(Hypertension. 1995;25:170-173.)
© 1995 American Heart Association, Inc.
Articles |
Production of Aldosterone in Isolated Rat Blood Vessels
From the Second Department of Internal Medicine, School of Medicine, Kanazawa (Japan) University (Y.T., I.M., T.Y., K.I., H.H., R.T.), and the Division of Clinical Pharmacology, Mass Spectrometry Resource, School of Medicine, Vanderbilt University, Nashville, Tenn (I.A.B., F.-Y.H.).
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Abstract |
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Abstract Angiotensin I (Ang I), Ang II, angiotensinogen, and renin are formed locally in the vasculature. We undertook this study to determine whether the rat mesenteric artery produces aldosterone and to investigate the effects of adrenalectomy, an angiotensin-converting enzyme inhibitor, Ang II, or potassium on aldosterone production in vascular tissue. Isolated rat mesenteric arteries were perfused with Krebs-Ringer solution for 4 hours. The perfusate was collected and chromatographed in a reversed-phase high-performance liquid chromatographic (HPLC) system. The fraction corresponding to synthetic aldosterone was collected and analyzed by mass spectrometry. The aldosterone concentration in the perfusate from the adrenalectomized rats and rats treated with an angiotensin-converting enzyme inhibitor was measured using radioimmunoassay after HPLC separation. The mass spectra of synthetic aldosterone and aldosterone isolated from the perfusate of rat mesenteric arteries were identical. Aldosterone production in the mesenteric arteries of adrenalectomized rats was increased and of rats treated with an angiotensin-converting enzyme inhibitor was reduced compared with that of controls. Ang II (1.9x10-10 mol/L) and potassium (6.0 mmol/L) increased aldosterone production in mesenteric arteries. This study shows that the rat mesenteric artery produces aldosterone and that the intravascular renin-angiotensin-aldosterone system may contribute to vascular tone.
Key Words: aldosterone • mesenteric artery • rats • adrenalectomy • angiotensin I–converting enzyme inhibitors • angiotensin II
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Introduction |
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Extra-adrenal steroid 21-hydroxylation and 11ß-hydroxylation occur in a variety of human tissues. In human adult and fetal extra-adrenal tissues, circulating progesterone is converted to deoxycorticosterone (DOC) or DOC sulfate.1 The extra-adrenal expression of steroid 21-hydroxylase and 11ß-hydroxylase by a benign testicular Leydig cell tumor has been reported.2 3 4 Recently, the physiological and pathophysiological importance of locally generated renin-angiotensin and angiotensin I (Ang I)–converting enzyme (ACE) in vascular tissue has been recognized.5 6 7 We undertook the present study to determine whether the rat mesenteric artery produces aldosterone and to investigate the effects of adrenalectomy, an ACE inhibitor, Ang II, or potassium on aldosterone production in vascular tissue.
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Methods |
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Male Wistar rats (Nippon Charles River) weighing 200 to 230 g 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). The first group of animals (n=7) was bilaterally adrenalectomized under ether anesthesia and allowed free access to 0.9% NaCl as drinking water at all times for 7 days. The control group (n=7) consisted of sham-operated animals drinking NaCl-free water. The second group of rats (n=14) was given 0.3 mg PO quinapril, a prodrug type of ACE inhibitor (Warner-Lambert Co Ltd), for 14 days. Age- and weight-matched Wistar rats receiving tap water to drink were used as controls. Completeness of adrenalectomy was confirmed at autopsy by visual inspection after experiments. Plasma concentrations of aldosterone and corticosterone were measured by radioimmunoassay after extraction with a Sep-Pak C18 cartridge (Waters Associates). Plasma renin activity (PRA) was measured using a commercial kit (Dinapot Co Ltd). With the animals under pentobarbital anesthesia (25 mg/kg IP), the mesenteric artery was immediately excised and prepared for perfusion following the methods originally described by McGregor8 with the minor modification previously reported by our laboratory.9 Briefly, the arteries were perfused with Krebs-Ringer solution, pH 7.4, prewarmed, and oxygenated with a 95% O2/5% CO2 gas mixture at a constant flow rate of 4 mL/min. The perfusion pressure was constantly monitored by a pressure transducer connected to a polygraph (RM 600, Nihon-Koden) and recorded. After 30 minutes of equilibration, the perfusate was collected for 4 hours. The perfusate was extracted with a Sep-Pak C18 cartridge and chromatographed in a reversed-phase high-performance liquid chromatographic (HPLC) system using methanol/water (40%/100%) for 60 minutes as the mobile phase at a flow rate of 1.5 mL/min. The retention times of 18-hydroxycorticosterone, aldosterone, corticosterone, deoxycorticosterone, progesterone, and pregnenolone were 35, 32, 43, 49, 55, and 59 minutes, respectively. The fraction corresponding to synthetic aldosterone was collected and analyzed by gas chromatography/mass spectrometry (GC/MS). The applied GC temperature was 90°C during injection, then 180° to 290°C at 4°/min. The MS conditions were electroimpact ionization (70 eV) and a linear up scan m/z of 70 to 750 in a 2-second scanning period. After derivatization as described,10 the samples were dissolved in hexane and injected into a GC/MS system.
The aldosterone concentration in the perfusate from the adrenalectomized rats (n=7), sham-operated rats (n=7), rats treated with the ACE inhibitor (n=7), and controls was measured using radioimmunoassay after HPLC separation. Mesenteric arteries from Wistar rats (n=14) were perfused with Krebs-Ringer solution. The concentration of 1.9x10-10 mol/L Ang II was administered by continuous injection for 4 hours. The Krebs-Ringer solution containing 6 mmol/L potassium was perfused for 4 hours. The aldosterone concentration in the perfusate was measured by the same methods as described above. After the experiments of perfusate, the mesenteric artery was homogenized in 10 mL Krebs-Ringer buffer solution in a tissue grinder. Protein assay was done by the method of Bradford.11
After rats were decapitated, mesenteric arteries from rats treated with the ACE inhibitor (n=7) and control rats (n=5) were removed and fixed in Duboscq-Brazil solution.12 After dehydration, those mesenteric arteries were embedded in paraffin and cut into 5-µm transverse sections and stained with orcein. The protocol was approved by the Animal Research Committee of this institution.
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±SEM. Statistical analysis of the results was done by Wilcoxon's unpaired t test, with a value of P<.05 accepted as statistically significant.
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Results |
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Fig 1 shows the HPLC elution profile of immunoreactive aldosterone in the perfusate of mesenteric arteries. Five peaks with aldosterone-like immunoreactivity were detected. The antibody of aldosterone has cross-reactivity with other steroids such as 19-noraldosterone, 18-hydroxydeoxycorticosterone, and 19-hydroxyaldosterone. One aliquot with a retention time of 32 minutes (the retention time of aldosterone) was injected into the GC/MS system. The top portion of Fig 2 shows the mass spectra obtained after the injection of synthetic aldosterone. As shown in the bottom portion of Fig 2, the mass spectra of aldosterone isolated from rat mesenteric arteries were identical to those of synthetic aldosterone. The immunoreactive peak of corticosterone was detected in the fraction with a retention time of 43 minutes (data not shown).
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The sensitivity of the assay of aldosterone or corticosterone was 30 fmol. The overall recovery was 70%, interassay variation was 13.5%, and intra-assay variation was 9.5% for aldosterone in the HPLC system.
The Table shows the data for PRA, plasma aldosterone concentration, and plasma corticosterone concentration in each experimental rat group. PRA was significantly higher in adrenalectomized rats than in sham-operated rats and lower in rats treated with the ACE inhibitor than in controls. In adrenalectomized rats, plasma aldosterone and corticosterone were not detected by radioimmunoassay when 1 mL plasma was used. Rats treated with the ACE inhibitor showed significantly lower plasma aldosterone concentrations than controls (P<.05). There were no significant differences in plasma corticosterone levels between rats treated with the ACE inhibitor and control rats. Apparently, the ACE inhibitor does not affect the activities of the enzymes involved in biosynthesis of corticosterone.
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Fig 3 shows the results of aldosterone production from mesenteric artery in each experimental rat group. Aldosterone production in rats treated with the ACE inhibitor was significantly reduced compared with that of controls (0.36±0.04 versus 0.70±0.14 pmol/mg protein per hour, P<.05). Adrenalectomy significantly increased aldosterone production compared with sham-operated rats (0.90±0.10 versus 0.71±0.12 pmol/mg protein per hour, P<.05).
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Ang II (1.9x10-10 mol/L) and potassium (6.0 mmol/L) significantly increased aldosterone production in the mesenteric artery from a basal value of 0.70±0.14 pmol/mg protein per hour to 1.1±0.20 and 1.0±0.15 pmol/mg protein per hour, respectively (P<.05).
There were no significant differences of mesenteric artery media thickness between rats treated with the ACE inhibitor and controls.
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Discussion |
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In this study we present evidence for aldosterone synthesis in vascular tissue. Extra-adrenal steroid synthesis has been widely reported. Steroid 21-hydroxylation occurs in a wide variety of human adult and fetal extra-adrenal tissues, which take up circulating progesterone and convert it to DOC or DOC sulfate. Namiki et al13 reported the production of DOC, corticosterone, and cortisol and also the expression of P-450C21 and P-450C11 mRNA in Leydig cell tumors, as well as the presence of steroid 21-hydroxylase activity in testicular tissues adjacent to Leydig cell tumors. Recently, aldosterone synthase cytochrome P-450 (P-450aldo) induced in sodium-deplete, potassium-replete rat adrenal cortex has been isolated, and it has been demonstrated that the P-450aldo catalyzes successive monooxygenation reactions of DOC to produce aldosterone as a final product, whereas rat P-45011ß does not sufficiently catalyze the reactions to form aldosterone.14 15 In addition, cDNAs for rat P-450 distinct from those of rat P-45011ß have been isolated.16 Imai et al15 reported that P-450aldo mRNA in the adrenal gland is detectable only by Ang II stimulation. Curnow et al17 demonstrated that P-450aldo mRNA in the adrenal gland is detectable using a polymerase chain reaction technique. Yamamoto et al (personal communication) detected P-450aldo mRNA in cultured vascular endothelial cells using a reverse transcriptase–polymerase chain reaction method. We confirmed the production of aldosterone in cultured rat aortic endothelial cells using the same methods (data not shown). These results support the hypothesis that aldosterone in the perfusate does not reflect uptake from plasma, in addition to the results that aldosterone in the perfusate from adrenalectomized rats, whose plasma aldosterone level is not detectable, is increased. Corticosterone-like immunoreactivity was detected in the perfusate. We detected the radioactive peak of progesterone, deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, and aldosterone in the perfusate after perfusing the mesenteric artery with Krebs-Ringer solution containing [14C]pregnenolone (data not shown). These results indicate that precursors of aldosterone may exist in the vasculature.
The amount of aldosterone produced in the mesenteric artery is very small compared with plasma or adrenal aldosterone. However, vascular endothelial cells are shown to possess aldosterone synthase and produce aldosterone. There is a possibility that systemic vessels are able to locally produce aldosterone. There is increasing evidence that the tissue renin-angiotensin system, which functions on the autocrine-paracrine level,18 is important for cardiovascular regulation.19 20 Mineralocorticoid receptors exist in the vasculature.21 22 Brilla et al23 reported that Ang II stimulated aldosterone synthesis in cultured bovine aortic endothelial cells and that the renin-angiotensin-aldosterone system exists in vascular tissues.
We previously reported that Ang II is produced independently of the systemic renin-angiotensin system.24 The amount of Ang II produced was reduced to approximately 50% of the control value after the administration of an ACE inhibitor, similar to the extent of aldosterone inhibition observed in this study after treatment with quinapril. In adrenalectomized rats, PRA was high and plasma aldosterone was not detected, but the aldosterone concentration in the perfusate was increased compared with that in sham-operated controls. Ang II and potassium increased aldosterone production in the mesenteric artery. Taken together, these results show that renin-angiotensin and aldosterone may be synthesized and regulated in a closely linked manner in the vascular system. Ang II and aldosterone may have cell-signaling paracrine functions18 25 that contribute to cardiovascular structure during normal growth26 27 and development and in pathological conditions.25 Further study is necessary to clarify the pathophysiological role of vascular aldosterone.
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Footnotes |
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Reprint requests to Isamu Miyamori, MD, Second Department of Internal Medicine, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920 Japan.
Received March 7, 1994; first decision April 13, 1994; accepted October 19, 1994.
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Y. Takeda, I. Miyamori, S. Inaba, K. Furukawa, H. Hatakeyama, T. Yoneda, H. Mabuchi, and R. Takeda Vascular Aldosterone in Genetically Hypertensive Rats Hypertension, January 1, 1997; 29(1): 45 - 48. [Abstract] [Full Text]
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M. E. Ullian, D. J. Hazen-Martin, L. G. Walsh, R. K. Davda, and B. M. Egan Carbenoxolone Damages Endothelium and Enhances Vasoconstrictor Action in Aortic Rings Hypertension, June 1, 1996; 27(6): 1346 - 1352. [Abstract] [Full Text]
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