study, we extended this method to study glomerular capillary pressures closer to the corticomedullary border. These measurements are the first observations of glomerular capillary pressures in the juxtamedullary cortex of SHR. The punctured glomeruli in this study all had good circulation as verified by direct observation after injection of Evans blue in the individual glomeruli. Although this procedure undoubtedly represents a major trauma, the functional consequences seemed to be acceptable. First, we did not observe any change of GFR in the cortex tissue neighboring the corticotomy, and the corticotomy did not adversely affect total GFR. Second, the sampling error in glomerular capillary measurements was probably least in the kidney without or with only minor degrees of glomerular sclerosis, i.e., the 10-wk WKY rats; consequently, the distribution of capillary pressures in these animals might provide a useful estimate of the error primarily due to the procedure of pressures measurements. It is important to note that the standard error of the mean of the glomerular capillary pressure measurements in these kidneys was not different in the juxtamedullary and the superficial cortex (Fig. 4). Together, these observations indicate that the corticotomy procedure did not introduce a significant measurement variability in addition to that inherent in similar pressure measurements in superficial cortex.

The numbers of micropunctures carried out did not permit an exact estimate of the distribution of pressures. The measurements suggest a biphasic population of pressures in the juxtamedullary glomeruli in the 70-wk SHR not present in the other cortical layers or groups of animals. The increased pressures in the 70-wk SHR seemed to be present only in one of the two populations; the other seems to overlap with the pressures in the superficial cortex. The question of whether the glomeruli with these increased pressures correspond with the subpopulation of glomeruli with the greatest diameters in the juxtamedullary cortex of 70-wk SHR cannot be answered from our data. The considerable subpopulation of glomeruli with the larger diameters observed in superficial cortex of both 10- and 70-wk WKY rats did not seem to induce a similar biphasic distribution of pressures in these layers, and serial micropunctures in the remnant kidney where the distribution of glomerular diameters is biphasic did not indicate a positive correlation between pressures and diameters in the superficial cortex in these kidneys (9). Previous investigations have postulated an important correlation between the glomerular size, pressure, and glomerulosclerosis in rats (12, 29, 30). One possible interpretation of the biphasic distribution of the glomerular capillary pressures in the juxtamedullary cortex of the old SHR is that the glomeruli with the highest pressures correspond to the subpopulation of glomeruli with the largest diameters in the young SHR. This suggestion remains hypothetical, as the degree of sclerosis, renal tuft diameter, and the glomerular capillary pressures were not measured in the same glomeruli. A less hypothetical explanation is that the distribution of glomerular capillary pressures in the juxtamedullary glomeruli of 70-wk SHR simply reflects the well-known uneven distribution of lesion of arterioles and glomeruli in kidneys damaged by systemic hypertension.

The well-documented relationship between glomerular capillary pressure and development of glomerulosclerosis seems to be strain dependent. In the Fawn-hooded rat, early increase in glomerular capillary pressure predicts glomerulosclerosis (23), despite unchanged glomerular volume. The analbuminemic rats with low glomerular capillary pressure do not develop glomerulosclerosis (10). In the Munich-Wistar rats, glomerulosclerosis due to aging seems to be associated with glomerular hypertension and can be reduced by lowering the glomerular capillary pressure by angiotensin converting enzyme inhibitors (1). On the other hand, normal glomerular pressure in superficial cortex has been found in 12- and 17-wk-old SHR (2, 4). This observation is consistent with our observations of normal glomerular pressure in the superficial cortex in young and old SHR.

Our study demonstrates that glomerulosclerosis may occur and increase without systemic hypertension and also without a measurable increase of glomerular capillary pressure. In the WKY rats, the relative increase of the sclerosis index with age was not significantly greater in the juxtamedullary cortex where glomerular capillary pressure did increase than in superficial cortex where the glomerular capillary pressure remained relatively constant. In SHR, however, the relative increase in sclerosis index was substantially greater in the juxtamedullary than in the superficial cortex. Thus a substantial increase in the glomerular capillary pressure was associated with an accelerated increase of glomerulosclerosis compared with the development of sclerosis in layers with normal glomerular capillary pressures with or without association with systemic hypertension.

The age-dependent increase in sclerosis index was associated with an increase of the glomerular tuft diameter in both WKY and SHR and in both cortical layers. Within the WKY and SHR groups, the glomerular tuft diameter seemed to present a similar relative increase in sclerosis index in both cortical layers, i.e., in glomeruli where glomerular capillary pressure remained constant, increased, or became reduced. This contrasts with the association between the glomerular capillary pressure and the increase of sclerosis index, which may indicate that an increase of glomerular capillary pressure does not always induce a major growth response in the glomerular capillary tuft. On the other hand, the observation that glomerulosclerosis may occur in glomeruli with unaltered glomerular capillary pressure indicates that the glomerulosclerosis and the growth of the capillary tuft may be caused by a common growth factor(s) and that the glomerular capillary pressure increases as a additional phenomenon serving as a secondary sclerosis-inducing factor, thus establishing a vicious circle. The effect of additional factors on glomerulosclerosis has been suggested by Yoshida et al. (29).

Autoregulation or the lack of it does not seem to be involved in the glomerular capillary pressure increase in the juxtamedullary cortex of 70-wk-old SHR. We observed an unaltered range of local RBF autoregulation in superficial and juxtamedullary cortex in WKY and SHR using laser-Doppler flowmetry. Our data agree with earlier studies in the normotensive hydropenic rats (18). The lack of RBF autoregulation frequently seen in kidneys with substantial nephron loss was not observed in the juxtamedullary cortex of old SHR (6, 16). Our observations from juxtamedullary cortex in SHR are new. A well-maintained GFR autoregulation in superficial and juxtamedullary cortex in 40-wk-old SHR using the aprotinin method for measurements of GFR (26) have recently been reported by us. The reduced glomerular capillary pressure in the superficial cortex of 70-wk-old WKY was probably not caused by insufficient autoregulation of RBF but might be due to an increased pressure reduction along the interlobular artery secondary to the sclerotic elongation and damage of this artery.

In conclusion, glomerulosclerosis in the juxtamedullary but not in the superficial cortex of 70-wk-old SHR and WKY rats was associated increased glomerular capillary pressure. An insufficient autoregulation does not seem to explain this pressure increase, which may be secondary to the sclerotic process. In both adult WKY and SHR, sclerosis index was correlated to glomerular size in both cortical layers.

One fundamental reservation has to be made. The glomerular capillary pressure was measured in anesthetized animals and correlated with anatomic changes that take place during a considerable period of time in the conscious animals. Transient variations of systolic blood pressure are seen in normotensive rats, and the amplitudes of the blood pressure variations are increased substantially in the hypertensive animals (7). An increase in glomerular capillary pressures may have occurred during transient increases of the systemic pressures occurring too acutely to be adequately compensated by the mechanisms of autoregulation. Resetting of RBF autoregulation does not seem to take place in the first minutes after a step input of systemic pressures changes in the rat (unpublished observations). The increase of single-nephron GFR measured by occlusion of tubular flow to the distal tubule is far greater in the juxtamedullary than in the superficial cortex, indicating a greater dependence of the tubuloglomerular feedback (TGF) system on autoregulation in deep cortex (5, 11). The dynamics of the TGF system have been shown to be slower than the myogenic response (8) and may thus be unable to compensate the fast change of perfusion pressures, especially in the juxtamedullary cortex. Transient capillary pressure changes may thus have induced the glomerulosclerosis before a permanent and measurable increase of glomerular capillary pressure became manifest. The suitability of the methods also must be considered. A correlation between sclerosis index and glomerular capillary pressure in the superficial cortex of SHR might simply have been disguised by the relatively great errors of the pressure measurements. Thus glomerular capillary pressure as the initial cause of glomerulosclerosis as well as the growth of the glomerular tuft cannot be excluded.