Published online before print December 1, 2003, doi: 10.1161/01.HYP.0000107194.44040.d4
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(Hypertension. 2004;43:87.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Hypersensitivity of the Adrenal Cortex to Trophic and Secretory Effects of Angiotensin II in Lyon Genetically-Hypertensive Rats
From the Inserm U-369, IFR-62 Laennec (F.A., J.M.S., J.Y.L.), Département de Physiologie et de Pharmacologie Clinique (F.A., M.L., J.S.), Faculté de Pharmacie, and Service de Médecine nucléaire (B.C.), Hôpital Neuro-Cardiologique, Lyon, France.
Correspondence to Jacques Y. Li, Faculté de Mécine Laennec, 7 Rue G Paradin, 69372 Lyon cedex 08, France. E-mail liyuan{at}lyon.inserm.fr
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Abstract |
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In Lyon hypertensive (LH) rats, a model of low-renin genetic hypertension, we investigated adrenal sensitivity to angiotensin II in terms of angiotensin II receptor (AT1 and AT2 receptors) regulation, morphological changes, and aldosterone and corticosterone secretion. Twelve-week-old LH rats, compared with normotensive LN and LL rats, were either untreated or treated for 4 weeks with AT1 receptor antagonist irbesartan (50 mg/kg/d), angiotensin-converting enzyme inhibitor perindopril (3 mg/kg/d), or perindopril (3 mg/kg/d) plus angiotensin II infusion (200 ng/kg/min). At 16 weeks, untreated LH rats had high systolic blood pressure (P<0.05), low aldosterone (P<0.05), and increased corticosterone (P<0.05) plasma levels. AT1-receptor binding density in the zona glomerulosa was similar in the three strains. In LH rats, angiotensin II infusion increased the relative adrenal weight from 10.5±0.3 to 16.7±0.7 mg/100g (P<0.05), whereas this change was very modest in normotensive rats. Zona glomerulosa enlarged and plasma aldosterone increased after angiotensin II infusion in the 3 strains, but more markedly in LH versus normotensive rats (2.4- versus 1.3- and 1.6-fold, respectively; 20- versus 10-fold in normotensive rats, P<0.05). Surprisingly, after angiotensin II infusion, despite the absence of angiotensin II receptors in the three strains, the zona fasciculata-reticularis enlarged 1.5-fold and plasma corticosterone increased 1.7-fold only in LH rats (P<0.05), suggesting an indirect control of this compartment by angiotensin II. The hypertrophy and hypersecretory activity of both zona glomerulosa and zona fasciculata-reticularis in LH rats in response to angiotensin II point to the adrenal cortex as a pivotal tissue in the pathophysiology of hypertension in LH rats.
Key Words: rats • hypertension, genetic • receptors, angiotensin II • adrenal gland • hypertrophy • aldosterone • corticosterone
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Introduction |
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Adult genetically-hypertensive rats of the Lyon strain (LH), contrary to their normotensive (LN) and low blood pressure (LL) controls, exhibit a low plasma and kidney renin content but an efficient blood pressure-lowering response to angiotensin converting enzyme (ACE) inhibition.1 Renin expression at other locations (eg, the adrenal gland and the brain) was not shown to differ in the Lyon rat strains.2 The paradox of this low renin form of hypertension could be explained by an increased sensitivity of LH rats to angiotensin II (ANG II)1 and could implicate an abnormal regulation of the number and/or function of ANG II receptors.
ANG II receptors can be divided into at least two subtypes: subtype 1 (AT1R) and subtype 2 (AT2R). In rodents, there are two AT1R subtypes, 1A and 1B, differentially expressed and regulated.3 ANG II receptors display a discrete localization in various organs, including the cardiovascular system, kidneys, adrenals, pituitary gland, and brain. Most, if not all, known actions of ANG II, such as aldosterone secretion, renal salt reabsorption, vasoconstriction, and cell proliferation, are mediated by AT1R.4
The adrenal gland is an important site for the regulation of fluid homeostasis and sympathetic function by ANG II.5 Stimulation of AT1R contributes to regulate aldosterone formation and release.6 In the adrenal medulla, although AT1R density is low, they partly control catecholamine release.7 Like in other tissues, the functions of AT2R are still a matter of controversy. Despite their noticeable density in the zona glomerulosa, AT2R do not participate in aldosterone formation or secretion.5,8 The presence of a large number of AT2R in the adrenal medulla has been linked to the control of catecholamine release by only a few authors.8,9 No significant amount of ANG II receptors has been reported in the zona fasciculata-reticularis of the rat. However, this compartment of the adrenal gland may contribute to hypertension in rodents and man through an adrenocorticotropin-dependent mechanism.10
We hypothesized that, in LH rats, an abnormal expression and/or regulation of ANG II receptor subtypes in the adrenal gland could contribute to an enhanced effect of ANG II in this model of low renin hypertension. Therefore, we studied the effects of pharmacological alterations of the renin-angiotensin system on blood pressure, adrenal morphology, ANG II receptors, and steroidogenic response. This was conducted in LH rats compared with their two genetically pure and different normotensive controls, the LN and LL rats.
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Materials and Methods |
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Experimental Protocol
Male Lyon rats bred in the laboratory were housed in controlled conditions (21°C ±1°C; humidity: 60%±10%; lighting 8 to 20 hours) with a standard rat chow containing 0.3% sodium and 0.75% potassium (A03; UAR, Villemoisson-sur-Orge, France). Experiments were conducted in accordance with our institutional ethical guidelines.
Twelve-week-old animals were divided into four groups of 10 LH, LN, and LL rats that were untreated or treated for 4 weeks as follows: group C, control untreated animals received buffered water (solution for irbesartan preparation); group I, orally treated with an AT1R antagonist, irbesartan (50 mg/kg/d; Sanofi, Montpellier, France), dissolved in 0.035-mol/L Na3PO4 and neutralized with 0.035-mol/L NaH2PO4; group P, orally treated with an ACE inhibitor, perindopril (3 mg/kg/d; Servier, Neuilly-sur-Seine, France); and group P+ANG II, orally treated with perindopril (3 mg/kg/d) associated with a subcutaneous infusion of ANG II (200 ng/kg/min; Sigma Chemical, St. Louis, Mo) through an osmotic minipump (Alzet 2ML4; ALZA, Palo Alto, Calif) to clamp at a stable level the circulating ANG II. Indirect systolic blood pressure (SBP) was measured weekly by tail-cuff plethysmography (Narco Biosystems, Houston, Tex) on freely moving preheated rats. At 16 weeks of age, animals were euthanized between 10 and 12 AM by decapitation 20 minutes after being tranquillized (diazepam 5 mg/kg, IP). Adrenals were dissected out, weighed, and frozen in liquid nitrogen. Blood collected on heparin at 4°C was centrifuged to obtain plasma.
Steroid Dosages
Plasma aldosterone levels were determined by radioimmunoassay using a commercial kit (Immunotech, Marseille, France). Plasma corticosterone levels were determined by radioimmunoassay.11
Autoradiography of ANG II Receptors
Adrenal 12-µm frozen sections were treated as described.12 Adjacent sections were incubated for 120 minutes with 1 nmol/L of 125I-ANG II (specific activity, 2200 Ci/mmol) alone (total binding) or in the presence of 10-µmol/L ANG II (nonspecific binding). Specific AT1R or AT2R binding was determined in the presence of 0.1-µmol/L CGP 42112A and 1-µmol/L irbesartan, respectively. Autoradiograms were generated by exposing dried sections to X-ray films for 1 to 2 days and analyzed by computerized microdensitometry using the NIH Image 1.6 software (NIMH, Bethesda, Md). Results were calculated in dpm/mm2 after comparison with a 125I-radioactivity standard.
Stereological Procedures
Serial adrenal cryosections (12 µm) were fixed, stained with eosin-hematoxylin, observed under light microscope, and photographed with a digital camera. The analysis was made with the NIH image 1.6 software. Every tenth section of each adrenal was measured for area of the medulla. Width of zona glomerulosa and diameter of adrenals were measured on equatorial sections. Volumes of the medulla were calculated from area x distance between sections. Volumes of the entire gland and the zona glomerulosa were calculated according to Nussdorfer et al.13 Volumes of the zona fasciculata-reticularis were obtained by subtracting the volumes of the zona glomerulosa and of the medulla from the volume of the whole gland.
Statistical Analysis
Results are reported as mean±SEM. Statistical analyses were performed by Student’s t tests, the level of significance being P<0.05. If statistically significant effects were found by the t tests, Bonferroni corrections for multiple comparisons were applied where appropriate. Comparison of indirect SBP with age used two-way analysis of variance with repeated measures over time. P<0.05 was considered as significant.
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Results |
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Systolic Blood Pressure
Control LH rats had a significantly higher SBP than age-matched LN and LL rats (Figure 1). As usual, these two latter did not differ. Irbesartan decreased SBP more markedly in LH than in LN and LL rats. A similar observation was made in perindopril-treated animals with the difference that perindopril lowered more SBP in LN and LL rats than did irbesartan. The infusion of ANG II in perindopril-treated rats induced during the first two weeks a similar increase in SBP in the three strains. During the two last weeks of infusion, SBP continued to increase in LH rats, whereas it remained stable in LN and LL rats.
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P<0.05 versus LL rats.
Trophic Effect of Angiotensin II on the Adrenals
Control LH rats had a significantly (P<0.05) larger body weight (BW) than LN and LL rats (Table 1). Neither irbesartan nor perindopril significantly changed the BW of the three strains of rats. On the contrary, the infusion of ANG II decreased markedly the BW in LH rats (Table 1). The relative adrenal weight (Figure 2) did not differ between control rats. ANG II infusion induced a modest increase in adrenal weight of LL rats whereas, in LH rats, a striking elevation (+60%) was observed. This ANG II-induced increase remained highly significant when absolute instead of relative adrenal weights were considered.
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P<0.05 versus C. 
P<0.05 P+ANG II versus P.To assess which zones of the adrenal were enlarged during ANG II treatment, we estimated the volumes of the different compartments of the adrenal in perindopril-treated rats which had or not been infused with ANG II (Table 2). Volumes of the entire gland, zona glomerulosa, zona fasciculata-reticularis, and medulla were not significantly different in the three strains treated with perindopril. ANG II infusion led to a much greater increase (2.4-fold) in the zona glomerulosa volume in LH than in normotensive rats (about 1.5-fold in both LN and LL rats). In addition, the volume of the zona fasciculata-reticularis increased only in LH rats. Whatever the strain of rats, the volume of the medulla was unaffected by ANG II infusion.
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Plasma Steroids
Basal levels of plasma aldosterone were significantly lower in 16-week-old LH rats (145±13 pg/mL) than in age-matched LN and LL rats (400±58 and 288±35 pg/mL, respectively, Figure 3). Irbesartan or perindopril induced a significant decrease of plasma aldosterone in LN and LL rats, but not in LH rats. ANG II infusion in perindopril-treated rats strongly elevated plasma aldosterone in the three strains, this increase being greater in LH rats (20-fold) than in normotensive rats (about 10-fold for both LN and LL rats). Basal levels of plasma corticosterone were higher in 16-week-old LH than in age-matched LN and LL rats. Plasma corticosterone levels were not altered significantly by AT1R blockade with irbesartan in the three strains. Perindopril treatment induced a modest plasma corticosterone increase in LL rats. ANG II infusion in perindopril-treated rats markedly increased plasma corticosterone in LH rats only.
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AT1R and AT2R Subtypes
The affinity of AT1R and AT2R in adrenal cell membranes from the four experimental groups was comparable in the three strains of rats and unaffected by the various treatments (data not shown). Figure 4 shows the autoradiographic localization of ANG II receptors in adrenal glands of 16-week-old Lyon rats. AT1R binding sites were highly expressed in the zona glomerulosa, slightly expressed in the medulla, and undetectable in the zona fasciculata-reticularis. AT2R binding sites were mostly present in the adrenal medulla and moderately in the zona glomerulosa. As for AT1R, no AT2R binding sites were detected in the zona fasciculata-reticularis. In the zona glomerulosa, AT1R and AT2R-binding site densities were similar in LH, LN, and LL rats, and not altered by irbesartan or perindopril treatments (Table 3). The chronic infusion of ANG II induced an upregulation of AT1R and AT2R in the zona glomerulosa of comparable intensity in the three strains (Table 3 and Figure 4B). In the adrenal medulla, AT1R density did not differ among the groups studied, whereas AT2R-binding site density was higher in LN than in LH and LL rats in the control groups (Table 3 and Figure 4A). Suppression of AT1R and AT2R stimulation with perindopril did not modify the density of AT2R binding sites. On the contrary, AT2R overstimulation either as a result of irbesartan treatment or ANG II infusion significantly decreased their density in the three strains of rats (Table 3 and Figure 4B).
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Discussion |
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The major finding of this study was that the high and sustained rise in blood pressure induced in LH rats by ANG II infusion was associated with an impressive enlargement of the adrenals and a marked increase of both plasma aldosterone and corticosterone levels.
ANG II Receptor Regulation in Control and Treated Animals
Binding studies on adrenal sections shown in the present study indicated that the general pattern of expression of the ANG II receptors in the adrenal gland was similar in the three strains of the Lyon rats and reflected the classical profile reported in the rodent adrenal gland.8,12
The design of the pharmacological protocol was aimed at creating in each group a clear-cut status of the renin-angiotensin system: in group C, ANG II receptors were under the control of endogenous ANG II; in group I, AT1R were blocked by irbesartan whereas AT2R were likely to be over-stimulated by the increase of endogenous circulating ANG II resulting from the lack of AT1R-mediated negative feed-back on renin release;14 in group P, ACE inhibition abolished the stimulation of both ANG II receptor subtypes;1 and in group P+ANG II, both ANG II receptor subtypes were over-stimulated at a constant level by an infusion of exogenous ANG II in animals deprived of endogenous and thus variable formation of ANG II via perindopril treatment. These various pharmacological treatments induced subtle differences in the levels of expression of the ANG II receptors in the three strains of Lyon rats.
In the zona glomerulosa, over-stimulation of both AT1R and AT2R by ANG II infusion induced an upregulation of AT1R and AT2R in the three strains of Lyon rats. In rodents, upregulation of AT1R in the zona glomerulosa by ANG II is well documented,12,15 and that of AT2R has been reported in a model in which ANG II was increased by low sodium diet.12
At 16 weeks of age, the medullas of control LN rats displayed a higher AT2R density than those of the LH and LL rats. High density of AT2R binding in the LN rats seems to be a peculiar feature of this strain. No significant differences of AT2R-binding site densities were reported in spontaneously hypertensive rats (SHR) versus Wistar Kyoto (WK) rats.16 AT2R binding sites in Lyon rats were down-regulated by an increased production of ANG II resulting either from AT1R blockade or ANG II infusion. This is at variance with the regulation of AT2R, reported above, in the zona glomerulosa by the same treatments. These differences illustrate in vivo the complexity of the regulation of AT2R expression by ANG II which resorts to specific mechanisms with regard to the cell type as reported in several in vitro models.17 Interestingly, biochemical evidence suggests that AT1R and AT2R make oligomers, which alter cellular responses to ANG II.18 The differences of expression of the two receptor subtypes we report in the zona glomerulosa and the medulla could have a functional relevance that is worth studying.
In the zona fasciculata-reticularis, AT1R or AT2R could not be detected in any strain of Lyon rats. Most authors agree with an absence of detectable ANG II receptors in the rat zona fasciculata-reticularis.12,19 However, their presence in minute amounts nondetectable by binding experiments on tissue section cannot be ruled out.20
Morphological and Functional Alterations of the Adrenal Gland Induced by the Treatments
The medulla was not implicated in adrenal hypertrophy of the LH strain in response to ANG II. No modification of the volume of this compartment was found in the three strains, despite the fact that AT2R have been reported to mediate, in vivo and in vitro, antiproliferative21 and proapoptotic effects22 in the medulla.
As expected,21,23,24 the zona glomerulosa grew in the three strains of Lyon rats in response to ANG II. Zona glomerulosa enlargement was remarkable in LH rats. In this strain, its volume increased 2.4-fold, which accounted for 37% of the hypertrophy of the whole gland, compared with 1.3- and 1.6-fold in LN and LL rats, respectively. Because AT1R densities did not differ among the three strains, LH rats appear to display an exquisite sensitivity of the zona glomerulosa to the trophic effects of ANG II in comparison with their normotensive controls. This hypersensitivity is not the consequence of an alteration of the constant of dissociation (Kd) of the AT1R, and suggests the alteration of post-receptor events affecting zona glomerulosa growth in the LH strain. A similar analysis can be made of the secretory activity of the zona glomerulosa in the three strains of rats in response to ANG II. As expected, aldosterone was massively increased in the three strains in response to ANG II.25 Taking into account that perindopril-treated LH rats displayed lower aldosterone plasma levels than LN or LL rats, the increase of aldosterone in LH rats after ANG II infusion was more than two-fold that in the LN and LL rats, so that it can be inferred that the zona glomerulosa of the LH rats has an increased sensitivity to ANG II. However, if the plasma aldosterone concentrations induced by ANG II in the three strains are referred to either the volume of the zona glomerulosa or the absolute number of AT1R, the amount of plasma aldosterone per volume unit of zona glomerulosa or per AT1R is lower in the LH than in the normotensive rats. Although the balance between the rates of aldosterone synthesis and excretion were not determined, such a calculation suggests a low sensitivity of the zona glomerulosa in the LH rats to the secretory effects of ANG II. In comparison to the normotensive controls, the LH rats display an imbalance between the trophic and the secretory effects of ANG II with a shift in favor of the growth-promoting effect of the AT1R.
In the zona fasciculata-reticularis, a highly unexpected piece of information was found. In LH rats only, the zona fasciculata-reticularis was prominently enlarged after ANG II infusion. This 1.5-fold increase in volume accounted for 63% of the hypertrophy of the whole gland. Available data21,23 do not favor the hypothesis of a growth-promoting effect of ANG II on the zona reticularis. Clues that the zona fasciculata was enlarged in LH rats in group P+ANG II were drawn from the measurements of plasma corticosterone concentrations in Lyon rats. Corticosterone is the main steroid secreted by the zona fasciculata. ANG II infusion induced a 1.7-fold increase in plasma corticosterone in LH rats compared with a limited 1.2-fold increase in the two normotensive strains. This is quite surprising because this compartment does not display detectable levels of either AT1R or AT2R under none of the pharmacological treatments. One cannot exclude that, according to the migration theory,26 cells in the outer regions of the adrenal cortex proliferate in response to ANG II, then migrate centripetally and acquire the differentiated functions of zona fasciculata cells. A more likely alternative explanation relies on the ability of ANG II to stimulate ACTH release by acting on central ANG II receptors, probably in the anterior pituitary, as shown by several studies.27,28 ACTH would bind to ACTH receptors and induce fasciculata cell growth and corticosterone secretion. Our results suggest that LH rats could be hypersensitive to ANG II-induced ACTH secretion. Because ACTH receptors are expressed in both the zona fasciculata and the zona glomerulosa,29 increased levels of plasma ACTH could also take part in the stimulation of zona glomerulosa hypertrophy and aldosterone secretion in the LH strain. This possible link between ANG II and ACTH secretion is in line with recent findings showing that, in SHR but not in their normotensive controls, a peculiar pattern of expression of AT1AR and AT1BR in the anterior pituitary could be responsible for increased plasma levels of ACTH and corticosterone in response to ANG II.30 Another specific alteration of the hypothalamo-pituitary-adrenal axis in LH control rats was the higher levels of plasma corticosterone they displayed at 16 weeks of age in comparison with age-matched normotensive rats. The elevated values of plasma corticosterone in control animals above 100 ng/mL are probably consecutive to IP injection of diazepam. The stress associated with the injection is certainly involved. A direct or indirect effect of diazepam on steroidogenesis through its receptors in the adrenal cortex or the anterior pituitary gland is unlikely because the dose we used was reported to be ineffective.31 However, our finding of higher corticosterone plasma levels in control LH rats is in keeping with the elevated urinary corticosterone levels found in 20-week-old LH rats maintained under unstressed physiological conditions.32,33 High plasma corticosterone levels in LH rats raise the question of the impact of glucocorticoids in the physiopathology of hypertension in this strain. It is established that mineralocorticoid receptors have the same affinity for both aldosterone and corticosterone. However, LH rats have been shown34 to exhibit an impaired 11ß-hydroxysteroid deshydrogenase type 1 (11ß-HSD1) activity, a situation that should theoretically decrease the availability of corticosterone to the mineralocorticoid receptors. The hypothesis of glucocorticoid-dependent hypertension has also been raised in SHR.35 Such convergent results in two independent models of genetically-hypertensive rats are an incentive to explore further the relevance of glucocorticoids in the physiopathology of hypertension in LH rats.
Perspectives
The massive adrenal enlargement in response to long-term ANG II infusion in LH rats is one of the hallmarks of the sensitivity of this genetically hypertensive rat strain to the effects of ANG II. This hypertrophic response does not depend on an alteration of the affinity nor an abnormal pattern of the regulation of the ANG II receptor subtypes in the adrenal gland. However, functional hypertrophy of both zona glomerulosa and zona fasciculata-reticularis is underlain by ANG II-dependent mechanisms, specific to or exacerbated in the LH rats. In the zona glomerulosa of LH rats, compared with normotensive controls, the proliferative effect of ANG II seems to prevail over its role on aldosterone production. In the zona fasciculata-reticularis, ANG II-dependent functional hypertrophy appears to be the result of an indirect mechanism that could involve the central control by ANG II of the hypothalamo-pituitary-adrenal axis. Our future direction will allow us to analyze more closely the possible anomalies of ANG II signaling or control in the zona glomerulosa and zona fasciculo-reticularis in the LH rats. Evidence for relevant alterations in this animal model would help deciphering forms of low-renin essential hypertension or ACTH-dependant hypertension in human beings.
Received June 18, 2003; first decision July 21, 2003; accepted November 4, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Lantelme P, Lo M, Luttenauer L, Sassard J. Pivotal role of the renin-angiotensin system in Lyon hypertensive rats. Am J Physiol. 1997; 273: R1793–R1799.[Medline] [Order article via Infotrieve]
2. Kaiser M, Vincent M, Kenyon CJ, Gomez-Sanchez CE, Cumin F, Lodwick D, Sassard J, Samani NJ. Analysis of phenotypic consequences of renin gene polymorphism in Lyon rats. J Hypertens. 1997; 15: 365–372.[CrossRef][Medline] [Order article via Infotrieve]
3. Kakar SS, Sellers JC, Devor DC, Musgrove LC, Neill JD. Angiotensin II type-1 receptor subtype cDNAs: differential tissue expression and hormonal regulation. Biochem Biophys Res Commun. 1992; 183: 1090–1096.[CrossRef][Medline] [Order article via Infotrieve]
4. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993; 45: 205–251.[Medline] [Order article via Infotrieve]
5. Vinson GP. The adrenal renin/angiotensin system. Adv Exp Med Biol. 1995; 377: 237–251.[Medline] [Order article via Infotrieve]
6. Tanabe A, Naruse M, Arai K, Naruse K, Yoshimoto T, Seki T, Imaki T, Kobayashi M, Miyazaki H, Demura H. Angiotensin II stimulates both aldosterone secretion and DNA synthesis via type 1 but not type 2 receptors in bovine adrenocortical cells. J Endocrinol Invest. 1998; 21: 668–672.[Medline] [Order article via Infotrieve]
7. Hano T, Mizukoshi M, Baba A, Nakamura N, Nishio I. Angiotensin II subtype 1 receptor modulates epinephrine release from isolated rat adrenal gland. Blood Press Suppl. 1994; 5: 105–108.[Medline] [Order article via Infotrieve]
8. Belloni AS, Andreis PG, Macchi V, Gottardo G, Malendowicz LK, Nussdorfer GG. Distribution and functional significance of angiotensin-II AT1- and AT2-receptor subtypes in the rat adrenal gland. Endocr Res. 1998; 24: 1–15.[Medline] [Order article via Infotrieve]
9. Martineau D, Lamouche S, Briand R, Yamaguchi N. Functional involvement of angiotensin AT2 receptor in adrenal catecholamine secretion in vivo. Can J Physiol Pharmacol. 1999; 77: 367–374.[CrossRef][Medline] [Order article via Infotrieve]
10. Whitworth JA, Schyvens CG, Zhang Y, Mangos GJ, Kelly JJ. Glucocorticoid-induced hypertension: from mouse to man. Clin Exp Pharmacol Physiol. 2001; 28: 993–996.[CrossRef][Medline] [Order article via Infotrieve]
11. Miachon S, Rochet T, Mathian B, Barbagli B, Claustrat B. Long-term isolation of Wistar rats alters brain monoamine turnover, blood corticosterone, and ACTH. Brain Res Bull. 1993; 32: 611–614.[Medline] [Order article via Infotrieve]
12. Lehoux JG, Bird IM, Briere N, Martel D, Ducharme L. Influence of dietary sodium restriction on angiotensin II receptors in rat adrenals. Endocrinology. 1997; 138: 5238–5247.
13. Nussdorfer GG, Mazzocchi G, Rebuffat P. An ultrastructural stereologic study of the effects of ACTH and adenosine 3', 5'-cyclic monophosphate on the zona glomerulosa of rat adrenal cortex. Endocrinology. 1973; 92: 141–151.
14. Campbell DJ. Endogenous angiotensin II levels and the mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor type 1 antagonists. Clin Exp Pharmacol Physiol Suppl. 1996; 3: S125–S131.[Medline] [Order article via Infotrieve]
15. Harrison-Bernard LM, El-Dahr SS, O’Leary DF, Navar LG. Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension. Hypertension. 1999; 33: 340–346.
16. Song K, Kurobe Y, Kanehara H, Wada T, Inada Y, Nishikawa K, Miyazaki M. Mapping of angiotensin II receptor subtypes in peripheral tissues of spontaneously hypertensive rats by in vitro autoradiography. Clin Exp Pharmacol Physiol. 1995; 22 (Suppl 1): S17–S19.[Medline] [Order article via Infotrieve]
17. Ouali R, Berthelon MC, Begeot M, Saez JM. Angiotensin II receptor subtypes AT1 and AT2 are down-regulated by angiotensin II through AT1 receptor by different mechanisms. Endocrinology. 1997; 138: 725–733.
18. AbdAlla S, Lother H, Abdel-tawab AM, Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem. 2001; 276: 39721–39726.
19. Healy DP, Maciejewski AR, Printz MP. Autoradiographic localization of [125I]-angiotensin II binding sites in the rat adrenal gland. Endocrinology. 1985; 116: 1221–1223.
20. Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AL. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989; 165: 196–203.[CrossRef][Medline] [Order article via Infotrieve]
21. McEwan PE, Lindop GB, Kenyon CJ. Control of cell proliferation in the rat adrenal gland in vivo by the renin-angiotensin system. Am J Physiol. 1996; 271: E192–E198.[Medline] [Order article via Infotrieve]
22. Horiuchi M, Hayashida W, Kambe T, Yamada T, Dzau VJ. Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem. 1997; 272: 19022–19026.
23. McEwan PE, Vinson GP, Kenyon CJ. Control of adrenal cell proliferation by AT1 receptors in response to angiotensin II and low-sodium diet. Am J Physiol. 1999; 276: E303–E309.[Medline] [Order article via Infotrieve]
24. Mazzocchi G, Malendowicz LK, Gottardo G, Rebuffat P, Nussdorfer GG. Angiotensin-II stimulates DNA synthesis in rat adrenal zona glomerulosa cells: receptor subtypes involved and possible signal transduction mechanism. Endocr Res. 1997; 23: 191–203.[Medline] [Order article via Infotrieve]
25. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension. 2002; 40: 504–510.
26. McNicol AM, Duffy AE. A study of cell migration in the adrenal cortex of the rat using bromodeoxyuridine. Cell Tissue Kinet. 1987; 20: 519–526.[Medline] [Order article via Infotrieve]
27. Sobel D, Vagnucci A. Angiotensin II mediated ACTH release in rat pituitary cell culture. Life Sci. 1982; 30: 1281–1286.[CrossRef][Medline] [Order article via Infotrieve]
28. Coiro V, Volpi R, Capretti L, Caffarri G, Colla R, Giuliani N, Chiodera P. Stimulation of ACTH and GH release by angiotensin II in normal men is mediated by the AT1 receptor subtype. Regul Pept. 1998; 74: 27–30.[CrossRef][Medline] [Order article via Infotrieve]
29. Lehoux JG, Bird IM, Rainey WE, Tremblay A, Ducharme L. Both low sodium and high potassium intake increase the level of adrenal angiotensin-II receptor type 1, but not that of adrenocorticotropin receptor. Endocrinology. 1994; 134: 776–782.
30. Johren O, Golsch C, Dendorfer A, Qadri F, Hauser W, Dominiak P. Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY. Hypertension. 2003; 41: 984–990.
31. Pohorecky LA, Cotler S, Carbone JJ, Roberts P. Factors modifying the effect of diazepam on plasma corticosterone levels in rats. Life Sci. 1988; 43: 2159–2167.[CrossRef][Medline] [Order article via Infotrieve]
32. Gomez-Sanchez CE, Bataillard A, Vincent M, Sassard J. Urinary mineralocorticoids in genetically hypertensive rats of the Lyon strain. J Hypertens. 1987; 5: S227–S229.
33. Vincent M, Gomez-Sanchez CE, Bataillard A, Sassard J. Steroids during development of genetic hypertension in rats of Lyon strain. Am J Physiol. 1989; 257: H506–H510.[Medline] [Order article via Infotrieve]
34. Lloyd-MacGilp SA, Nelson SM, Florin M, Lo M, McKinnell J, Sassard J, Kenyon CJ. 11beta-hydroxysteroid dehydrogenase and corticosteroid action in lyon hypertensive rats. Hypertension. 1999; 34: 1123–1128.
35. Hashimoto K, Makino S, Hirasawa R, Takao T, Sugawara M, Murakami K, Ono K, Ota Z. Abnormalities in the hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats during development of hypertension. Endocrinology. 1989; 125: 1161–1167.
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