Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective?
1. Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2. Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11+/-4 and 9+/-2%, and decreased coronary flow (CF) by maximally 36+/-7 and 20+/-4%, respectively. Spironolactone did not significantly affect LVP or CF. 3. In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68+/-2 to 45+/-3%, similar to the reduction (34+/-2%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71+/-5%). 4. In cardiomyocytes, aldosterone decreased [(3)H]thymidine incorporation maximally by 73+/-3%, whereas in cardiac fibroblasts it decreased [(3)H]proline incorporation by 33+/-7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5. In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.
|Keywords||*Cardiotonic Agents/pharmacology, Aldosterone Antagonists/*pharmacology, Aldosterone/*pharmacology, Angiotensin II/pharmacology, Animals, Animals, Newborn, Blood Pressure/drug effects, Cells, Cultured, Collagen/biosynthesis/genetics, Coronary Circulation/drug effects, DNA/biosynthesis/genetics, Fibroblasts/drug effects, Heart/*drug effects, Male, Myocardium/pathology, Rats, Rats, Wistar, Receptors, Mineralocorticoid/drug effects/*genetics, Spironolactone/*pharmacology, Thymidine/pharmacology, Vasoconstrictor Agents/pharmacology, Ventricular Function, Left/drug effects|
|Persistent URL||dx.doi.org/10.1038/sj.bjp.0706220, hdl.handle.net/1765/13783|
Chai, W., Garrelds, I.M., Arulmani, U., Schoemaker, R.G., Lamers, J.M.J., & Danser, A.H.J.. (2005). Genomic and nongenomic effects of aldosterone in the rat heart: why is spironolactone cardioprotective?. British Journal of Pharmacology, 145(5), 664–671. doi:10.1038/sj.bjp.0706220