(Hypertension. 1995;25:335-342.)
© 1995 American Heart Association, Inc.
Articles |
Enalapril Does Not Prevent Renal Arterial Hypertrophy in Spontaneously Hypertensive Rats
From the Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria, and the Emily E.E. Stewart Renal Laboratory, Baker Medical Research Institute (W.P.A.), Prahran, Victoria, Australia.
Correspondence to Dr Warwick P. Anderson, Baker Medical Research Institute, Alfred Hospital, Commercial Rd, Prahran, Vic 3181, Australia.
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Abstract |
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Abstract Angiotensin-converting enzyme inhibitors prevent the development of vessel wall hypertrophy in some vascular beds in spontaneously hypertensive rats (SHR), but their effects on hypertrophy of renal arterial vessels have not been studied. We therefore used stereological techniques to study wall and lumen dimensions of the interlobular (cortical radial) and arcuate arteries in the kidneys of SHR (n=7), SHR treated from 4 to 10 weeks of age with enalapril (25 to 30 mg/kg per day; SHR-E, n=7), and Wistar-Kyoto rats (WKY, n=7). All kidneys were perfusion-fixed at 10 weeks. Systolic blood pressure was 199±9, 139±11, and 156±8 mm Hg in the SHR, SHR-E, and WKY groups, respectively. For the interlobular arteries, the volume density of artery wall, wall-to-lumen ratio, and wall thickness in the untreated SHR were significantly greater than in the WKY (0.84±0.09 versus 0.69±0.07x10-3, 0.75±0.20 versus 0.53±0.08, and 13.6±3.3 versus 10.6±0.8 µm, respectively), but values in the SHR-E were similar to those in the untreated SHR (1.10±0.20x10-3, 0.88±0.22, and 14.0±2.6 µm, respectively). For the arcuate arteries, wall thickness and volume density were significantly greater in SHR than WKY (17.3±3.0 versus 13.9±1.7 µm and 1.63±0.51 versus 1.14±0.27x10-3, respectively), and values in the SHR-E (15.7±1.7 µm and 1.69±0.50x10-3, respectively) were not significantly different from those in SHR. Thus, enalapril treatment did not prevent vessel wall hypertrophy of both the interlobular and arcuate arteries in SHR despite the normalization of arterial pressure. These results suggest that renal arterial hypertrophy in SHR is not caused by either angiotensin II or elevated arterial pressure.
Key Words: kidney • hypertension, renovascular • hypertrophy • angiotensin II • arteries
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Introduction |
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Strong evidence exists that there is a renal basis to the development of hypertension in spontaneously hypertensive rats (SHR). The most convincing evidence has come from studies in which SHR kidneys were transplanted into normotensive recipients, resulting in hypertension in the recipients.1 2 Similar findings have been made in other hypertensive strains.1 3 Furthermore, treatment of the SHR donors with antihypertensive drugs, including prenatally, does not prevent the development of hypertension in normotensive recipients (F1 hybrids4 5 ). Although questions have been raised about the interpretation of the results of such studies,1 the results do suggest that hypertension in the SHR primarily is due to some renal factor. One possibility is that there is hypertrophy of the preglomerular vessels in the SHR kidney. Such arterial hypertrophy occurs in other nonrenal beds,6 7 8 9 and if it occurred in the kidney, it could increase renal resistance by vessel wall encroachment into the vessel lumen and by eliciting increased responsiveness to vasoconstrictor substances.9 10 Goldblatt himself pointed out that narrowing of intrarenal arteries would be functionally identical to narrowing of the main renal artery, a known cause of hypertension.11 Several reports have now indicated that there is indeed renal vessel hypertrophy in SHR. Smeda and colleagues12 have reported increased medial cross-sectional area throughout the renal arterial tree in both prehypertensive (4 weeks) and older hypertensive (21 weeks) rats, and other researchers13 14 have shown narrowing of the afferent arteriolar lumen without medial hypertrophy.
There are several reasons for suspecting that angiotensin II (Ang II) might be responsible for such vessel wall hypertrophy. It is known to stimulate smooth muscle cell proliferation in culture,15 16 17 and treatment of SHR with converting enzyme inhibitors is known to prevent structural alterations in other peripheral vascular beds (mesenteric and hind limb).18 19 We have now investigated whether Ang II may be responsible for renal arterial wall hypertrophy in the SHR. We used stereological techniques to study renal vessels from rats at 10 weeks of age, a time when arterial pressure is rising rapidly in untreated SHR and thus when the vessel changes might be most marked.
We studied two groups of SHR, one untreated and the other treated with enalapril from weaning to 10 weeks. Measurements in the untreated SHR were also compared with values in a group of normotensive Wistar-Kyoto rats (WKY) to confirm the renal vessel hypertrophy in our colony of SHR. We studied the arcuate and interlobular arteries because it has been reported that vessels of this size are responsible for much of the difference in resistance between SHR and WKY in other nonrenal vascular beds.10 20
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Methods |
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Male SHR and WKY were obtained from the Baker Medical Research Institute breeding colony at 4 weeks of age. Three rat groups were used: untreated SHR (n=7), SHR treated with enalapril (SHR-E, n=7), and WKY (n=7). Rats were housed three to a cage in a room maintained at 23° to 25°C with a 12-hour light/dark cycle. Standard rat chow and water were supplied ad libitum. Enalapril treatment of the SHR-E group began at 4 weeks of age. Enalapril (Merck, Sharp & Dohme) was administered to these rats in their drinking water at a dosage of 25 to 30 mg/kg body wt per day as described by Adams et al.19 Apart from the enalapril, all groups were treated identically. The experiments were approved in advance by the Alfred Hospital/Baker Institute Animal Experimentation Committee as being in accord with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes.
Measurements of systolic blood pressure (BP) using the tail-cuff method began at 8 weeks of age and were performed four to six times over the next 2 weeks to allow the rats to become accustomed to handling.
At 10 weeks of age, final measurements of systolic BP were made, and 24 hours later the rats were anesthetized with thiobutabarbital (100 mg/kg IP, Institute of Drug Technology). The abdominal aorta and vena cava were exposed via a midline incision. The lower abdominal aorta was cannulated with an 18-gauge needle for retrograde perfusion, and 250 IU heparin (Commonwealth Serum Laboratories) was administered via an exposed jugular vein. With the use of a modification of previously described methods,21 kidneys were perfusion-fixed with Karnovsky's fixative (0.25 mol/L glutaraldehyde and 0.67 mol/L paraformaldehyde in 0.1 mol/L phosphate buffer) at a pressure corresponding to the final systolic BP measured (plus 30 mm Hg to allow for the inherent resistance of the perfusion apparatus). The left kidney was then removed and placed in 3.3 mol/L buffered formalin.
The left kidneys were sliced into 1-mm slices using a holder fitted with razor blades set at 1-mm intervals. After estimation of kidney volume (see below), every second slice was dehydrated through graded alcohol, processed into glycolmethacrylate (Polaron embedding medium, Bio-Rad Polaron Instruments), and flat embedded into molds. One section from each block (approximately 10 per kidney) was cut at 2 µm and stained with hematoxylin and eosin. Light microscopy was used to assess overall kidney vascular arrangement and to set up the stereological protocols. The proximal interlobular (cortical radial) and arcuate arteries of the kidney were analyzed. The proximal interlobular arteries were defined as being within the inner cortex (Fig 1a), branching for 500 µm from the arcuate arteries at the corticomedullary junction. The proximal interlobular arteries were always accompanied by their vein (Fig 1b) and easily distinguished from afferent arterioles (Fig 1a). Arcuate arteries were identified along the corticomedullary junction and differentiated from the larger interlobar arteries farther upstream as being completely surrounded by tubules rather than being next to an epithelial surface (Fig 1c). The investigator performing the stereological measurements was blinded to kidney origin.
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Stereology
Volume Estimations
An unbiased estimate of fixed kidney volume was obtained using
the Cavalieri Principle.22 23 In brief, 1-mm slices of
fixed rat kidney were viewed with a stereoscopic microscope at a
magnification of x1.36. An orthogonal grid was placed over the slices.
Kidney volume (Vkid) was estimated by
 | (1) |
where 
P is the sum of grid intersections (points) overlying
the cut surfaces of the kidney slices, a(p) is the area associated with
each grid point (3.11 mm2), and T is slice thickness (1
mm).
To estimate the volume densities of the wall (VVwall,kid) and lumen (VVlum,kid) of the proximal interlobular and arcuate arteries, the glycolmethacrylate section from each block was examined on a microfiche reader (magnification x19) fitted with an orthogonal grid. The area of the kidney (Akid) in the sections was calculated using
 | (2) |
where P is the total number of grid points overlying the
kidney sections and a(p) is the area associated with each grid point
(1.78 mm2).
Then, for estimation of the area of the wall (Awall, excluding adventitia) and lumen (Alum) of the vessels, the sections were projected at a magnification of x305 onto a table using an Olympus BH-2 microscope modified for projection. Proximal interlobular and arcuate arteries were then traced. The number of interlobular arteries traced in SHR, SHR-E, and WKY averaged 70, 94, and 71, respectively, and for the arcuate arteries, 40, 41, and 33, respectively. An orthogonal grid was then placed over the tracings and the total area of the walls determined by
 | (3) |
where P is the total number of points overlying the walls and
a(p) is the area associated with each grid point (25 mm2).
Between 1500 and 2500 points overlying artery walls were counted per
rat. Then the volume density of the vessel wall in the kidney was
determined using a standard stereological formula24 :
 | (4) |
Absolute volumes of proximal interlobular artery and arcuate artery walls in the kidney (Vwall) were then determined using
 | (5) |
where Vwall/Vkid was determined using equation 4 and Vkid was estimated using the Cavalieri Principle (equation 1). Equations 3, 4, and 5 were modified to estimate Alum, Vlum/Vkid, and Vlum.
The wall-to-lumen ratio was determined using
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Digitizer Analysis
To estimate the mean thickness of the walls of the arteries and
mean lumen diameter, the outer diameter of the vessels and lumens was
digitized at the point of minimum diameter and measured with a
digitizing tablet and MEASURE software (Capricorn
Scientific Software). The cross-sectional areas of the vessel walls
were calculated from determinations of cross-sectional area of the
whole vessel minus the cross-sectional area of the lumen.
Shrinkage Factor
It is important to note that the Cavalieri method provided an
estimate of perfusion-fixed kidney volume, whereas the estimates of
volume density and Vwall were for perfused, embedded, and
sectioned kidney specimens. It is well known that the processing of
tissue for microscopy often alters the volumes of tissue
components24 25 26 ; therefore, it was necessary to estimate
the effects of these dimensional changes on these estimates.
Accordingly, the lengths of one side of at least two kidney slices from
two animals from each experimental group were measured both before
processing and in the final section. The linear shrinkage factor was
less than 3% in all specimens, and therefore no correction for
shrinkage was introduced into the calculations.
Statistics
Data are expressed as mean±SD and were analyzed using one-way
ANOVA. When this indicated a difference, the Tukey multicomparison test
was used to locate differences. Nonparametric (rank) tests were used to
compare calculated vascular resistances.
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Results |
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At 10 weeks of age, the mean systolic BP in SHR (199±9 mm Hg) was significantly greater than in WKY (156±8 mm Hg, P<.001), whereas in SHR-E (139±11 mm Hg) systolic BP was significantly lower than in WKY (P<.01, Fig 2). Body weights of SHR were significantly less than those of WKY at 10 weeks (P<.05), and body weights of SHR-E were significantly less than those of SHR (P<.001, Table 1). However, kidney volumes did not differ significantly between the groups (Table 1).
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Interlobular Arteries
Volume Estimations
The volume density of the interlobular artery wall in the
kidney (VVwall,kid) was significantly greater in SHR
(0.84±0.09x10-3) compared with WKY
(0.69±0.07x10-3, P<.05, Fig 3). The volume density of the wall in SHR-E
(1.10±0.20x10-3) was significantly greater than in
untreated SHR (P<.01). The volume density of the lumen of
the interlobular artery in the kidney (VVlum,kid) did not
differ significantly between the three groups (Fig 3). However, the
wall-to-lumen ratio was significantly greater in SHR (0.75±0.20)
compared with WKY (0.53±0.08, Fig 3). The wall-to-lumen ratio in SHR-E
(0.88±0.22) was not significantly different compared with that in
SHR.
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P<.01, SHR vs SHR-E; 
P<.05,
SHR vs WKY.The volume densities given above are expressed per unit kidney volume of each individual rat; Table 1 also includes the absolute interlobular artery wall and lumen volumes.
Digitizer Analysis
A digitizer was used to measure outer vessel and lumen diameters
and wall thickness. The outer diameters of the proximal
interlobular arteries did not differ significantly between the groups
(98.1±7.9, 93.5±9.9, and 96.5±6.1 µm in SHR, SHR-E, and WKY,
respectively) (Fig 4). Average lumen diameter in the SHR
was 71.1±9.8 µm and in the SHR-E was 65.5±8.6 µm
(P=NS). Pooling of the results for lumen diameter in the two
SHR groups showed that lumen diameters tended to be smaller than those
in WKY (75.4±6.3 µm, P=.08, Fig 4). Interlobular artery
wall thickness was found to be significantly greater in SHR and SHR-E
(13.6±3.3 and 14.0±2.6 µm, respectively) compared with WKY
(10.6±0.8 µm, P<.05), but with this method no difference
was demonstrated between SHR and SHR-E (Fig 4). Mean cross-sectional
area of the wall of the interlobular artery was 3572±827
µm2 in SHR, 3509±849 µm2 in SHR-E, and
2849±275 µm2 in WKY (Fig 4).
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Fig 5 illustrates the typical histological appearance of the proximal interlobular arteries of WKY, SHR, and SHR-E. The vessels were lined by a single layer of endothelial cells, and the media contained two to four layers of smooth muscle cells. Each vessel was separated from the surrounding tubular tissue and accompanying vein by a thin adventitia.
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Arcuate Arteries
The arcuate vessels showed results broadly similar to those for
the interlobular arteries. However, there were fewer arcuate arteries
(see "Methods"), and therefore the standard deviations of each
estimate of the mean values tended to be greater than for the
interlobular arteries.
Volume Estimations
The volume density of the arcuate artery wall in the kidney
(VVwall,kid) was significantly greater in SHR
(1.63±0.51x10-3) compared with WKY
(1.14±0.27x10-3, P=.05, Fig 6). The volume density of the wall of SHR-E
(1.69±0.50x10-3) was significantly greater than that of
WKY (P<.05), but there was no significant difference
between treated and untreated SHR (Fig 6). There was no significant
difference in either the volume density of the arcuate artery lumen in
the kidney (Table 2) or wall-to-lumen ratio (Fig 6)
between the three groups.
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Digitizer Analysis
The outer diameters of the arcuate arteries were 200.0±12.7,
188.5±24.5, and 193.1±23.1 µm in SHR, SHR-E, and WKY, respectively
(P=NS, Table 2). The lumens of the arcuate arteries (of the
order of 160 µm) and the outer vessel diameters were also not
different between the groups (Table 2). However, the wall thickness was
significantly greater in SHR (17.3±3.0 µm) compared with WKY
(13.9±1.7 µm, P<.01, Fig 6). The wall thickness of SHR-E
(15.7±1.7 µm) was not significantly different from that of the
untreated SHR.
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Discussion |
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Our aim was to determine whether Ang II was important in the development of hypertrophy of arterial walls in SHR kidneys. We found that there was marked hypertrophy of interlobular and arcuate artery walls in SHR compared with WKY, as other researchers have shown previously.12 27 We have now shown for the first time that this hypertrophy was not apparently caused by Ang II, because it was not prevented by blockade of Ang II production with enalapril. The enalapril treatment did obviate the rise in arterial pressure in the SHR known to occur from 4 to 10 weeks of age, suggesting that the hypertrophy was also not the direct result of elevated arterial pressure.
Renal transplantation studies have indicated that the kidney plays an important role in the development of hypertension, but there have been few studies of the morphology of renal vessels in the SHR. Smeda et al12 have provided the most comprehensive analysis, reporting vessel wall hypertrophy throughout the renal arterial tree in SHR compared with WKY at both 4 and 21 weeks of age. Other studies have analyzed the afferent arteriole only. Both Skov et al14 and Gattone et al13 cast the renal arterioles with plastic and concluded that the lumen diameter of SHR afferent arterioles was reduced compared with that of WKY but that there were no differences in the wall dimensions between the two groups.
None of these previous studies of SHR renal arteries and arterioles have investigated the role of Ang II in the development of hypertrophy of resistance vessels in hypertension. However, studies of other vascular beds, especially the mesenteric, have provided clear evidence that arterial wall hypertrophy in SHR is dependent on Ang II. For example, Lee and Smeda and their colleagues have shown that treatment with the angiotensin-converting enzyme inhibitor captopril (Lee et al18 ) but not the vasodilator hydralazine (Smeda and Lee28 ) prevented the structural alterations of the mesenteric vasculature in SHR despite both agents normalizing arterial BP. Previously, Smeda et al27 showed that hydralazine, despite normalizing arterial BP, had no effect on the structural changes in arterial walls within the kidney. However, stimulation of renin release and thus Ang II production by this dilator agent29 confounds the interpretation of these results.
In the present investigation, enalapril prevented the rise in arterial pressure in SHR but did not prevent renal arterial hypertrophy. Enalapril was administered to SHR continuously from 4 to 10 weeks of age. The interlobular arteries and the larger arcuate arteries of these enalapril-treated SHR did not have reduced vessel wall dimensions (wall volume, wall thickness) compared with untreated SHR. Stereologically, both SHR groups had greater wall dimensions than WKY. The hypertrophy occurred not only despite Ang II blockade but also despite the prevention of the rise in arterial BP, which was actually slightly lower at measurement than in the WKY group. Thus, our results provide evidence that the hypertrophy of the arcuate and interlobular arteries in SHR was caused neither by Ang II nor directly by elevated arterial pressure.
We chose to study the relatively large arcuate and interlobular arteries rather than the conventional "resistance" arterioles because of the arguments advanced by Korner and Angus10 that vessels 90 µm in diameter and greater are responsible for the elevation in peripheral resistance in SHR. Their argument is supported particularly by the results of Bohlen20 30 and Borders and Granger.31 Study of the effects of angiotensin-converting enzyme inhibitors on afferent arteriole morphology will also be confounded by phenotypic changes in afferent arteriolar smooth muscle cells as they become renin synthetic. Strict criteria were followed for the identification of the proximal interlobular and arcuate arteries in the present study, and the analyses were carried out with the investigator unaware of kidney origin until statistical analysis began. Because of the lower incidence of arcuate arteries in our sampled sections of kidneys (a total of approximately 40 per rat) compared with proximal interlobular arteries (approximately 70 per rat), the conclusions regarding the arcuate arteries are less securely based than those for the interlobular vessels. However, the results of the arcuate arteries followed the same trend as that seen in the proximal interlobular arteries, in that the walls of the SHR vessels were significantly thicker than in WKY vessels, and there were no significant differences between treated and untreated SHR vessels.
It is possible that the effects of enalapril on the metabolism of local bradykinin and other peptides may have had an influence on vessel wall growth in our rats, and studies are currently underway using an angiotensin type 1 receptor antagonist. We also cannot exclude the possibility that Ang II initiated the development of vessel hypertrophy before 4 weeks of age when our enalapril treatment began. Smeda and colleagues12 have shown that the walls of the renal arteries change some at 4 to 5 weeks of age. There is also evidence of early increased renin and Ang II levels in the SHR. For example, kidney renin mRNA levels in 5-week-old SHR are reported to be four times greater than those in age-matched WKY.32 It is also known that the establishment of hypertension in SHR is preceded by significant increases in renal renin33 34 and Ang II35 concentrations compared with WKY. Similarly, it might be argued that the barely detectable difference in arterial pressure reported for SHR compared with WKY in the prehypertensive phase36 might have initiated the structural changes. However, this would still argue for a distinctive cause of the vessel hypertrophy in the kidney because enalapril treatment did not reverse this hypertrophy, whereas it does so in other beds.18 19 Although we did not measure BP before enalapril treatment began in the present study, it has been shown that BP in 4-week-old SHR in our colony is not different from19 37 or only slightly elevated38 39 compared with that in age-matched WKY. It is still possible, although unlikely, that small changes in BP before 4 weeks of age are responsible for the large changes in vessel morphology in our SHR-E group at 10 weeks of age after 6 weeks of enalapril treatment.
It might be argued that the hypertrophy of the renal arteries should tend to reduce lumen diameter by encroaching on the lumen and by a greater contraction in response to given levels of vasoconstrictor agents, as argued for other peripheral resistance vessels by Folkow et al,7 9 Korner and Angus,10 and others. Although the vessel lumen dimensions tended to be lower in SHR than in WKY, none of the differences in VVlum,kid or lumen diameter between groups were significant. It should be noted, however, that the total volume of the vessels investigated in this study make up only 0.9% of the kidney parenchyma. Korner et al40 proposed that a decrease in vessel lumen diameter of as little as 10%, accompanied by a slight increase in wall thickness, would be required to produce hypertension. Thus, even though significant differences in wall thickness were observed, the methods undertaken in this study may not have been sensitive enough to detect a change as small as 10% in lumen volume. Furthermore, it is difficult to exclude possible changes in the lumen during the preparation and perfusion-fixation process. We therefore draw no conclusion from this study as to whether luminal encroachment occurs as a consequence of the vessel wall hypertrophy. To study this specifically, fixation at maximal dilation would have been necessary, as in the study of Skov et al,14 preferably making plastic casts of the vessels and assessing them with scanning electron microscopy as in Denton et al41 and Gattone et al.13 This method minimizes the plane-of-section effect that may have contributed to the high variance in this parameter in the present study. Instead, we aimed to fix the vessels as close to the in vivo situation as possible to assess the functional effects of hypertrophy on vessel dimensions and therefore on vascular resistance. Finally, it must be added that remodeling of the vessels (rearrangement of wall elements around a smaller diameter) could have occurred in response to converting enzyme inhibition. We would not necessarily detect such a change, although this has been documented in other vascular beds.42
Interestingly, Goldblatt11 originally established his model of main renal artery stenosis as a simulation of distal renal vessel narrowing that would increase vascular resistance. Vessel resistance varies with the fourth power of the radius. Transforming measured lumen diameters to resistance gives values of 5.26±1.7, 7.15±2.9, and 9.94±4.97x105 mm-4 for the interlobular arteries of the WKY, SHR, and SHR-E, respectively, in the present study. These values for the SHR groups are significantly greater than those for WKY (P<.05 using the nonparametric signed rank test because variances were nonuniform). Previous physiological measurements of intrarenal vascular resistance have shown that they are elevated in young SHR.43 44 45 Furthermore, Harrap and Doyle46 found a genetic link between the lower renal blood flow and glomerular filtration rate in 4-week-old SHR and the level of hypertension in the adult SHR. They also proposed that the increased renal vascular resistance in the young rats was responsible for the rise in systemic pressure, which in turn helps restore renal blood flow and glomerular filtration rate. Thus, the possibility that hypertrophy of preglomerular arteries could be the primary hypertensive stimulus in SHR causing hypertension via mechanisms similar to those that occur in Goldblatt hypertension should be further investigated.
In conclusion, we have demonstrated that the walls of proximal interlobular and arcuate arteries of SHR were hypertrophied compared with those of WKY and that these changes did not appear to be dependent on Ang II or elevated pressure.
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Acknowledgments |
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This work was supported by the National Health and Medical Research Council of Australia. Michelle Kett held a Melbourne University Postgraduate Scholarship. We gratefully acknowledge the assistance of Debra Ramsey and Jan Morrison.
Received February 22, 1994; first decision March 23, 1994; accepted October 13, 1994.
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