(Hypertension. 1996;27:364-370.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Lisinopril on the Structure of Renal Arterioles
From the Developmental Research Laboratories, Shionogi & Co, Ltd, Osaka, Japan.
Correspondence to Mitsuru Notoya, Developmental Research Laboratories, Shionogi & Co, Ltd, 3-1-1 Futaba-cho, Toyonaka-shi, Osaka 561, Japan.
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Abstract |
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Abstract We investigated the effect of long-term administration of the angiotensin-converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area, and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media growth.
Key Words: kidney • rats, inbred SHR • renin-angiotensin system • arterioles
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Introduction |
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Although the causes of essential hypertension vary, it has been postulated that the kidney may be primarily involved.1 2 3 4 5 This view is supported by reports demonstrating that essential hypertension in humans was permanently cured by nephrectomy and transplantation of a kidney from a normotensive donor.6 7 Results from transplantation experiments in which SHR and normotensive WKY were used have also shown that a renal defect is responsible in the pathogenesis of genetic hypertension.8 9
Among the renal defects in SHR, the hemodynamic abnormality as indicated by an elevated RVR is of particular interest. It is established that in young SHR, RVR is increased, and glomerular filtration rate and renal blood flow are reduced compared with age-matched WKY.10 11 These abnormalities may be responsible for the sodium and water retention observed in young SHR.12 It has been reported that elevated RVR resides predominantly within the preglomerular arterioles.13 14 Evidence from microsphere15 and vascular cast16 17 studies has demonstrated a 10% to 30% reduction of afferent arteriolar lumen diameter in SHR compared with WKY. Whether this is caused by functional or structural changes in the vascular wall has been discussed. A morphometric study by Skov et al18 clearly showed that structural differences in the afferent arteriole do exist between SHR and WKY. Even when renal vasculature was maximally relaxed with papaverine, the lumen diameter of the afferent arterioles showed a 17% reduction in SHR. This structural alteration of the afferent arteriole is not secondary to the elevated blood pressure. Rather, it was shown recently by Nørrelund et al19 that the narrowed lumen of this vessel contributes to the development of hypertension.
The renin-angiotensin system may play a pivotal role in the increased RVR in SHR. If SHR are treated from an early age with ACE inhibitors, elevation of RVR20 21 and development of hypertension can be prevented.20 21 22 23 24 25 26 27 Interestingly, the renal vascular response to Ang II was significantly greater in SHR than WKY.20 21 28 29 30 A recent study30 showed that the enhanced responsiveness to Ang II occurred selectively in the kidney of SHR and not in other vessels, carotid, hindquarter, or mesenteric vasculatures. Another recent study31 demonstrated that a low dose of type 1 Ang II receptor antagonist significantly reduced the blood pressure of SHR in a dose-related manner if administered by intrarenal infusion, whereas these low doses had no significant effect on blood pressure if administered intravenously. Taken together, the kidney and renin-angiotensin system are implicated in the pathogenesis of hypertension in SHR.
Thus, investigation of the effects of ACE inhibitors on the structure of the renal vessels seems particularly important. In extrarenal vessels, eg, mesenteric, cerebral, hindquarter, and thoracic aorta, previous investigations have indicated that media hypertrophy occurs in the various sizes of vessels—aorta,32 arteries,33 34 35 36 and arterioles37 38 —in SHR and that antihypertensive treatment with ACE inhibitors prevents media growth.24 27 32 35 36 38 Since Ang II is known to cause hypertrophy of vascular smooth muscle cells,39 ACE inhibitors, by blocking the actions of Ang II, may have the opposite effect in SHR, as several experimental studies have shown.32 36 However, contrary findings were also reported25 that suggested that ACE inhibitors may prevent the media hypertrophy through blood pressure reduction, not as a consequence of growth factor inhibition.
Also, in the renal vasculature in SHR, some reports40 41 42 have indicated that there is media hypertrophy in the main renal, arcuate, and interlobular arteries. A recent study42 suggested that enalapril may not prevent hypertrophy in arcuate and interlobular arteries in SHR. In contrast, recent morphological evidence18 19 demonstrated that hypertrophy is not present in renal afferent arterioles in SHR. Given all this experimental evidence, a question arises as to how ACE inhibitors normalize RVR in SHR. Normalization of the renal vascular structure is highly probable, because without it, reduction of blood pressure would cause a serious problem. We chose to study the structure of renal afferent arterioles because among the various preglomerular vascular segments, the afferent arteriole is thought to account for most preglomerular resistance.
The aim of the present study was to investigate the effects of chronic ACE inhibitor treatment with lisinopril on the vascular structure of the renal arterioles and thus gain insight into the mechanism with which RVR is normalized by ACE inhibitors.
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Methods |
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Animals
Male SHR and male WKY were obtained at 4 weeks of age from Charles River Breeding Laboratories (Hino, Shiga, Japan). The rats were maintained on normal rat chow (CA-1, Japan-Clea) and given water laced with lisinopril ad libitum. The amount of lisinopril added to the drinking water was adjusted twice a week according to body weight and water intake to provide an approximate dose of 3 mg/kg per day. Body weight and systolic pressure of the rats were measured weekly, the latter by the indirect tail-cuff compression method in conscious animals. All procedures performed were in accordance with our institutional guidelines.
Surgery
At 15 weeks of age, with rats under sodium
pentobarbital
anesthesia (veterinary Nembutal, Abbott Laboratories; 50
mg/kg IP), a polyethylene catheter (PE-90) was inserted in a retrograde
manner into the abdominal aorta. Ligatures around the mesenteric artery
and aorta proximal to the origin of the right renal artery were tied.
Immediately after, the right and left kidneys were transfused to wash
out the blood with a buffered solution of the following composition:
112 mmol/L NaCl, 5.0 mmol/L KCl, 1.0 mmol/L
NaH2PO4, 1.2 mmol/L
MgSO4, 25 mmol/L
NaHCO3, 11.2 mmol/L glucose, 0.1 mmol/L sodium
nitroprusside, 15 g/L dextran, and 1000 U/L heparin. The vena cava was
opened by a small incision to allow escape of blood and
perfusate. Smeda et al41 have suggested that the
renal vasculature is maximally dilated when perfused with Krebs'
solution at a low flow rate of 0.82 mL/min per kidney. In the
present study, the flow rate was set at 2.0 mL/min for perfusion of
both kidneys.
After the perfusion was started, the rat was killed by opening the thorax and removing the heart. The heart was gently blotted with towels to remove excessive water and was weighed immediately. After 10 minutes of perfusion with sodium nitroprusside, the perfusate was switched with a three-way stopcock to the fixative (2.0% formaldehyde, 0.5% glutaraldehyde, 75 mmol/L phosphate buffer, pH 7.2). In preliminary experiments, under light and electron microscopic observation, shrinkage or swelling of the cells including smooth muscle cells in renal vasculatures was minimal. After 30 minutes of perfusion of the fixative, the left renal artery was ligated, and the left kidney was removed, blotted with towels, and weighed. The left kidney was used for morphometric studies as described below. Then, acryl resin (Mercox, Dai-Nihon Inki Co) was infused to make a cast of the vascular system in the right kidney.
Vascular Cast and Morphometric Studies
After the cast had
cured sufficiently, the renal tissue of the
right kidney was digested and removed in 20% sodium hydroxide at
approximately 50°C. Digestion was done several times until renal
tissue was completely removed. The cast was rinsed several times in
distilled water and then air dried.
The renal cast was subsequently dissected under a stereomicroscope (Nikon Co) and mounted on stubs. The sample was coated with gold palladium with an ion sputter coater (SC500A, Emscope Co) and examined with a scanning electron microscope (S-800, Hitachi) at an accelerating voltage of 10 kV and working distance of 15 mm.
Photographs either were printed on paper with an image processor (EP-1040, Hitachi) and printer (EP-P1, Hitachi) or they were recorded on Neopan 400 Presto film (Fuji-Film Co). Arteriole diameters were measured on the photographic prints taken at x350. In both afferent and efferent arterioles, diameters were measured at three points, 30, 40, and 50 µm from the glomerulus, and averaged. Only the vessels of glomeruli in the outer cortex were examined. Identification of each arteriole was based on the finding that the afferent arterioles branched from the interlobular artery, whereas the efferent arterioles branched to the peritubular capillary network.
The opposite kidney, ie, the left kidney, for which a cast had not been taken, was cut into segments, dehydrated, and embedded in resin (Technovit 7100, Kulzer & Co GmbH). This tissue was sectioned at 1 µm with a microtome and stained with a mixture of methylene blue and basic fuchsin. Tissue sections were examined with a light microscope (Microphoto-FXA, Nikon). Measurements of morphometric parameters were performed with a video-plan image-analysis system (Nihon-Avionics). Only the vessels in the outer cortex were selected. The short and long internal diameters of the vessels, defined as the shortest and longest distances between the two perpendicular lines across the vessel from one adluminal side of the internal elastic lamina to the other, were found. Assuming that the elliptical form of the vessel was due to oblique sectioning, the short internal diameter measured was the true internal diameter of the vessel at a relaxed state.
The media cross-sectional area (CSA) of the
vessel was calculated
as
CSA=(CSAtot-CSAlum)x(IDshort/IDlong),
where CSAtot and CSAlum are the total
(lumen plus vessel wall) and luminal cross-sectional areas,
respectively, and IDshort and IDlong are the
short and long internal diameters, respectively. The external diameter
(ED) was determined from
ED=2x(CSAtotxIDshort/IDlong/
)½.
Media thickness was determined from (ED-IDshort)/2,
and the media-lumen ratio from
(ED-IDshort)/2/IDshort.
Afferent arterioles were identified by the following criteria: (1) presence of a large population of nearly equally sized arterioles, providing a histological criterion of distinction among renal vessels, and (2) presence of an internal elastic lamina, because this lamina is consistently absent in efferent arterioles. Vessels that were cross-sectioned with epithelioid cells in their walls were identified as afferent arterioles; however, they were excluded from the morphological measurements because no information is available on the change in cell volume accompanying the change in phenotype. The percentage of vessels excluded because of this was 3.8%, 8.0%, 22.1%, and 24.6% in control SHR, control WKY, treated SHR, and treated WKY, respectively.
Vessels that were not sectioned transversely (ie, wall thickness was asymmetrical) were excluded from the study.
Statistical Analysis
Results are expressed as
mean±SEM. An unpaired t
test was used to analyze statistical differences. The means of
two groups were considered significantly different at a value of
P<.05.
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Results |
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Systolic pressure profiles of the SHR and WKY used in this study are given in Fig 1
. The blood pressure of treated
SHR was maintained within the normotensive range and was similar to
that of untreated WKY. The blood pressure of treated WKY was
significantly lower than that of control WKY. Lisinopril
treatment lowered body weight in both SHR and WKY (Table 1).
Heart rate was faster in SHR than WKY, and
lisinopril did not affect the heart rate of SHR and WKY.
Treatment prevented the development of hypertrophy of SHR
heart but did not affect heart weight in WKY. It also did not affect
the weight of the left kidney, which was about the same for both SHR
and WKY.
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), lisinopril-treated SHR (
), control
WKY (
), and lisinopril-treated WKY (
).
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Vascular Cast Study
Figs 2 and
3 present the
vascular casts of glomeruli with the afferent and efferent arterioles
from the outer cortex. Fig 2 shows vascular casts from control
and
lisinopril-treated SHR. The diameter of the afferent
arteriole is markedly larger in treated than control SHR, whereas the
diameters of the efferent arterioles are similar. Fig 3
displays casts
from control and lisinopril-treated WKY. They show even
larger diameters of the afferent arterioles in control and treated WKY
than those in corresponding SHR.
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The statistics of renal arteriolar
measurements by the vascular cast
study are given in Table 2. In control groups, afferent
arteriolar diameter at maximal relaxation was significantly smaller in
SHR than WKY. In treated SHR, afferent arteriolar diameter was
significantly larger than in control SHR. Likewise, in treated WKY,
afferent arteriolar diameter was significantly larger than in control
WKY.
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On the other hand, efferent arteriolar diameter did not differ between SHR and WKY in both control and treated groups. Moreover, lisinopril treatment did not affect efferent arteriolar diameter in either SHR or WKY.
Morphometric Study
Histological examination of the left
kidney showed
that the renal parenchyma and vasculature were well fixed. No
convolution of the internal elastic lamina was noted, providing
evidence that the vasculature was fixed in a relaxed condition.
External diameter, media thickness, and media-lumen ratio were
calculated on the basis of measurements of the short and long internal
diameters and total and luminal cross-sectional areas of the
vessel. The results of these calculations are shown in Table 3.
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In both control and lisinopril-treated groups, afferent arteriolar diameter was significantly smaller in SHR than WKY. Lisinopril treatment significantly increased the lumen diameter of afferent arterioles in both SHR and WKY. These results agreed with the cast study findings.
Similarly to internal diameter results for both control and lisinopril-treated groups, the external diameter of afferent arterioles was also significantly smaller in SHR than WKY. Also, lisinopril treatment significantly increased the external diameter of afferent arterioles in both SHR and WKY.
The media-lumen ratio of SHR vessels tended to be greater than that of WKY vessels in both control and treated groups (P=.26 in the control group; P=.07 in the treated group). Lisinopril treatment significantly reduced the media-lumen ratio in both SHR and WKY. However, media thickness remained consistent in the four groups examined. Media cross-sectional area was significantly reduced in SHR compared with WKY in both treated and control groups. Lisinopril treatment significantly increased media cross-sectional area in both SHR and WKY.
Remodeling and growth indexes were 123% and 21% in SHR and 123% and 63% in WKY, respectively. These were calculated from the equations defined by Heagerty et al.43
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study confirmed a difference in the structure of renal afferent arterioles between SHR and WKY (Fig 4
). Using
the vascular casting technique, we showed the diameter of afferent
arterioles to be reduced in SHR compared with WKY, whereas the diameter
of efferent arterioles was similar. By the morphometric method, we
confirmed that the reduced diameter in afferent arterioles in SHR was a
consequence of vascular remodeling plus a decreased amount of vascular
media rather than a consequence of media growth.
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The effect of lisinopril, an ACE inhibitor, on the structure of afferent and efferent arterioles showed that (1) lisinopril treatment results in a larger lumen diameter in afferent arterioles, without a change in efferent arteriolar diameter in either SHR or WKY, and (2) larger afferent arteriolar diameter with lisinopril treatment is accounted for by a process of reverse remodeling plus an increased amount of vascular media rather than by a preventive action on cellular growth.
In the present investigation, we used two techniques to evaluate structural changes of renal vessels: a vascular casting technique and a morphometric technique. The vascular cast study made possible easy differentiation of interlobular arteries and afferent and efferent arterioles because their branching can be directly observed with a scanning electron microscope. However, this technique, in which the surrounding tissue is digested, cannot provide information on structural changes of the vascular wall. To obtain such information, external and internal diameters must be determined.
This led us to also perform a morphometric study. The afferent arterioles were identified on the basis of size and the existence of internal elastic lamina. The large population of nearly equally sized arterioles provides a histological criterion of distinction among renal vessels. Moreover, there was a great difference (37% in the case of control SHR to 193% in lisinopril-treated WKY) in lumen size between the afferent and efferent arterioles, as shown in the present casting study. Observation of several glomeruli sectioned with afferent or efferent arterioles at the vascular poles aided the identification, although such vessels were excluded from the measurement because they were not sectioned transversely. One limitation of the identification method used in this study may come from tapering of the afferent arterioles. Previous investigations16 18 have suggested that the lumen diameter of the afferent arteriole is larger in the proximal part than in the distal part (ie, it becomes smaller toward the glomerulus). Gattone et al16 found 22.2% (WKY, 12 weeks old) and 30.2% (SHR, 12 weeks old) tapering, and Skov et al18 observed that tapering was 7.5% in WKY and 10.6% in SHR. However, in the present study, results obtained from two methods of determination of afferent arteriolar internal diameter (ie, vascular cast study and morphological technique) mostly coincided, and any sampling error would have been minor.
In renal16 17 18 and extrarenal24 25 27 33 34 36 37 arteries in SHR, a structurally determined lumen reduction is observed compared with arteries in normotensive WKY. Lumen reduction in these vessels is consistently associated with an increased ratio of media thickness to lumen.24 25 27 34 35 36 37 40 41 42
An increased media-lumen ratio sometimes has been interpreted to be synonymous with media hypertrophy; however, this is not necessarily the case. It is becoming clear that part of the increased ratio can be accounted for by a process called vascular remodeling37 43 : the rearrangement of existing material around a smaller lumen, without a change in media cross-sectional area or an increase in growth. This process would result in a reduction in the external and internal diameters of the vessel. Remodeling is distinct from growth but can occur in conjunction with it.
In the present study, the increase in the media-lumen ratio in SHR was a consequence of vascular remodeling because both external and internal diameters were significantly smaller. In agreement with earlier reports,18 19 we found no evidence of media hypertrophy in the afferent arterioles of SHR compared with those of WKY. Rather, media cross-sectional area was significantly smaller in SHR, indicating inhibited growth. Our observation agreed with that of a recent study by Nørrelund et al.19 They performed a crossbreeding experiment in which an F2 generation of SHR and WKY was produced. In their histological studies, the reduced lumen of the afferent arteriole was accompanied by a smaller media cross-sectional area. Quite interestingly, quartile analysis that was based on lumen diameter at 7 weeks of age demonstrated that rats with narrowed afferent arterioles had developed hypertension before they reached 23 weeks of age. This evidence strongly suggests an involvement of growth inhibition of the afferent arteriole in the development of hypertension.
The influence of Ang II on vascular structure has been widely studied. Tested in vitro, Ang II has mitogenic and trophic actions on vascular smooth muscle cells.39 In vivo, theoretically, ACE inhibitors may have opposite effects on vascular smooth muscle cells. Indeed, Owens32 demonstrated that captopril had a preventive effect on medial hypertrophy in the thoracic aorta over and above that predicted by its blood pressure–lowering effect; furthermore, propranolol lowered blood pressure but did not affect medial hypertrophy. A recent study by Rizzoni et al36 showed that a subhypotensive dose of fosinopril prevented structural alterations of mesenteric resistance vessels in SHR. Conflicting results were reported by Thybo et al25 that suggested that normalization of artery (mesenteric, femoral, cerebral, and coronary) structure may not be due to any specific effect of ACE inhibitors. In a more recent study,44 however, they reported that perindopril caused a greater normalization of gluteal small artery structure than atenolol. Although data concerning the specificity of ACE inhibitors are conflicting, earlier studies* are in good agreement that ACE inhibitors normalize the increased media-lumen ratio and increased media cross-sectional area.
In the present study, consistent with earlier studies in
extrarenal arteries,
treatment with lisinopril resulted
in a larger lumen diameter and smaller media-lumen ratio in
afferent arterioles in SHR and WKY. However, our present data
demonstrated that media cross-sectional area was markedly greater
in lisinopril-treated SHR and WKY than in the
corresponding control groups, which appears to be in contrast to
previous findings on extrarenal arteries. However, in contrast to
studies on extrarenal arteries, earlier studies have indicated that
media hypertrophy does not exist in renal afferent
arterioles in SHR.18 19 Rather, media growth has been
found to be inhibited in this vessel in SHR, which was also confirmed
in our study.
In contrast to the findings on afferent arteriolar diameter, the present cast study revealed no difference in efferent arteriolar diameters between SHR and WKY nor between treated and control groups. In agreement with this are the results from a hemodynamic study13 in which efferent arteriolar resistance was similar in SHR and WKY. Kimura et al17 fixed SHR and WKY kidneys at the functional state and measured the diameters of afferent and efferent arterioles. In captopril-treated SHR, the diameters of afferent arterioles were larger, whereas the diameters of efferent arterioles were similar to those of untreated SHR, in agreement with our present observations.
Unexpectedly, larger diameters of afferent arterioles were observed in treated WKY than in control WKY, despite only a small reduction in systolic pressure. Our results resemble data on small mesenteric arteries reported by Lee et al24 and more recent data on hindquarter resistance vessels by Korner and Bobik.27 These data and ours indicate a marked reduction in media-lumen ratio in WKY and SHR. However, a closer comparison reveals a difference between the cited reports24 27 and ours. In mesenteric and hindquarter arteries, reduction in the media-lumen ratio was accompanied by a substantial decrease in the media cross-sectional area. On the contrary, the present study demonstrated that media cross-sectional area is significantly larger in lisinopril-treated WKY. Unfortunately, the effects of ACE inhibitors on renal vascular remodeling in WKY have been poorly investigated. Further study is needed to solve the problem concerning strain difference.
An important question about normalization of vascular structure is whether it was due to a direct effect of lisinopril or was a consequence of blood pressure reduction. We could gain no information from this study about this question, and data have been poor concerning the structure of the renal afferent arteriole. However, it can be speculated that prevention of hypertension in SHR was through treatment that prevented vascular structural alteration of renal afferent arterioles, as discussed below. The observation that the antihypertensive response induced by a renin or ACE inhibitor or by Ang II receptor antagonism in SHR is abolished after bilateral nephrectomy45 46 47 suggests that the kidney is the major site of action of these agents. This conclusion was further confirmed by Wood et al,31 whose study showed that valsartan, a type 1 Ang II receptor antagonist, lowered blood pressure in SHR after intrarenal administration but had no significant effect on blood pressure after intravenous administration. More importantly, Harrap et al48 reported observations that chronic treatment (between 4 and 16 weeks of age) with perindopril, an ACE inhibitor, prevented the development of hypertension in SHR. After withdrawal of perindopril treatment, the antihypertensive effect persisted and was accompanied by a reduction in RVR. Interestingly, in essential hypertensive patients, lisinopril increased renal blood flow significantly during blood pressure reduction, whereas nifedipine, a calcium antagonist, did not.49 This finding supports the concept that lisinopril may have direct effects on renal resistance vasculature. This was partly confirmed in the morphological study by Kimura et al,17 who used a vascular cast technique. In their study, 2 weeks of captopril treatment (from 4 to 6 weeks of age) resulted in dilatation of afferent arterioles in SHR, but treatment with trichlormethiazide plus hydralazine for the same period did not. However, they did not observe such an ACE inhibitor–specific effect after 16 weeks of administration of these drugs. Further study is necessary to clarify the regional heterogeneity of the effects of ACE inhibitors and whether such effects are direct or through hemodynamic change.
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Selected Abbreviations and Acronyms |
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Footnotes |
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1 References 24, 25, 27, 32, 35, 36, 38, 43, 44.
2 References 24, 25, 27, 32, 35, 36, 38, 43, 44.
Received June 9, 1995; first decision July 11, 1995; accepted November 30, 1995.
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