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Hypertension. 1997;30:953-956

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(Hypertension. 1997;30:953-956.)
© 1997 American Heart Association, Inc.

Articles

Brain Nitric Oxide Synthase Messenger RNA in Central Mineralocorticoid Hypertension

Yoshiyu Takeda; Isamu Miyamori; Takashi Yoneda; Kenji Furukawa; Satoru Inaba; Ryoyu Takeda; ; Hiroshi Mabuchi

From the Second Department of Internal Medicine (Y.T., I.M., T.Y., K.F., S.I., H.M.) and Department of Health Sciences (Y.T.), School of Medicine, Kanazawa University, and the KKR Hokuriku Hospital (R.T.), Izumigaoka, Kanazawa 920, Japan.

Correspondence to Yoshiyu Takeda, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan.


*    Abstract
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 *Abstract
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Abstract The mechanism underlying the central hypertensinogenic effects of mineralocorticoids remains unclear. Given that nitric oxide (NO) is thought to act at autonomic sites in the brain to regulate arterial blood pressure, the effects of the potent mineralocorticoids aldosterone and 19-noraldosterone on the abundance of neuronal NO synthase (nNOS) mRNA in the brain were investigated. Wistar-Kyoto rats received a continuous intracerebroventricular infusion of aldosterone or 19-noraldosterone (5 ng/h) from an implanted osmotic minipump for 4 weeks. Total RNA was purified from microdissected tissue blocks containing the hypothalamus, dorsal medulla, rostral ventrolateral medulla, or caudal ventrolateral medulla, and changes in the abundance of nNOS mRNA were determined with a semiquantitative competitive polymerase chain reaction method. Blood pressure was significantly increased in rats 2, 3, and 4 weeks after the onset of intracerebroventricular aldosterone or 19-noraldosterone infusion compared with that in animals receiving vehicle. Subcutaneous infusion of either mineralocorticoid had no effect on blood pressure. Compared with controls, rats treated with aldosterone or 19-noraldosterone for 4 weeks showed significant decreases in the amount of nNOS mRNA in the hypothalamus and rostral and caudal ventrolateral medulla. These data suggest that reduced nNOS activity may contribute to the increase in blood pressure in rats with central mineralocorticoid-induced hypertension.


Key Words: mineralocorticoid • RNA • nitric oxide • nitric oxide synthase • aldosterone


*    Introduction
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 *Introduction
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Nitric oxide, an important regulatory molecule produced by endothelial cells, neurons, macrophages, and other cell types,1 is generated from L-arginine in a reaction catalyzed by the enzyme NOS. The cytokine-inducible isoform of NOS is activated by various immunological stimuli, which results in the production of large quantities of NO that can be cytotoxic.2 The endothelial isoform of NOS is thought to be a physiological regulator of basal vascular tone.3 Thus, mice lacking the gene for this isozyme are hypertensive.4 nNOS also plays an important role in cardiovascular homeostasis.5

The steroid 19-noraldosterone, like aldosterone, possesses potent mineralocorticoid and hypertensinogenic activity.6 We previously have shown that 19-noraldosterone is synthesized by human adrenal glands and that urinary excretion of this mineralocorticoid is increased in individuals with primary aldosteronism and in some patients with essential hypertension.7 8 9 However, urinary excretion of 19-noraldosterone is lower than that of aldosterone.

The mineralocorticoid receptor is distributed widely; it is present in the colon, parotid, vasculature, and specific areas of the brain.10 In addition to classical sites of steroid synthesis, brain is also a steroidogenic tissue.11 12 Although the pathophysiological role of central mineralocorticoids is unclear, ICV infusion of aldosterone induces hypertension in rats.13 19-Noraldosterone possesses more hypertensinogenic potency than aldosterone.14 To clarify the mechanism underlying the central hypertensinogenic effect of mineralocorticoid, we have examined the concentration of nNOS mRNA in the brains of normotensive rats and rats with hypertension induced by ICV infusion of aldosterone and compared them with rats treated with ICV infusion of 19-noraldosterone. The amount of nNOS mRNA was measured in regions of the brain important in regulation of arterial blood pressure with the use of semiquantitative PCR assay.


*    Methods
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 *Methods
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Animals and Experimental Protocol
All experiments were performed according to guidelines for the use of experimental animals of the Animal Research Committee of Kanazawa University. Wistar-Kyoto (WKY)/Izm rats15 (body weight, 160 to 180 g), donated by the 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 Na, 0.24 mmol/g K; Nippon Charles River, Kanagawa, Japan). Animals were maintained in a constant-temperature environment, with a 12-h-light/12-h-dark cycle.

Blood pressure was determined by the plethysmographic tail-cuff method as previously described.16 Plasma concentrations of aldosterone and corticosterone were determined by radioimmunoassay after extraction with a Sep-Pak C18 cartridge (Waters Assoc).

The rats were anesthetized with sodium pentobarbital 50 mg/kg, intraperitoneally. With aseptic surgical techniques, a cannula was placed into the right lateral cerebral ventricle of the rats under anesthesia and was connected to an implanted miniosmotic pump (Alzet 2002, Alza) that delivered 0.49±0.02 µL/h for 14 days. Alternatively, the pump was implanted subcutaneously. Pumps were changed on day 14 under isoflurane anesthesia, and pumps of the same lot were used throughout the experiment to ensure consistency. Artificial CSF (Na+, 152 mmol/L; K+, 3 mmol/L; Mg+, 1.6 mmol/L; HCO3-, 25 mmol/L; PO43-, 0.5 mmol/L; Cl-, 135 mmol/L) was prepared as previously described.13 The rats were divided into five experimental groups, with 8 animals per group. Group 1 received ICV CSF containing aldosterone in 5% (vol/vol) ethanol at a rate of 5 ng/h. Group 2 received ICV CSF containing 19-noraldosterone in 5% ethanol at a rate of 5 ng/h. Group 3 received subcutaneous CSF containing aldosterone in 5% ethanol at a rate of 5 ng/h. Group 4 received subcutaneous CSF containing 19-noraldosterone in 5% ethanol at a rate of 5 ng/h. Group 5 received ICV CSF containing vehicle in 5% ethanol. All solutions were prepared and sterilized by filtration through 0.22-µm filters (Nihon Millipore Ltd) immediately before filling and implanting the pumps.

Brains were removed immediately after animals were killed by decapitation, and necropsies, including dye infusions to check cannula placement, were performed. Animals in which there was doubt about the correct delivery of solution or that showed evidence of illness or high levels of stress were excluded from data analysis. Brains were frozen rapidly in liquid nitrogen and stored at -80°C until RNA isolation.

Isolation of RNA and PCR Analysis
Frozen brains were dissected into tissue blocks that included the hypothalamus, dorsal medulla, RVLM, or CVLM. The extent of tissue blocks according to coordinates from Paxinos and Watson17 was as follows: hypothalamus (rostral, 0.2 mm caudal to the optic chiasm; caudal, 1.8 mm caudal to the optic chiasm; dorsal, 4 mm from the ventral surface; ventral, ventral surface of the brain; and lateral, 3.5 mm lateral to the midline), dorsal medulla (rostral, 12.1 mm caudal to the optic chiasm; caudal, 14.4 mm caudal to the optic chiasm; dorsal, dorsal surface of the brain stem; ventral, 2 mm from the dorsal surface of the brain stem; and lateral, 2 mm lateral to the midline), RVLM (rostral, 11.1 mm caudal to the optic chiasm; caudal, 13.0 mm caudal to the optic chiasm; dorsal, 2 mm from the dorsal surface of the brain stem; ventral, ventral surface of the brain stem; and lateral, lateral edge of the brain stem), and CVLM (rostral, 13.0 mm caudal to the optic chiasm; caudal, 14.4 mm caudal to the optic chiasm; dorsal, 1.5 mm from the dorsal surface of the brain stem; ventral, ventral surface of the brain stem; and lateral, lateral edge of the brain stem).

Total RNA was extracted with guanidinium thiocyanate and isolated by centrifugation in a CsCl gradient as previously described.18 RNA (200 ng) was then incubated at 42°C for 60 minutes with 2.5 U of Moloney murine leukemia virus reverse transcriptase (Takara) in a 20-µL reaction volume containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 5 mmol/L MgCl2, 1 mmol/L each of deoxynucleoside triphosphate, and 2.5 mmol/L of a random hexanucleotide primer (Takara). After subsequent incubation for 5 minutes at 99°C, the resulting single-stranded cDNA was subjected to competitive PCR analysis. The sequences of the sense and antisense primers for nNOS were 5'-TCAACAGCGTCTCCT-CCTA-3' and 5'-GTCGATCGGCTGAACTTAGG-3', respectively, as described by Krukoff et al,19 and correspond to nucleotides 2882 to 2990 and 3364 to 3383, respectively, of the cDNA.20 The competitive template was prepared with a PCR MIMIC Construction kit (Clontech). After quantification, a series dilution was used as an internal standard for competitive PCR as previously described.21 Competitive PCR was performed with 2.5 µL of cDNA, 2 µL of various concentrations of the competitive template, 0.5 µmol/L each of the sense and antisense primers, and 0.5 U of Taq DNA polymerase (Perkin-Elmer Japan) in a total volume of 50 µL containing 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 2 mmol/L MgCl2, and 0.2 mmol/L of each deoxynucleoside triphosphate. The amplification protocol consisted of 30 cycles of 1 minute at 94°C, 1 minute at 59°C, and 2 minutes at 72°C. The reaction products (10 µL) were subjected to electrophoresis on a 3.0% agarose gel, which was then stained with ethidium bromide and photographed.

Signal intensity was quantified by computerized densitometry with the BIO-PROFIL BIO-1D system (Compak). The intensities of the products from each cDNA and the competitive template were plotted as a function of the known amounts of the competitive template. The intra-assay and interassay variabilities of the competitive PCR assay were 11.2% and 13.6%, respectively. The amount of nNOS mRNA was expressed as attomoles per 100 ng of RNA.

Statistical Analysis
Data are expressed as mean±SD. The statistical significance of differences was assessed by one-way ANOVA and multiple comparison test. A value of P<.05 was considered statistically significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
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There were no signs of illness, infection, or behavioral deficits in any of the rats in the five study groups. The blood pressure of rats infused ICV with aldosterone (5 ng/h) or 19-noraldosterone (5 ng/h) was significantly higher than that of controls (vehicle, ICV) by day 14 and remained so until the end of the experiment on day 28 (Fig 1Down); there was no significant difference between rats receiving aldosterone and those receiving 19-noraldosterone. The blood pressure of animals infused subcutaneously with aldosterone or 19-noraldosterone did not differ significantly from that of controls throughout the 28-day experiment period.



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  		Figure 1. Effects of ICV infusion of aldosterone ({square}), 19-noraldosterone ({bullet}), or vehicle (control) ({circ}), subcutaneous infusion of aldosterone ({bigtriangleup}), and 19-noraldosterone ({diamondsuit}) on systolic blood pressure in rats. Data are presented as mean±SD (n=8). *P<.05 versus control.

The plasma concentrations of aldosterone, corticosterone, K, and Na did not differ among rats treated ICV with aldosterone, 19-noraldosterone, or vehicle (TableDown).


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  		Table 1. Plasma Concentration of Aldosterone, Corticosterone, Na, and K in Rats After ICV Infusion of Aldosterone, 19-Noraldosterone, or Vehicle for 4 Weeks

Fig 2Down shows that the competitive template for nNOS inhibited the amplification by PCR of brain nNOS cDNA in a concentration-dependent manner.



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  		Figure 2. Effect of concentration of the competitive template on the amplification of PCR products derived from brain nNOS cDNA and the competitive template (Mimic).

The amount of nNOS mRNA in the dorsal medulla did not differ significantly between controls and rats infused ICV with either aldosterone or 19-noraldosterone for 4 weeks (Fig 3Down). In contrast, the amount of nNOS mRNA in the hypothalamus, RVLM, or CVLM of rats treated ICV with either aldosterone or 19-noraldosterone was significantly reduced compared with that in the corresponding brain region of controls (P<.05). There were no significant differences in the amount of nNOS mRNA in the hypothalamus, RVLM, or CVLM between rats treated with aldosterone or 19-noraldosterone.



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  		Figure 3. Effect of ICV infusion of aldosterone (solid bars), 19-noraldosterone (striped bars), or vehicle (open bars) for 4 weeks on the amount of nNOS mRNA in the dorsal medulla, hypothalamus, RVLM, and CVLM. Data are presented as mean±SD (n=8). *P<.05 versus vehicle-treated rats.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The central nervous system has been shown to be important in the development of mineralocorticoid-induced hypertension.22 Mineralocorticoid receptors are present in the hippocampus, amygdala, lateral septum, and hypothalamus, especially in the periventricular regions, areas known or thought to be important in the regulation of ACTH release, arousal, fluid and osmolality equilibrium, and the maintenance of normal blood pressure. Mineralocorticoids also are synthesized outside the adrenal gland, especially by the vasculature23 24 and brain.25 The expression of nNOS is highly localized within the brain, with many nNOS-containing regions also important in regulation of the cardiovascular system. In the hypothalamus, NOS-positive neurons are present primarily in the paraventricular nucleus and supraoptic nucleus,26 27 the former being an especially important integrating center for autonomic information.28 In the medulla, nNOS-containing neurons29 and nerve terminals30 are found in the nucleus of the tractus solitarius and the RVLM, an area known as a pressor region.30 In addition, the CVLM, the so-called depressor area, contains nNOS-expressing neurons, albeit in smaller numbers than the RVLM.31

We have now shown that the amount of nNOS mRNA in the hypothalamus and RVLM of rats with central mineralocorticoid-induced hypertension was significantly reduced compared with that in normotensive controls. Thus, reduced NO synthesis in these areas of the brain may contribute to the increase in blood pressure in the mineralocorticoid-treated animals. The central effects of 19-noraldosterone both on the blood pressure and gene expression of nNOS are equal with those of aldosterone. These results suggest that 19-noraldosterone possesses central hypertensinogenic potency as well as aldosterone. However, urinary excretion of 19-noraldosterone is much lower than that of aldosterone.32 Local concentration of these mineralocorticoids should be further studied.

L-Nitroarginine and other NOS inhibitors increase the blood pressure of many species, including rats, guinea pigs, rabbits, dogs,33 and mice.3 El Karib et al34 showed that infusion of the NOS blocker L-NNA into the lateral cerebral ventricle of rats increased arterial pressure, whereas intravenous administration of the same dose had no effect. These researchers concluded that L-NNA acts directly in the central nervous system to increase blood pressure, probably by increasing the activity of the sympathetic nervous system. Increases in NO concentration produced by microinjecting sodium nitroprusside into the RVLM resulted in a decrease in blood pressure. Injection of L-NNA into the RVLM to block endogenous production of NO increased the frequency of nerve activity and blood pressure.35 Harada et al36 observed that microinjection of an NOS inhibitor into the nucleus tractus solitarius in the rabbit increased renal sympathetic nerve activity and blood pressure. Changes in nNOS mRNA abundance in the hypothalamus and the CVLM have been detected in two-kidney, one clip hypertensive rats.19 These results, together with our data, suggest that a decrease in NO production may contribute to increases in blood pressure mediated by the central nervous system.

We have also detected aldosterone synthase mRNA rat brain (Takeda et al, unpublished data, 1996), and Gomez-Sanchez et al25 have demonstrated presence of several steroid synthases, including aldosterone synthase, in rat brain. Further study is necessary to clarify the relation between brain mineralocorticoid hormones and the NO system in the regulation of blood pressure.


*    Selected Abbreviations and Acronyms
 
CVLM = caudal ventrolateral medulla
ICV = intracerebroventricular
L-NNA = N{omega}-nitro-L-arginine
nNOS = neuronal nitric oxide synthase
NO = nitric oxide
NOS = nitric oxide synthase
PCR = polymerase chain reaction
RVLM = rostral ventrolateral medulla

Received January 16, 1997; first decision February 12, 1997; accepted March 11, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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