Glucocorticoids activate cardiac mineralocorticoid receptors in adrenalectomized Dahl salt-sensitive rats - PubMed (original) (raw)

. 2014 Feb;76(1-2):59-72.

Glucocorticoids activate cardiac mineralocorticoid receptors in adrenalectomized Dahl salt-sensitive rats

Masafumi Ohtake et al. Nagoya J Med Sci. 2014 Feb.

Abstract

We previously showed that selective mineralocorticoid receptor (MR) blockade by eplerenone is cardioprotective in Dahl salt-sensitive (DS) rats. To clarify the consequences of glucocorticoid-mediated MR activation in these animals, we investigated the effects of exogenous corticosterone on blood pressure as well as cardiac remodeling and function after adrenalectomy. DS rats were subjected to adrenalectomy at 6 weeks of age and thereafter fed a high-salt diet and administered corticosterone (20 mg/kg per day) or vehicle. Systolic blood pressure was higher in the corticosterone group than in the vehicle group at 7 weeks and thereafter. By 11 weeks, corticosterone had reduced left ventricular (LV) mass and induced LV diastolic dysfunction. The ratio of collagen type I to type III mRNA levels in the left ventricle was increased in the corticosterone group compared with the vehicle group. Administration of a non-antihypertensive dose of the MR antagonist spironolactone (20 mg/kg per day) from 6 weeks inhibited the effects of corticosterone on both the collagen type I to type III mRNA ratio and diastolic function without affecting the decrease in LV mass. Spironolactone attenuated both the increase in NADPH oxidase activity in the left ventricle and coronary vascular inflammatory responses apparent in the corticosterone group. These results indicate that exogenous glucocorticoids induce hypertension, cardiac remodeling, and diastolic dysfunction in adrenalectomized DS rats fed a high-salt diet. The cardiac effects of exogenous glucocorticoids are likely attributable, at least in part, to myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

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Figures

Fig. 1

Fig. 1

Plasma renin activity and aldosterone concentration in DS rats of the five experimental groups at 11 weeks of age. Renin activity (A) and aldosterone concentration (B) are presented as means ± SEM for animals in each group (n = 8, 7, 10, 10, and 9 for CONT, LVH, ADX+V, ADX+CTC, and ADX+CTC+SPL groups, respectively). *P < 0.05 versus CONT group; †P < 0.05 versus LVH group.

Fig. 2

Fig. 2

Time course of SBP in DS rats of the five experimental groups. Data are means ± SEM for animals in each group. *P < 0.05 versus CONT group; †P < 0.05 versus LVH group; ‡P < 0.05 versus ADX+V group.

Fig. 3

Fig. 3

Cardiomyocyte size and expression of ANP, BNP, and IGF-1 genes in the left ventricle of DS rats in the five experimental groups at 11 weeks of age. (A) Hematoxylin-eosin staining of transverse sections of the LV myocardium. Scale bars, 50 µm. (B) Cross-sectional area of cardiac myocytes determined from sections similar to those in (A). (C–E) Quantitative RT-PCR analysis of ANP, BNP, and IGF-1 mRNAs, respectively. The amount of each mRNA was normalized by that of 18S rRNA and then expressed relative to the corresponding mean value for the CONT group. Data in (B) through (D) are means ± SEM for animals in each group. *P < 0.05 versus CONT group; †P < 0.05 versus LVH group; ‡P < 0.05 versus ADX+V group.

Fig. 4

Fig. 4

Cardiac fibrosis and expression of collagen genes in the left ventricle of DS rats in the five experimental groups at 11 weeks of age. (A) Collagen deposition as revealed by Azan-Mallory staining in perivascular (upper panels) or interstitial (lower panels) regions of the LV myocardium. Scale bars, 200 µm. (B, C) Relative extents of perivascular and interstitial fibrosis, respectively, in the LV myocardium as determined from sections similar to those in (A). (D) Ratio of the amount of collagen type I mRNA to that of collagen type III mRNA. Data in (B) through (D) are means ± SEM for animals in each group. *P < 0.05 versus CONT group; †P < 0.05 versus LVH group; ‡P < 0.05 versus ADX+V group; §P < 0.05 versus ADX+CTC group.

Fig. 5

Fig. 5

Superoxide production as well as NADPH oxidase activity and gene expression in the left ventricle of rats in the five experimental groups at 11 weeks of age. (A) Superoxide production as revealed by dihydroethidium staining in perivascular (upper panels) or interstitial (lower panels) regions of the LV myocardium. Scale bars, 100 µm. (B) NADPH-dependent superoxide production in LV homogenates. Results are expressed as relative light units (RLU) per milligram of protein. (C–G) Quantitative RT-PCR analysis of p22phox, gp91phox, p47phox, p67phox, and Rac1 mRNAs, respectively. The amount of each mRNA was normalized by that of 18S rRNA and then expressed relative to the corresponding mean value for the CONT group. Data in (B) through (G) are means ± SEM for animals in each group. *P < 0.05 versus CONT group; †P < 0.05 versus LVH group; ‡P < 0.05 versus ADX+V group; §P < 0.05 versus ADX+CTC group.

Fig. 6

Fig. 6

Macrophage infiltration as well as expression of MCP-1, osteopontin, and COX-2 genes in the left ventricle of rats in the five experimental groups at 11 weeks of age. (A) Immunohistochemical staining for the monocyte-macrophage marker CD68. Scale bars, 50 µm. (B–D) Quantitative RT-PCR analysis of MCP-1, osteopontin, and COX-2 mRNAs, respectively. The amount of each mRNA was normalized by that of 18S rRNA and then expressed relative to the corresponding mean value for the CONT group. Data in (B) through (D) are means ± SEM for animals in each group. *P < 0.05 versus CONT group; †P < 0.05 versus LVH group; ‡P < 0.05 versus ADX+V group; §P < 0.05 versus ADX+CTC group.

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