(Hypertension. 1995;25:928-934.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin Peptides in Spontaneously Hypertensive and Normotensive Donryu Rats
From St Vincent's Institute of Medical Research, Fitzroy; and the Department of Medicine, Austin Hospital, Heidelberg, (S.B.H.), Victoria, Australia.
Correspondence to Dr D.J. Campbell, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
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Abstract The renin-angiotensin system has been implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Given that SHR may have normal or suppressed plasma levels of renin and angiotensin peptides, we examined whether the tissue levels of angiotensin peptides are elevated in these rats. We measured angiotensin-(1-7) [Ang-(1-7)], Ang II, and Ang I in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats at 6, 10, and 20 weeks of age. SHR had higher blood pressures and ratios of heart weight to body weight at all ages. Plasma renin levels of SHR were 13% to 32% of the levels of Donryu rats. Although plasma angiotensin-converting enzyme activity was lower in SHR than in Donryu rats, lung was the only SHR tissue with a reduced Ang II–Ang I ratio. Ang II levels in SHR adrenal were 24% to 42% of the levels of Donryu adrenal, and for SHR plasma, aorta, brown adipose tissue, and lung, Ang II levels were 38% to 93% of the levels of Donryu rats. For kidney and heart, Ang II levels were similar in SHR and Donryu rats at 6 weeks of age although suppressed in SHR at 10 and 20 weeks. Moreover, brain Ang II levels were higher in SHR than Donryu rats at 6 weeks of age and similar at 10 and 20 weeks of age. Our finding that all SHR tissues, except for brain at 6 weeks of age, showed Ang II levels similar to or less than the levels of Donryu rats indicates that, apart from a possible role for brain of young rats, the hypertension of SHR is not due to increased Ang II levels.
Key Words: angiotensins • rats, inbred SHR • rats, inbred strains • renin • angiotensinogen • angiotensin-converting enzyme • aldosterone
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Introduction |
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The spontaneously hypertensive rat (SHR) is a valuable model of genetic hypertension. Several lines of evidence implicate the renin-angiotensin system in the pathogenesis of hypertension in SHR. These include the cosegregation of the SHR renin allele with blood pressure in genetic studies,1 the reduction in blood pressure that accompanies active and passive immunization against renin,2 3 and administration of renin inhibitors,4 angiotensin-converting enzyme (ACE) inhibitors,2 3 4 and angiotensin II (Ang II) antagonists.3 4 Although there were some early reports of elevated plasma renin levels,5 most studies found renin levels in SHR to be either similar to2 6 7 8 9 10 or suppressed11 12 13 14 compared with those of normotensive strains. Moreover, plasma Ang II levels are not elevated in SHR10 or stroke-prone SHR.15 To account for the apparent Ang II dependence of blood pressure of SHR in the absence of an increase in circulating renin and Ang II, several researchers have proposed that tissue levels of Ang II may be elevated in sites such as the vascular wall,7 brain,16 and adrenal.17 In the present study, we examined the hypothesis that SHR have elevated tissue levels of Ang II by measuring Ang-(1-7), Ang II, and Ang I in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and Donryu rats (DRY) at 6, 10, and 20 weeks of age. These tissues were chosen for study because they encompass those tissues implicated in the pathogenesis of hypertension in SHR. Rats were studied at the ages of 6, 10, and 20 weeks because these are the ages of onset, rapid development, and plateau phases of hypertension in SHR, respectively.
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Methods |
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Animals
Male SHR (n=105) and DRY (n=110) were from colonies maintained in the Genetic Physiology Unit, Austin Hospital (Heidelberg, Australia). Rats were fed normal rat chow (Norco Pty Ltd) containing 3.6 g/kg sodium and 4.2 g/kg potassium. SHR were derived originally from National Institutes of Health SHR stock. DRY were obtained from Dr Tanase, Sankyo Co Ltd, Shizuoka, Japan, in 1989 at generation F56. Both strains are subject to regular tests with polymorphic markers to confirm their inbred status. DRY were chosen as the normotensive control for these studies because they are genetically homogeneous, whereas the genetic homogeneity of Wistar-Kyoto rats (WKY) is in doubt.18 These studies were performed in accordance with the guidelines of St Vincent's Hospital Animal Experimentation Ethics Committee.
This study of the angiotensin peptide levels in plasma and tissues of SHR and DRY was performed in conjunction with a study of the effects of ACE inhibition and ACE inhibitor withdrawal (unpublished data, 1994). Control SHR and DRY were administered vehicle (water) by daily gavage from the age of 6 weeks.
Blood pressures and body weights were measured at 5, 9, and 19 weeks; body weights were also measured at the time of collection of samples for peptide measurement. Measurements of systolic blood pressure were made by the tail-cuff method (model 12-28 BP system, IITC Inc, Life Science Instrumentation) approximately 2 hours after gavage. Rats were killed by decapitation between 11 AM and 3 PM without prior anesthetic 2 to 5 hours after gavage.
Extraction and Radioimmunoassay of Angiotensin Peptides from
Plasma
Plasma levels of angiotensin peptides were measured as described
previously.19 Briefly, trunk blood (2 to 3 mL) was rapidly
collected into tubes containing 0.5 mL inhibitor solution (1 mmol/L SQ
30697, 146 µmol/L pepstatin, 50 mmol/L 1,10-phenanthroline, 125
mmol/L EDTA, 2 g/L neomycin sulfate, 2% dimethyl sulfoxide, and 2%
ethanol in water) at 4°C. The blood was centrifuged and the plasma (1
to 2 mL) immediately extracted with Sep-Pak C18 cartridges (Waters
Chromatography Division, Millipore). Angiotensin peptides were
acetylated before high-performance liquid chromatography (HPLC), and
assay of HPLC fractions was performed by
N-terminal–directed radioimmunoassay (RIA).19
Data were corrected for recovery, as reported
elsewhere.19
Extraction and RIA of Angiotensin Peptides From Tissues
Kidney, adrenals, heart (cardiac ventricles), aorta, periaortic
brown adipose tissue with associated connective tissue, lung, and brain
(comprising brain stem, hypothalamus, thalamus, septum, and midbrain)
were rapidly removed, weighed, and immediately homogenized in 4 mol/L
guanidine thiocyanate and 1% (vol/vol) trifluoroacetic acid in water
and processed as described previously20 before
acetylation, HPLC, and measurement of angiotensin peptides by
N-terminal–directed RIA.19 Data were corrected
for recovery, as reported elsewhere.19 The time delay
between decapitation and homogenization for adrenals was 60 seconds and
for kidney was 90 seconds; heart and lung were homogenized within 120
seconds, aorta and brown adipose tissue were homogenized within 150
seconds, and brain was homogenized within 180 seconds. For plasma,
adrenals, lung, aorta, brown adipose tissue, and brain of 6-week-old
rats, plasma or homogenates from two rats were pooled to obtain
sufficient sample for analysis.
Measurement of ACE, Renin, Angiotensinogen, and Aldosterone in
Plasma
The plasma concentrations of ACE enzymatic activity, active
renin, and angiotensinogen were measured as described
previously.21 ACE enzymatic activity was measured with the
use of 3-(2-furylacryloyl)-L-phenylalanyl-glycyl-glycine
(FAPGG) as substrate.22 Plasma aldosterone was measured by
RIA (Coat-a-Count Direct RIA, Diagnostics Products Corp).
Assay Strategy and Statistical Analysis
For the measurement of ACE, renin, angiotensinogen, and
aldosterone, all samples from SHR and DRY of each age were included in
a single assay. For the measurement of angiotensin peptides by
HPLC-based RIA, recoveries were not determined in this study, but the
historical recoveries of the laboratory determined for tissues of
Sprague-Dawley rats19 were used to correct for
peptide levels. Corresponding DRY and SHR samples were analyzed in
parallel, with alternating DRY and SHR samples run on HPLC and both DRY
and SHR samples included in each RIA.
Data are presented as mean±SEM. When more than half of the samples comprising a mean had values below the minimum detectable, the sample mean is shown as less than the minimum detectable. Except in the case of blood pressure and body weight, data were analyzed by ANOVA for all rats. When a statistically significant difference between strains was indicated, contrasts were calculated for DRY and SHR at each age separately; when contrasts indicated a statistically significant difference between strains, this was confirmed by t test. The a priori null hypothesis was that SHR and DRY were identical for each of the parameters studied at each age. Any parameter of SHR was compared with only the corresponding parameter of age-matched DRY. None of the comparisons was post hoc. According to Armitage and Berry,23 the t test is appropriate for these comparisons. In the case of blood pressure and body weight, data for each age were analyzed separately. When values were below the minimum detectable, they were set at half the minimum detectable for statistical calculations. Logarithmic transformation of data was performed when appropriate to obtain similar variances among groups. Analyses were performed with the use of SUPERANOVA (Abacus Concepts, Inc).
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Results |
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SHR had higher blood pressures and ratios of heart weight to body weight than DRY at all ages (Fig 1). SHR were approximately 19 g lighter than DRY at 6 weeks of age, of similar body weight at 10 weeks, and approximately 30 g heavier at 20 weeks (Fig 1).
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Plasma renin levels were suppressed in SHR (ANOVA for all ages: P<.0001, with statistically significant differences for all ages), being 13% to 32% of those of DRY (Fig 2). Plasma angiotensinogen levels of SHR were higher than those of DRY (ANOVA for all ages: P<.0001), and this increase was statistically significant at 10 weeks of age, when plasma angiotensinogen levels of SHR were 22% higher than those of DRY (Fig 2). Plasma ACE levels were lower in SHR (ANOVA for all ages: P<.0001, with statistically significant differences for all ages), being 58% to 70% of those of DRY (Fig 2). Plasma aldosterone levels of SHR were less than those of DRY (ANOVA for all ages: P=.0268), and this decrease was statistically significant at 20 weeks of age (Fig 2).
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Plasma levels of Ang II and Ang I for SHR were less than those of DRY (ANOVA for all ages: P<.0001) (Fig 3). Despite the difference in plasma ACE levels, there were no differences between the plasma Ang II–Ang I ratios for SHR and DRY. The levels of Ang-(1-7) in plasma of SHR and DRY were less than the minimum detectable (<3 fmol/mL).
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Ang II levels in lung were lower in SHR than DRY (ANOVA for all ages: P<.0001) (Fig 4). Lung Ang I levels were also lower in SHR (ANOVA for all ages: P=.0282), and this decrease was statistically significant at 20 weeks of age. Of all tissues, only lung showed a lower Ang II–Ang I ratio for SHR (ANOVA for all ages, P=.0117), being 59% to 69% of the ratio for DRY, consistent with the lower plasma ACE levels of SHR. However, when Ang II–Ang I ratios for lung were analyzed for each age separately, no comparison achieved statistical significance, because of the higher variance associated with the measurement of Ang II–Ang I ratio compared with that of plasma ACE. The levels of Ang-(1-7) in lung of SHR and DRY were less than the minimum detectable (<6 fmol/g).
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Renal Ang-(1-7) levels were lower in SHR (ANOVA for all ages: P<.0001, with statistically significant differences for all ages) (Fig 5). Renal Ang II and Ang I levels were similar at 6 weeks of age and were suppressed in SHR at 10 and 20 weeks of age. There were no differences between SHR and DRY for the Ang II–Ang I ratios for kidney.
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For 6-week-old SHR, cardiac levels of Ang-(1-7), Ang II, and Ang I were no different from the levels in DRY (Fig 6). Ang-(1-7) levels were lower in SHR at 20 weeks (ANOVA for all ages: P=.0512), and Ang II levels were lower at 10 and 20 weeks (ANOVA for all ages: P<.0001). There were no differences between SHR and DRY for cardiac Ang I levels and Ang II–Ang I ratios.
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Ang II levels in adrenal, aorta, and brown adipose tissue were lower in SHR than DRY (ANOVA for all ages: P<.0001 for adrenal and aorta, P=.0002 for brown adipose tissue) (Fig 7). By contrast, Ang II levels in SHR brain were higher than those of DRY at 6 weeks of age and similar at 10 and 20 weeks. When compared by t test, the Ang II levels in 6-week-old SHR brain were significantly higher than for DRY at this age (P=.0413). However, ANOVA of brain Ang II levels at all ages did not achieve statistical significance (P=0.6569 for between strains, and P=.0863 for strain-age interaction). Ang-(1-7) and Ang I levels of adrenal, aorta, brown adipose tissue, and brain of SHR and DRY were close to or less than the minimum detectable [Ang-(1-7): <50, <20, <10, and <13 fmol/g for adrenal, aorta, brown adipose tissue, and brain, respectively; Ang I: <30, <12, <4, and <5 fmol/g, respectively], and the Ang II–Ang I ratios for these tissues could not be reliably estimated.
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Discussion |
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In the present study, we examined whether the apparent Ang II dependence of hypertension of SHR is due to increased Ang II levels in tissues. The methods we used to measure plasma and tissue levels of angiotensin peptides have undergone extensive validation.19 21 24 Except for brain at 6 weeks of age, all SHR tissues showed Ang II levels similar to or less than those of DRY tissues.
The question of the most appropriate control for SHR has been discussed previously.25 26 We chose the DRY as control because it is genetically homogeneous, thus allowing us to test the linkage between angiotensin peptide levels and blood pressure in SHR and DRY in future crossbreeding experiments. The genetic homogeneity of WKY is in doubt.18 The genealogy of SHR and WKY27 indicates that selection of WKY was made 12 years after that of SHR and that after distribution to the National Institutes of Health in 1971, a number of substrains appeared.
The present results for 10-week-old DRY are similar to our previous data for Sprague-Dawley rats.19 28 In a recent study of 6-week-old male Sprague-Dawley rats, we found plasma renin levels of 8±1 pmol Ang I/mL per hour (mean±SEM, n=10), as well as levels of plasma Ang II, 31±3 fmol/mL; kidney Ang II, 155±10 fmol/g; adrenal Ang II, 2225±162 fmol/g; heart Ang II, 15±3 fmol/g; aorta Ang II, 290±28 fmol/g; brown adipose tissue Ang II, 157±11 fmol/g; lung Ang II, 174±8 fmol/g; and brain Ang II, 14±2 fmol/g (unpublished data, 1994). For plasma and all tissues, the Ang II levels of 6-week-old male Sprague-Dawley rats were similar to or higher than those for DRY of this age. Although there is a need for caution in the comparison of data obtained from different experiments, the similarities in renin and Ang II levels of Sprague-Dawley rats and DRY at different ages indicate that the DRY is representative of normotensive rats.
There have been several reports of angiotensin peptide levels in SHR and WKY. Kohara et al10 found plasma levels of Ang II and Ang I in SHR to be similar to those of WKY, but plasma Ang-(1-7) levels were higher in SHR. Although the plasma Ang II levels in WKY reported by Kohara et al were similar to those of DRY in the present study, those authors found much higher Ang I levels, probably because of their failure to adequately inhibit renin during processing of the plasma samples. Whereas Kohara et al used pepstatin, we used the more potent renin inhibitor SQ 30697. This aspect of methodology also relates to the measurement of plasma levels of Ang-(1-7). Ang-(1-7) is an important metabolite of Ang I, and failure to inhibit renin may result in artifactually high levels of Ang-(1-7) consequent to continued Ang I formation during sample processing, which may account for the higher plasma Ang-(1-7) levels in SHR measured by Kohara et al than measured in the present study. Matsushima et al6 measured kidney Ang II levels in pentobarbital-anesthetized SHR and WKY aged 4 and 20 weeks. Although plasma renin levels were similar in the two strains at both ages, renal Ang II levels of SHR were increased at 4 weeks and suppressed at 20 weeks.6 However, Matsushima et al measured much higher Ang I levels in kidney than found in the present study, which may have been due to Ang I formation during freezing and thawing of the tissue.29 Ang II levels in adrenal of young stroke-prone SHR are reported to be less than30 or similar to15 levels in WKY adrenal. However, the high adrenal Ang I levels reported15 30 again suggest a failure to prevent Ang I generation during sample processing. Phillips and Stenstrom31 found no difference between hypothalamic Ang II levels of SHR and WKY. Ganten et al32 also found similar Ang II levels in hypothalamus of stroke-prone SHR and WKY. Subsequent studies by Phillips and Kimura33 34 found higher levels of immunoreactive Ang II in brain of SHR than of WKY. However, these studies31 32 33 34 report levels of brain Ang II (50 to 300 fmol/g) that are higher than the levels measured in the present study.
A primary role for kidney-derived renin in the Ang II–dependent hypertension of SHR is indicated by the abolition of the hypotensive effects of renin antisera, ACE inhibitors, and Ang II antagonists after bilateral nephrectomy.3 In regard to extrarenal synthesis of renin, several authors have measured renin mRNA in tissues of SHR. Iwai and Inagami35 found increased renin mRNA levels in brain of SHR of 4, 6, and 16 weeks compared with WKY of the same age. Moreover, Samani et al36 found higher renin mRNA levels in kidney, liver, brain, adrenal, and heart of 5-week-old SHR than in WKY and similar renin mRNA levels in aorta of the two strains. For 10- to 12-week-old rats, increased renin mRNA levels persisted in the liver, brain, and adrenal of SHR,36 but renin mRNA levels were similar in kidney of the two strains13 36 and were suppressed in the heart and aorta of SHR.36 However, renin mRNA codes for the inactive prorenin, and the extent to which extrarenal tissues activate prorenin is unknown. Moreover, there must be some doubt concerning the renin mRNA levels in heart and aorta reported by Samani et al because other researchers35 found no convincing evidence for renin mRNA in cardiac ventricle and aorta using the polymerase chain reaction.
Although Bagby et al8 found plasma angiotensinogen to be suppressed in SHR, other researchers found similar10 or elevated9 plasma angiotensinogen in SHR. There are no differences in hepatic angiotensinogen mRNA levels in SHR and WKY,13 37 although Pratt et al13 found lower angiotensinogen mRNA levels in SHR kidney, and angiotensinogen and angiotensinogen mRNA are reported to be elevated in SHR brain compared with WKY brain.37 38 Increased plasma and tissue angiotensinogen levels may counteract the effects of suppressed renin levels on angiotensin peptide formation in SHR.
Plasma ACE levels of SHR may be higher, lower, or similar to the levels of WKY depending on the source of the rats.2 10 39 In the present study, despite the lower plasma ACE levels in SHR, only lung showed a statistically significant difference in Ang II–Ang I ratio from DRY. The similar Ang II–Ang I ratio in plasma and tissues other than lung of SHR and DRY suggests that ACE levels in tissues other than lung are similar for the two rat strains.
Apart from the brain of 6-week-old SHR, plasma and tissue Ang II levels of SHR were either less than or similar to those of DRY. Thus, the question arises as to whether our data are consistent with a role for Ang II in the pathogenesis of hypertension in SHR. Ang II receptor number is increased in the mesenteric vasculature and renal cortical brush border membranes of young SHR6 11 and in SHR brain40 compared with WKY. There are no differences in Ang II receptor number in the renal vasculature of SHR and WKY,41 but SHR show an increased renal vascular responsiveness to Ang II42 43 that may relate to a lack of buffering effect of prostaglandins in SHR.41 When taken together with this evidence for increased Ang II receptor number and increased responsiveness of SHR to Ang II, the normal Ang II levels in kidney and heart and elevated Ang II levels in brain of 6-week-old SHR identified in the present study are consistent with a role for Ang II in the pathogenesis of hypertension in SHR.
A large body of data implicates the kidney in the pathogenesis of hypertension in SHR.44 45 Evidence for a primary role for the kidney in the pathogenesis of hypertension in SHR is provided by renal transplantation studies, which show that blood pressure of the donor SHR is transplanted with the kidney.44 Genetic studies reveal a cosegregation of renal hemodynamics and blood pressure in SHR.46 Moreover, Nørrelund et al47 found that a reduced afferent arteriole diameter at 7 weeks of age is a predictor of increased blood pressure at 23 weeks in an F2 generation from SHR and WKY.
We found similar renal Ang II levels in 6-week-old SHR and DRY despite much lower plasma renin levels in SHR. A previous comparison of SHR and DRY by Shiono and Sokabe14 also found lower plasma renin levels in SHR at 5, 10, 20, and 30 weeks of age. The paradox of "normal" renal Ang II levels despite suppressed plasma renin levels in 6-week-old SHR resembles that shown by the unclipped kidney of two-kidney, one clip Goldblatt hypertensive rats, in which renal Ang II levels are normal48 or elevated49 despite renin depletion.48 Maintenance of renal Ang II levels may contribute to the shift in the arterial pressure–urinary output relationship in SHR45 and thus to the pathogenesis of hypertension in SHR. Although an increase in renal ACE activity may contribute to the renal Ang II levels of the unclipped kidney,49 the renal Ang II–Ang I ratio of SHR kidney was no different from that of DRY, indicating normal renal ACE activity in SHR. For both the unclipped kidney of two-kidney, one clip Goldblatt hypertensive rats49 and kidney of 6-week-old SHR, the maintenance of normal renal Ang I levels may be due to a mechanism that determines the partition of renin within the kidney, such that local angiotensin peptide production is maintained despite decreased renin secretion. Such a mechanism may relate to tissue binding of renin, and a similar mechanism may also operate in heart, brain, and other SHR tissues.
Of all SHR tissues, adrenal Ang II levels were most concordant with the plasma renin levels, being 22% to 42% of the Ang II levels of DRY adrenal. SHR also had suppressed plasma aldosterone, in agreement with previous studies12 and consistent with the lower plasma and adrenal levels of Ang II in SHR. Renin activity and renin mRNA are increased in SHR adrenal compared with WKY adrenal,17 36 and adrenal renin has been proposed to contribute to the regulation of aldosterone secretion via local Ang II formation.50 Although we did not measure adrenal renin in this study, the present data question the role of adrenal renin in local adrenal Ang II formation and are more consistent with a primary role for plasma renin in the determination of adrenal Ang II levels and aldosterone secretion.
Several authors have proposed that a brain-angiotensin system may contribute to the pathogenesis of hypertension in SHR.16 Renin activity, renin mRNA, angiotensinogen, and angiotensinogen mRNA are increased in SHR brain.35 36 37 38 51 Given that angiotensinogen and its mRNA are confined to glia,52 53 the nature of neuronal immunoreactive Ang II is uncertain. The low levels of Ang II we measured in brain indicate that if Ang II is a neuropeptide, it is of very low abundance, and an alternative concept of the brain-angiotensin system is that of volume transmission.54 Nevertheless, the increased Ang II levels in brain of 6-week-old SHR are consistent with a role for brain Ang II in the pathogenesis of hypertension in SHR.
In summary, our finding that all SHR tissues, except for brain at 6 weeks of age, showed Ang II levels similar to or less than the levels of DRY indicates that, apart from a possible role for brain of young rats, the hypertension of SHR is not due to increased Ang II levels. Inasmuch as the hypertension of SHR is Ang II dependent, it may be due to the increased Ang II receptor number6 11 40 and increased responsiveness to Ang II42 43 shown by these rats.
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Acknowledgments |
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This study was funded by grants from the National Health and Medical Research Council of Australia and from Servier Laboratories. We are grateful to Thaddeus P. Gorski for performing the assays for plasma ACE, and to Shari Datodi for technical assistance.
Received April 27, 1994; first decision June 29, 1994; accepted January 25, 1995.
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