Saori Matsui

Non-genomic effects of aldosterone on intracellular ion regulation and cell volume in rat ventricular myocytes.

Aldosterone has non-genomic effects that express within minutes and modulate intracellular ion milieu and cellular function. However, it is still undefined whether aldosterone actually alters intracellular ion concentrations or cellular contractility. To clarify the non-genomic effects of aldosterone, we measured [Na+]i, Ca2+ transient (CaT), and cell volume in dye-loaded rat ventricular myocytes, and we also evaluated myocardial contractility. We found the following: (i) aldosterone increased [Na+]i at the concentrations of 100 nmol/L to 10 micromol/L; (ii) aldosterone (up to 10 micromol/L) did not alter CaT and cell shortening in isolated myocytes, developed tension in papillary muscles, or left ventricular developed pressure in Langendorff-perfused hearts; (iii) aldosterone (100 nmol/L) increased the cell volume from 47.5 +/- 3.6 pL to 49.8 +/- 3.7 pL (n=8, p<0.05); (iv) both the increases in [Na+]i and cell volume were blocked by a Na+-K+-2Cl- co-transporter (NKCCl) inhibitor, bumetanide, or by a Na+/H+ exchange (NHE) inhibitor, 5-(N-ethyl-N-isopropyl) amiloride; and (v) spironolactone by itself increased in [Na+]i and cell volume. In conclusion, aldosterone rapidly increased [Na+]i and cell volume via NKCC1 and NHE, whereas there were no changes in CaT or myocardial contractility. Hence the non-genomic effects of aldosterone may be related to cell swelling rather than the increase in contractility.

Non-Genomic Effects of Aldosterone on Intracellular Ion Regulation and Cell Function in the Heart

Serum aldosterone levels are often elevated in patients with heart failure and are associated with poor clinical outcomes. Aldosterone can be produced in extra-adrenal tissues including the heart, and the local increase in aldosterone exerts deleterious effects on heart structure and function. Aldosterone has 2 types of effects on intracellular ion milieu and cellular function. One is the classical genomic effect in which aldosterone combines with the intracellular mineralocorti- coid receptor, transfers to the nucleus, and stimulates synthesis of various proteins. Another is the non-genomic effect that expresses within minutes without synthesizing proteins. The non-genomic effects of aldosterone are less proved in the heart, but it has been shown that aldosterone rapidly activates Na + influxes via Na + -K + -2Cl - co-transport and Na + /H + ex- change, resulting in an increase in intracellular Na + concentration and intracellular alkalinization. These changes in intra- cellular ion milieu cause positive inotropy, cell swelling, and generation of reactive oxygen species. Thus, the non- genomic effects of aldosterone may contribute, in concert with the genomic effects, to cardiac hypertrophy, fibrosis, and remodeling. This review will discuss the experimental studies examining the mechanisms and physiological/patho- physiological relevance regarding the non-genomic effects of aldosterone in the heart.