ABSTRACT
Spironolactone (SPIR) and its main metabolite canrenone (CAN) were given orally in two different doses to male rats for 6 weeks. Changes in the renin-angiotensin-aldosterone-system (RAAS) served as indicators for alterations in the electrolyte and water balance and thus for the pharmacological activity of the spirolactones studied.
SPIR treatment activated the RAAS dependent on the dose and over the entire period of investigation. In contrast, a comparable activation of the RAAS by CAN was only observed during the first week of treatment. Subsequently the CAN-induced increase in plasma renin activity, plasma aldosterone concentration and urinary aldosterone excretion continuously dropped, indicating a progressive loss in the anti-mineralocorticoid activity of CAN. Plasma sodium and potassium concentrations were significantly changed by SPIR only.
From the results it is concluded that during chronic treatment in the rat the aldosterone-antagonistic effect of SPIR can only be attributed for a limited period to its main metabolite CAN. In long-term treatment CAN is obviously subject to an accelerated metabolism and thus contributes only to a limited extent to the anti-mineralocorticoid effects of SPIR. In the rat the major part of the aldosterone-antagonistic effect of SPIR is possibly maintained during long-term treatment by sulphur-containing SPIR metabolites which arise from SPIR by metabolic degradation of the thioacetyl group.
More evidence on blocking the renin–angiotensin–aldosterone system in cardiovascular disease and the long-term treatment of hypertension: data from recent clinical trials (CHARM, EUROPA, ValHEFT, HOPE-TOO and SYST-EUR2)
