Spironolactone was developed to treat edema and hypertension by regulating fluid and electrolyte balance in the kidney.1,2 Mineralocorticoid receptors in the distal tubule and collecting duct of the kidney bind with aldosterone. Aldosterone increases reabsorption of sodium and excretion of potassium by the kidney, which results in increased salt and water retention, increased blood volume, and increased blood pressure.3,4 Spironolactone achieves its primary effect by competing with aldosterone for receptor sites in the renal tubules.1,2 By blocking aldosterone, spironolactone causes fluid and sodium loss and retention of potassium which results in lowered blood pressure.5–7
Aldosterone has been shown to have far-reaching effects on the cardiovascular, renal, and myocardial tissues that affect cardiac health8 and is a factor in the development of resistant hypertension.9 It increases vascular tone and promotes collagen synthesis leading to arterial stiffness and increased blood pressure. Studies have found receptors with high affinity for aldosterone in cardiac myocytes and fibroblasts obtained from human hearts.10 Animal studies suggest that chronic exposure to high aldosterone levels can induce myocardial tissue damage with mechanisms that are independent of blood pressure elevation.11,12 These studies suggest that the presence of aldosterone over time can induce tissue inflammatory changes13 that lead to fibrosis of myocardium14 that appear to be prevented by administration of aldosterone antagonists.15
It is probable that spironolactone’s aldosterone-blocking function has a direct beneficial effect on cardiovascular and heart tissue processes.12,16–18 Although the mechanism of action is not completely understood, as aldosterone receptors have been identified in tissue outside of the renal tubule, including the heart, spironolactone has been used to control other (volume-independent) detrimental cardiac effects of aldosterone, including heart failure and resistant hypertension.1,9,17
- Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev 2005; 10 (1): 23-29.
- Kolkhof P, Bärfacker L. Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 2017; 234 (1): T125-T140.
- Pimenta E, Gaddam KK, Pratt-Ubunama MN, et al. Aldosterone excess and resistance to 24-h blood pressure control. J Hypertens 2007; 25 (10): 2131-2137.
- Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med 1976; 59 (4): 105-110.
- Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association professional education committee of the council for high blood pressure research. Circulation 2008; 117 (25): e510-e526.
- Calhoun DA. Aldosteronism and hypertension. Clin J Am Soc Nephrol 2006; 1 (5): 1039-1045.
- Pimenta E, Gaddam K, Oparil S. Mechanisms and treatment of resistant hypertension. J Clin Hypertens 2008; 10 (3): 239-244.
- Catena C, Colussi G, Brosolo G, Iogna-Prat L, Sechi LA. Aldosterone and aldosterone antagonists in cardiac disease: what is known, what is new. Am J Cardiovasc Dis 2012; 2 (1): 50-57.
- Epstein M, Duprez DA. Resistant hypertension and the pivotal role for mineralocorticoid receptor antagonists: a clinical update 2016. Am J Med 2016; 129 (7): 661-666.
- Lombes M, Alfaidy N, Eugene E, Lessana A, Farman N, Bonvalet JP. Prerequisite for cardiac aldosterone action. Mineralocorticoid receptor and 11 beta-hydroxysteroid dehydrogenase in the human heart. Circulation 1995; 92 (2): 175-182.
- Marney AM, Brown NJ. Aldosterone and end-organ damage. Clin Sci (Lond) 2007; 113 (6): 267-278.
- Zwadlo C, Bauersachs J. Mineralocorticoid receptor antagonists for therapy of coronary artery disease and related complications. Curr Opin Pharmacol 2013; 13 (2): 280-286.
- Rocha R, Rudolph AE, Frierdich GE, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002; 283 (5): H1802-10.
- Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992; 120 (6): 893-901.
- Martinez D V, Rocha R, Matsumura M, et al. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertens (Dallas, Tex 1979) 2002; 39 (2 Pt 2): 614-618.
- Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: Prospects for novel therapeutics. Mol Cell Endocrinol 2012; 350 (2): 310-317.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341 (10): 709-717.
- Bauersachs J, Jaisser F, Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertens 2015; 65 (2): 257-263.
- Yang J, Young MJ. Mineralocorticoid receptor antagonists - pharmacodynamics and pharmacokinetic differences. Curr Opin Pharmacol 2016; 27 : 78-85.