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Kaoru Nomura, Mitsuhide Naruse, Kiyoko Naruse, Hiroshi Demura and Kazuo Shizume

Abstract. This study was done to confirm that aldosterone-producing adenomas secrete cortisol in vivo. Plasma cortisol and aldosterone concentrations were measured in samples obtained by selective adrenal-vein sampling in 8 patients with primary aldosteronism due to unilateral adenoma. All cases revealed higher adrenal-vein plasma cortisol concentrations on the adenoma side than the opposite, irrespective of adenoma location. These concentrations correlated significantly with plasma aldosterone concentrations (r = 0.972, P < 0.001) in effluents from the adenoma side, but not from the opposite. Plasma concentrations also correlated significantly with estimated adenoma volume (r = 0.918, P < 0.05). These findings strongly suggest that aldosterone-producing adenomas secrete cortisol in vivo. In a second study, we used metyrapone to test 6 patients with adenomas. Their responsiveness to cortisol and corticotrophin was found to be the same as that in normal subjects, suggesting that adenoma-secreted cortisol did not disturb the relationship between corticotrophin and cortisol. We thus concluded that cortisol is secreted concomitantly with aldosterone from aldosterone-producing adenomas under corticotrophin influence.

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Mitsuhide Naruse, Kazuo Shizume and Tadashi Inagami

Abstract. Mouse adrenal tissue has been reported to contain high renin activity. However, it is not clear whether the renin is produced inside the tissue or is derived from a blood-borne component. We have investigated a cloned cell line of mouse adrenocortical tumour (Y-1) which has a steroidogenic activity. Sizable quantities of renin were demonstrated, predominantly in the cell lysate. This renin activity was distinguished from cathepsin D in view of its specific affinity to anti-renin antibody, optimal pH was determined, and the substrate specificity was checked with haemoglobin. Immunoreactive angiotensins were also detectable, but were demonstrated both in the cell and in the culture medium. This study provides further evidence for the existence of renin intrinsic to the adrenal gland. This study also suggests an intracellular role for renin and possible secretion of generated angiotensins.

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Mitsuhide Naruse, Kohsaku Nitta, Tsutomu Sanaka, Kiyoko Naruse, Hiroshi Demura, Tadashi Inagami, Kazuo Shizume and Nobuhiro Sugino

Abstract. Since the kidney is one of the major sites of action for atrial natriuretic peptide (ANP) and immunoreactive ANP has been detected in tissue extract by radioimmunoassay, we have applied the immunohistochemical technique by using the avidin-biotin complex method to investigate ANP binding sites in the rat kidney. Although no immunostaining was observed in the kidney of control rats, immunoreactive ANP was present in the juxtaglomerular cells, the vascular walls of interlobular arteries, arcuate arteries, arterioles including vas afferens and vas efferens, and the medullary peritubular capillary of ANP-pretreated rats. In contrast, no tubular structure was stained. These results suggest that ANP may affect renin secretion via its direct action on the juxtaglomerular cells and that it predominantly induces natriuresis by its effects on renal hemodynamics.

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Akiyo Tanabe, Mitsuhide Naruse, Taro Wasada, Kiyoko Naruse, Takanobu Yoshimoto, Yasue Omori and Hiroshi Demura

Tanabe A, Naruse M. Wasada T, Naruse K, Yoshimoto T, Omori Y, Demura H. Effects of acute hyperinsulinemia on plasma atrial and brain natriuretic peptide concentrations. Eur J Endocrinol 1995;132:693–8. ISSN 0804–4643

Impaired renal sodium excretion and increased plasma atrial natriuretic peptide (ANP) levels have been reported in patients with hypertension associated with insulin resistance and hyperinsulinemia. To clarify the interrelationship between hyperinsulinemia and plasma natriuretic peptides, we investigated the effects of physiological and non-physiological hyperinsulinemia on the plasma ANP and brain natriuretic peptide (BNP) levels. Plasma immunoreactive insulin (IRI), ANP and BNP levels were determined by a euglycemic–hyperinsulinemic glucose clamp in 20 patients with non-insulin-dependent diabetes mellitus, by a glucose challenge test in 22 normal subjects and by an insulin challenge test in six normal subjects. Both in the glucose clamp and the glucose challenge test, plasma ANP showed a significant increase in association with increased plasma IRI and plasma volume. However, there was no significant correlation between the changes in plasma ANP levels and plasma IRI levels in view of the peak values and the area under the curve of their responses. In addition, the plasma ANP did not show any significant change despite the marked elevation of plasma IRI in the insulin challenge test. There was no significant change in plasma BNP under any of the hyperinsulinemic conditions. These findings provide in vivo evidence for the lack of a direct effect of acute hyperinsulinemia on natriuretic peptides, although the chronic effects of hyperinsulinemia remain to be elucidated.

Akiyo Tanabe, Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan

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Yujiro Nakano, Takanobu Yoshimoto, Ryo Watanabe, Masanori Murakami, Tatsuya Fukuda, Kazutaka Saito, Yasuhisa Fujii, Takumi Akashi, Toshihiro Tanaka, Tetsuya Yamada, Mitsuhide Naruse and Yoshihiro Ogawa

Objective

The pathophysiology of aldosterone-producing adenomas (APAs) has been intensively investigated using genetic and epigenetic approaches. However, the role of miRNAs in APA is not fully understood. The present study profiled miRNAs in APAs as an exploratory approach to elucidate their pathophysiological roles in APAs.

Design

Tissues of APAs and other adrenocortical adenomas were obtained from patients who underwent adrenalectomy.

Methods

Candidate miRNAs differentially detected from samples were examined by whole miRNA sequencing. The expression of candidate miRNAs in APA tissues were further validated by real-time quantitative polymerase chain reaction (qPCR). Further, differential miRNA expression between APAs with and without KCNJ5 somatic mutations was examined. Prediction of miRNA target genes was performed by bioinformatics analysis. For specific miRNAs, correlation analysis between the levels of their target genes and CYP11B2 was analyzed in APA tissues.

Results

Our study determined differential expression of six miRNAs in APA or APA with KCNJ5 mutations. We further demonstrated that miR299 levels were negatively correlated with mRNA levels of CACNB2, which encodes the beta-subunit of the L-type calcium channel. Additionally, we found significant correlations among miR299, CACNB2, and CYP11B2 levels in APA tissues.

Conclusions

Our study suggests the possible pathophysiological involvement of specific miRNAs in calcium signaling and aldosterone hypersecretion in APAs. Further studies, including in vitro analyses, are required to clarify these findings.

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Akiyuki Kawashima, Masakatsu Sone, Nobuya Inagaki, Yoshiyu Takeda, Hiroshi Itoh, Isao Kurihara, Hironobu Umakoshi, Takamasa Ichijo, Takuyuki Katabami, Norio Wada, Yoshihiro Ogawa, Junji Kawashima, Megumi Fujita, Shozo Miyauchi, Shintaro Okamura, Tomikazu Fukuoka, Toshihiko Yanase, Shoichiro Izawa, Yuichiro Yoshikawa, Shigeatsu Hashimoto, Masanobu Yamada, Tatsuya Kai, Tomoko Suzuki, Mitsuhide Naruse and the JPAS and JRAS groups

Objective

Several clinical studies have reported that renal impairments are sometimes observed in patients with primary aldosteronism (PA). We analyzed the prevalence of renal impairments in PA patients and identified parameters that increase the risk for them.

Design

This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan PA study (JPAS). Data were also collected from patients with essential hypertension (EHT).

Methods

We compared the prevalences of proteinuria and lowered estimated glomerular filtration rate (eGFR) between patients with PA and age, sex, blood pressure and duration of hypertension-matched patients with EHT. We also performed logistic regression analysis to identify parameters that increase the risk for these renal impairments.

Results

Among 2366 PA patients, the prevalences of proteinuria and lowered eGFR were 10.3 and 11.6%, respectively. The prevalence of proteinuria was significantly higher in PA patients than matched-EHT patients (16.8 vs 4.4%), whereas there was no significant difference in the prevalence of lowered eGFR (17.2 vs 15.0%). The logistic regression analysis also showed that the plasma aldosterone concentration (PAC) significantly increases the risk of proteinuria and lowered eGFR, independent of other known risk factors.

Conclusion

Plasma aldosterone levels are closely associated with renal impairment in patients with PA. This is contrast to our earlier finding that the PAC was not itself linearly associated with cardiovascular events such as stroke or ischemic heart disease. The mechanism underlying the kidney damage in patients with PA may differ from that affecting the cardiovascular system.

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Hiroki Kobayashi, Yoshihiro Nakamura, Masanori Abe, Isao Kurihara, Hiroshi Itoh, Takamasa Ichijo, Yoshiyu Takeda, Takashi Yoneda, Takuyuki Katabami, Mika Tsuiki, Norio Wada, Yoshihiro Ogawa, Ryuichi Sakamoto, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Tetsuya Yamada, Ryuji Okamoto, Yuichi Matsuda, Megumi Fujita, Minemori Watanabe, Kouichi Tamura, Akiyo Tanabe, Mitsuhide Naruse and JPAS/JRAS Study Group

Objectives

We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA).

Design

Multicenter retrospective study by Japan PA study.

Method

We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria.

Results

Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI.

Conclusions

Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group.