Aldosterone-induced changes in the cardiac L-type Ca(2+) current can be prevented by antioxidants in vitro and are absent in rats on low salt diet.
Mineralocorticoid receptor (MR) activation modulates cardiac L-type Ca(2+) current (I (CaL)) and transient outward K(+) current (I (to)). The exact circumstances of MR activation, however, remain elusive. Here, we investigate the influence of corticosteroids on MR-mediated changes in cellular electrophysiology. In vitro incubation of adult rat ventricular myocytes with the MR agonist aldosterone (100 nM, 24 h) increased I (CaL) density by 34% (n = 16; p < 0.01). This effect was abrogated by co-incubation with the MR antagonist spironolactone (10 muM). To investigate whether an increase in serum aldosterone concentration is sufficient for an increase in I (CaL) in vivo, rats were subjected to low Na(+) diet (LSD, 0.013% Na(+)) for 28 days. This increased serum aldosterone concentration from 0.19 +/- 0.04 nM (n = 6) in control animals (0.3% Na(+), CSD) to 16.1 +/- 2.1 nM (n = 6; p < 0.0001). Strikingly, I (CaL) density was similar in both CSD and LSD rats (-12.9 +/- 0.9 pA pF(-1), n = 18 and -13.7 +/- 1.1 pA pF(-1), n = 16, respectively), as was I (to) density. In vitro, the glucocorticoid corticosterone (1 microM) also increased I (CaL) and this effect was blocked by spironolactone (10 microM). Co-incubation with corticosterone (1 microM, the normal serum concentration) and aldosterone (100 nM, mimicking low Na(+) intake) did not further increase I (CaL) compared to corticosterone alone. Moreover, co-incubation of myocytes with N-acetylcysteine (10 mM) prevented the aldosterone (100 nM) or corticosterone (1 microM)-induced increase in I (CaL). In conclusion, an increase in serum aldosterone concentration in response to LSD is not sufficient for an increase in I (CaL) density in cardiomyocytes in vivo. This is supported in vitro by the absence of an effect of aldosterone on I (CaL) in the presence of a physiological concentration of corticosterone. Moreover, the cellular redox state may modulate MR activation.
Wagner
Michael
M
Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstrasse 6, 91054, Erlangen, Germany.
Rudakova
Elena
E
Volk
Tilmann
T
D000111:Acetylcysteine / Q000494:pharmacology*; D000200:Action Potentials; D000450:Aldosterone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004039:Diet, Sodium-Restricted; D004562:Electrocardiography; D006339:Heart Rate; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
D000975:Antioxidants; D020746:Calcium Channels, L-Type; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D011188:Potassium; D003345:Corticosterone; D000111:Acetylcysteine