Role of 11β-Hydroxysteroid Dehydrogenase in Nongenomic Aldosterone Effects in Human Arteries

Abstract

Abstract-The aim of the present study was to demonstrate rapid effects of aldosterone on the Na ϩ -H ϩ exchanger in strips of human vascular vessels and to determine whether 11␤-hydroxysteroid dehydrogenase enzyme (11␤-HSD) could play a protective role in this response, such as that described for the classic type I mineralocorticoid receptor (MR). The activity of 11␤-HSD isoforms 1 and 2 were measured in fetal and adult arteries. Both isoforms are present in adult and fetal vessels. However, a significant difference in the proportion of each isoform was found. Isoform 1 activity (in pmol ⅐ min Ϫ1 ⅐ 100 mg Ϫ1 protein) was 42Ϯ5 in fetal vessels and 29Ϯ2 in adult arteries, and isoform 2 activity was 78Ϯ7 in fetal and 12Ϯ2 in adult tissue. The nongenomic effect of aldosterone on Na ϩ -H ϩ exchanger activity was measured in strips of chorionic and radial uterine arteries loaded with the pH-sensitive dye 2Ј,7Ј-bis(2-carboxyethyl)-5,6-carboxyfluorescein. Recordings of intracellular pH (pH i ) were made by videofluorescence microscopy. Aldosterone (0.5 nmol/L) rapidly increased pH i , with a half-maximal effect between 2 and 3 nmol/L in both fetal and adult vessels. Ethylisopropylamiloride, a specific inhibitor of the Na ϩ -H ϩ exchanger, inhibited this effect. The hormone-mediated increase in pH i was unaffected by spironolactone, a classic antagonist of MR, but was completely blocked by RU28318. Cortisol (up to 1 mol/L) had no effect on pH i , but when applied in the presence of carbenoxolone, a dramatic increase in Na ϩ -H ϩ exchanger activity was evident. The increments on pH i for each cortisol concentration were similar to those observed for aldosterone. These findings suggest that vascular 11␤-HSD plays an active role in maintaining the specificity of the rapid effects of aldosterone.

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

“…Reasoning that this may have resulted from nanomolar (MR-activating) concentrations of levels of corticosterone in the culture medium, cells were exposed to two MR antagonists, SPIRO (a) and RU28318 (b); these compounds display slightly different pharmacological profiles. [33][34][35] In the absence of DEX, addition of SPIRO (10 À8 -10 À5 M) dose dependently increased the incidence of apoptosis (a); RU28318 at a dose of 10 À5 M also significantly stimulated apoptosis (b). In combination with the apoptosis noninducing dose of DEX (10 À6 M; a and b), all doses of SPIRO and RU28318 led to levels of cell death that were significantly greater than those seen after treatment with the antagonist alone, that is, blockade of MR with either SPIRO or RU28318 increased neuronal sensitivity to the apoptotic actions of DEX.…”

“…The less-potent MR antagonist oxprenoate (RU28318) [33][34][35] only stimulated apoptosis when used at 10 À5 M, the highest dose tested (Figure 4b). The apoptotic actions of SPIRO and RU28318 most probably result from their counteraction of the prosurvival effects of the nanomolar (MR-activating) levels of corticosterone in the B27/Neurobasal medium; these results indicate that tonic occupation of MR is essential for neuronal survival.…”

Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart

“…Based on these characteristics, nongenomic effects of aldosterone have been reported from a number of laboratories in renal epithelial cells, 13 vascular smooth muscle cells, 14,15 skeletal muscle cells, 16 and colonic. The molecular basis of these nongenomic effects of aldosterone actions have been ascribed to changes in intracellular pH (pHi), [17][18][19] 20 -25 Although it has been observed that aldosterone does have rapid effects on protein kinase C activity in cultured cardiac cells, 26 and that aldosterone has rapid effects on cardiac sodiumhydrogen exchange, 27 the molecular mechanism of the rapid inotropic effect of aldosterone is still unclear.The spironolactone issue is less well defined and perhaps of greater interest because of the favorable results of the RALES trial. 1 We previously observed that substantial inotropy could be observed with levels of spironolactone that were comparable to those achieved with this agent in standard clinical practice.…”

“…Based on these characteristics, nongenomic effects of aldosterone have been reported from a number of laboratories in renal epithelial cells, 13 vascular smooth muscle cells, 14,15 skeletal muscle cells, 16 and colonic. The molecular basis of these nongenomic effects of aldosterone actions have been ascribed to changes in intracellular pH (pHi), [17][18][19] intracellular calcium ([Ca 2ϩ ] i ), 20 -23 and intracellular sodium ([Na ϩ ] i ) 13 in various tissues. Different effects on cytosolic pH and cytosolic [Ca 2ϩ ] have been observed in different tissues.…”

Aldosterone, hypertension and heart failure: insights from clinical trials

“…9 The vessel wall is an aldosterone target tissue, in that it coexpresses MR and 11bHSD2; the actions of aldosterone are mimicked by cortisol in the presence, but not the absence, of carbenoxolone to block the action of 11bHSD2. 10 Cardiomyocytes, in contrast, do not co-express 11bHSD2 with MR, so that in this tissue MR are normally overwhelmingly glucocorticoid-occupied-but not activated. 11 In the failing heart, as in RALES, or post-myocardial infarction, as in EPHESUS, 12 cardiomyocytes show high levels of reactive oxygen species, with accompanying changes in intracellular redox state.…”