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(Hypertension. 1997;29:45.)
© 1997 American Heart Association, Inc.
Research Articles (Issue 1, Part 1) |
Vascular Aldosterone in Genetically Hypertensive Rats
the Second Department of Internal Medicine (Y.T., I.M., S.I., K.F., H.H., T.Y., H.M.) and Department of Health Sciences (Y.T.), School of Medicine, Kanazawa University, and KKR Hokuriku Hospital (R.T.), Kanazawa, Japan.
Correspondence to Yoshiyu Takeda MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan.
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Abstract |
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We have reported that aldosterone is synthesized and cytochrome P450aldo mRNA exists in the vasculature. To clarify the pathophysiological role of vascular aldosterone in hypertension, we compared aldosterone production in the mesenteric arteries of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats (WKY). The expressions of mRNA of cytochrome P450aldo, mineralocorticoid receptor, and
1 Na,K-ATPase in the mesenteric arteries were compared between the two groups. Aldosterone concentration in the perfusate of the vasculature was measured by radioimmunoassay after purification with high-performance liquid chromatography. Cytochrome P450aldo and mineralocorticoid receptor mRNA levels were quantified by Southern blot analysis of the products of reverse-transcribed polymerase chain reaction. Levels of 1 Na,K-ATPase mRNA were measured by Northern blot analysis. Vascular aldosterone and cytochrome P450aldo mRNA levels of 2-week-old SHRSP were significantly increased compared with those of age-matched WKY. However, vascular aldosterone in 4- and 9-week-old SHRSP did not differ from that in age-matched WKY. Expression levels of mineralocorticoid receptor mRNA in the vasculature of 4- and 9-week-old SHRSP were significantly increased compared with those in age-matched WKY. Concentrations of vascular 1 Na,K-ATPase mRNA of 2-, 4-, and 9-week-old SHRSP also were significantly higher than those in age-matched WKY. These results suggest that vascular aldosterone contributes to the pathophysiology of hypertension in SHRSP in the early stage.
Key Words: aldosterone • rats, inbred SHR • receptors, mineralocorticoid • Na+,K+-exchanging ATPase • RNA, messenger
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Introduction |
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The renin-angiotensin-aldosterone system plays an important role in the control of BP and water and electrolyte balance. It has been shown that all components of the renin-angiotensin system are expressed in both the vascular wall and heart and function on an autocrine-paracrine level.1 2 3 4 The physiological functions of such a locally acting tissue renin-angiotensin system have been postulated but are still subject to further investigation. We have reported that aldosterone, synthesized in the vasculature, is partly controlled by Ang II and participates in the development of vascular hypertrophy in relative accordance with Ang II.5 6 The spontaneously hypertensive rat (SHR) has been studied extensively and suggested as a model for the investigation of hypertension in humans. The SHRSP, a substrain of SHR developed by Okamoto et al,7 is a useful model of human malignant hypertension. To clarify the pathophysiological role or roles of vascular aldosterone in hypertension, we compared aldosterone production in mesenteric arteries of 2-, 4-, and 9-week-old SHRSP with that in age-matched WKY. We compared the expression of mRNA of cytochrome P450aldo (CYP11B2), MCR, and
1 Na,K-ATPase in the mesenteric arteries between the two groups at each age. |
Methods |
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Two-, 4-, and 9-week-old SHRSP (n=26 in each group) and age-matched WKY/Izm8 (n=26 in each group) donated by Disease Model Cooperative Research Association (Kyoto, Japan) were housed in metabolic cages with free access to tap water and normal rat chow (0.1 mmol/g sodium, 0.24 mmol/g potassium; Nippon Charles River). SHRSP were kindly donated by Dr Kozo Okamoto (Kinki University School of Medicine, Osaka, Japan). Rats were maintained in a constant-temperature environment, with a 12-hour light/dark cycle.
BP was determined by a plethysmographic tail-cuff method previously reported.9 Blood was collected from the tail vein as previously reported.9 Plasma concentrations of corticosterone and aldosterone were estimated by radioimmunoassay after extraction with a Sep-Pak C18 cartridge (Waters).10
Eight rats from each group were used for the experiments involving mesenteric arterial perfusion. After the rat was put under pentobarbital anesthesia, the superior mesenteric artery was isolated at its junction with the abdominal aorta and freed of fat and connective tissue by the method of McGregor11 with minor modifications as we have previously reported.12 Briefly, the isolated artery with the second branch was perfused with Krebs-Ringer solution, pH 7.4, at a temperature of 37°C and oxygenated with a 95% O2/5% CO2 gas mixture at a constant flow rate of 3 mL/min. The perfusion pressure was constantly monitored and recorded by means of a pressure transducer connected to a polygraph (RM 600, Nihon-Koden). After 30 minutes of equilibration, the perfusate was collected for 4 hours. The perfusate with tritium-labeled aldosterone (3000 cpm, Amersham Japan) used for recovery monitoring was extracted with a Sep-Pak C18 cartridge in preparation for chromatography with a reversed-phase high-performance liquid chromatographic (HPLC) system. Methanol/water (40%/100%) was used as the mobile phase at a flow rate of 1.5 mL/min for 60 minutes.5 The retention times of 18-hydroxycorticosterone, aldosterone, corticosterone, deoxycorticosterone, progesterone, and pregnenolone were 35, 32, 43, 49, 55, and 59 minutes, respectively. The aldosterone concentration in the perfusate from SHRSP and WKY of each age was measured by radioimmunoassay after HPLC separation. After these experiments on the perfusate, the mesenteric artery was homogenized in 10 mL Krebs-Ringer buffer solution in a tissue grinder. Protein assay was performed according to the method of Bradford.13
Six rats from each group were used for quantification of mRNA of CYP11B2 and MCR, and 12 rats were used for measurement of 1 Na,K-ATPase mRNA in the mesenteric arteries. Mesenteric arteries with the first branch were removed immediately after the rat was decapitated and were freed of fat and connective tissue. The tissue was promptly weighed, frozen in liquid nitrogen, and stored at -80°C before use. Total RNA from rat mesenteric arteries was separated with guanidine thiocyanate followed by centrifugation in a CsCl solution.13 One microgram of total RNA was incubated at 42°C for 60 minutes with 2.5 U Moloney murine leukemia virus (MMLV) reverse transcriptase (RT) (Perkin-Elmer Japan) in a 20-µL reaction mixture containing a random hexanucleotide primer. After incubation for 5 minutes at 99°C, the single-stranded cDNA in the 20-µL reaction mixture was amplified with the polymerase chain reaction (PCR) mixture containing 0.2 mmol/L of each dNTP. The reaction was followed by incubation at 92°C for 3 minutes and 30 cycles of the following sequential steps: 92°C for 1 minute, 60°C for 1 minute, and 72°C for 2 minutes.
The sequences of sense and antisense primers for CYP11B2 were 5'-ACTCCGTGGCCTGAGACG-3' and 5'-TTCAAGTC-CACCACACAG-3', respectively, according to the sequences published by us.14 The MCR sense primer was 5'-GTGTGTGA-GATGAGGCTTCTGGG-3' and the antisense primer was 5'-TTCTTCCTGGCCGGTATCTCCCG-3' according to the sequences published by Loffreda et al.15 We performed RT-PCR using ß-actin as an internal standard. The primers were defined as previously reported by Krapf and Solioz.16 The RT-PCR products in 20-µL aliquots were electrophoresed on a 1.5% agarose gel and transferred to nylon membranes. The membranes were prehybridized in 50% formamide, 5x saline/sodium/phosphate/EDTA, 5x Denhardt's reagent, 1% sodium dodecyl sulfate (SDS), and 0.5 g/L salmon sperm DNA at 50°C for 6 hours. They were then hybridized in the same buffer at 50°C for 15 hours with a specific oligoprobe for CYP11B2, MCR, or ß-actin that had been end-labeled with [32P]ATP (6000 Ci/mmol, New England Nuclear) using a 5'-end oligonucleotide labeling kit. Next, the membrane was washed twice in 2x SSC/0.1% SDS at room temperature for 20 minutes and twice in 0.1x SSC/0.1% SDS at 50°C for 20 minutes in preparation for autoradiography. The hybridized signals were analyzed with a BAS 2000 Bioimaging Analyzer (Fuji Photo Film Co Ltd). The oligonucleotide probes specific for CYP11B2 and MCR were 5'-TGGATGTCCAGCAAAGTC-3' and 5'-TGGCAGCGAAACAGATGATC-3', respectively.14
Pooled poly(A)+ RNAs (5 µg per lane, n=4) of mesenteric arteries of three rats from each experimental group were separated by formaldehyde/agarose gel electrophoresis, transferred to a nylon membrane (Hybond-N+, Amersham Japan), and hybridized with 32P-labeled cDNA probes. The filters were washed and radioactive bands detected by autoradiography. The 1 Na,K-ATPase cDNA probe used in these experiments was obtained from an EcoRI fragment of rat 1 Na,K-ATPase cDNA. The hybridized signals were analyzed with a BAS 2000 Bioimaging Analyzer. For quantification of relative levels of expression of 1 Na,K-ATPase mRNA, the autoradiographic signals were standardized to signals determined from ß-actin mRNA in each preparation to control for amounts of RNA loaded per lane.
The protocol was approved by the Animal Research Committee of the School of Medicine, Kanazawa University.
The time course of aldosterone production in isolated perfused mesenteric preparations was examined up to 5 hours. Aldosterone production was found to be stable up to 4 hours (data not shown). Data are expressed as mean±SE. The significance of differences was assessed by one-way ANOVA and Wilcoxon's unpaired t test. A value of P<.05 was considered statistically significant.
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Results |
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The sensitivity of the aldosterone assay was 30 fmol. The overall recovery was 70%; the interassay variation was 13.5%; and the intra-assay variation was 9.5% for aldosterone in the HPLC system.
The Table summarizes body weight, systolic BP, heart rate, and plasma concentrations of aldosterone and corticosterone in the experimental groups. BP in 9-week-old SHRSP was significantly higher than that of WKY (P<.05). Plasma concentrations of corticosterone did not differ significantly between SHRSP and WKY of each age. The plasma aldosterone concentration was significantly higher in 9-week-old SHRSP than in WKY of the same age (P<.05).
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The production level of aldosterone from the mesenteric arteries of 4- and 9-week-old SHRSP did not differ significantly from that in WKY of the same age (Fig 1). However, 2-week-old SHRSP showed a significantly higher production of aldosterone from their vasculature than WKY of the same age (P<.05) (Fig 1). The concentration of CYP11B2 mRNA in the mesenteric arteries of 2-week-old SHRSP was significantly increased compared with WKY of the same age (P<.05) (Fig 2). Although MCR mRNA levels in the mesenteric arteries of 2-week-old SHRSP did not differ from those of age-matched WKY, the relative concentrations of MCR mRNA in 4- and 9-week-old SHRSP were significantly higher than those in WKY at each age (P<.05) (Fig 3). Fig 4 shows the results of Northern blot analysis and 1 Na,K-ATPase mRNA concentrations in the mesenteric arteries of SHRSP and WKY. Concentrations of 1 Na,K-ATPase mRNA in the mesenteric arteries of 2-, 4-, and 9-week-old SHRSP were significantly increased compared with those in age-matched WKY (P<.05).
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Discussion |
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There has been increasing evidence that mineralocorticoids, acting directly on peripheral vascular tissue, cause hypertension.17 18 Tobian and Redleaf19 have proposed that aldosterone affects salt and water balance in vascular cells and thereby influences vessel lumen size. Hansen and Bohr20 have proposed a direct mineralocorticoid effect on vascular tone and contractility. We have reported that aldosterone increased tritiated leucine incorporation in vascular smooth muscle cells, which was inhibited by a specific aldosterone antagonist.6 Studying rat mesenteric arteries, Funder et al21 found that vascular type I aldosterone binding sites were physiological MCRs. We detected the expression of MCR mRNA in cultured vascular smooth muscle cells. These findings suggest a local rather than a systemic effect of aldosterone via MCRs.
The SHRSP serves as a model of human malignant hypertension. However, the pathophysiological factors that cause malignant hypertension in the SHRSP remain to be established. Adrenal mineralocorticoids are thought to be responsible for the abnormal vascular reactivity observed in the SHRSP.22 Howe et al23 have reported that plasma catecholamine concentrations are higher in SHRSP than WKY. Adrenomedullary activity is enhanced in the SHRSP, along with the adrenal renin-angiotensin system.24
In the present study, vascular aldosterone levels were increased in young prehypertensive SHRSP. Increased levels of CYP11B2 mRNA in the vasculature of SHRSP suggest that local synthesis of aldosterone is increased. The expression of 1 Na,K-ATPase mRNA was increased in the vasculature of SHRSP of the same age. Aldosterone directly stimulates Na,K-ATPase gene expression and induces activation and accumulation in vascular smooth muscle cells.25 26 Locally increased levels of aldosterone in the vasculature may contribute to the pathophysiology in SHRSP in the early stage. In 9-week-old SHRSP, vascular aldosterone production did not differ from that in WKY of the same age. However, the expressions of both 1 Na,K-ATPase mRNA and MCR mRNA in the vasculature were increased. Plasma aldosterone concentrations also were elevated in 9-week-old SHRSP compared with those in age-matched WKY. Kim et al24 reported that plasma aldosterone concentration is high in 18-week-old SHRSP with malignant hypertension. These findings suggest that circulating rather than vascular aldosterone contributes to the sustained hypertension in SHRSP.
In 4-week-old SHRSP, circulating and vascular aldosterone levels did not differ from those in WKY of the same age. However, 1 Na,K-ATPase and MCR mRNA expressions were increased compared with expressions in WKY. These findings suggest the increased aldosterone effect in the vasculature of SHRSP. 11ß-Hydroxysteroid dehydrogenase has been proposed to play an important role in aldosterone target cells by degrading endogenous glucocorticoids, thus allowing aldosterone to bind to the relatively nonselective MCR.27 28 Previously, we have reported that vascular 11ß-hydroxysteroid dehydrogenase activity is lower in SHR.29 Locally increased glucocorticoids also may affect vascular tone and contractility via MCRs.
Recently, the hypothesis that a local renin-angiotensin system plays an important role in BP regulation has received strong support from studies in rats transgenic for the mouse Ren-2 gene.30 These rats develop severe hypertension despite low or normal plasma renin, kidney tissue renin, and plasma Ang II concentrations.31 Furthermore, the BP is lowered by treatment with angiotensin-converting enzyme inhibitors.31 It is not known whether endogenous vascular aldosterone is sufficient to cause vascular remodeling or contractility. We have reported that aldosterone participates in the development of vascular hypertrophy in relative accordance with Ang II.6 Vascular Ang II and aldosterone may contribute to hypertension in this model. Further study is necessary to clarify the role of vascular aldosterone in hypertension using transgenic models that overexpress aldosterone in their vasculature.
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Selected Abbreviations and Acronyms |
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Received April 29, 1996;
first decision May 16, 1996; first decision August 14, 1996;
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