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Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present
M de Mendonça1, M L Grichois, M G Pernollet
1INSERM U7, Hôpital Necker, Paris, France.
Abstract:
The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.
Insights
Canrenone, an antialdosterone drug, effectively lowers blood pressure in rats with hypertension. It combats volume expansion and reduces digitalis-like compounds, suggesting a novel therapeutic mechanism for hypertension management.
Area of Science:
- Cardiovascular Physiology
- Renal Physiology
- Pharmacology
Background:
- Rats with reduced renal mass and excess sodium intake (RRM-salt) exhibit volume expansion and hypertension.
- These RRM-salt rats display increased endogenous digitalis-like compounds, inhibited Na+, K+-ATPase activity, and reduced Na+ pump function in erythrocytes.
- Low plasma renin activity is also characteristic of the RRM-salt model.
Purpose of the Study:
- To investigate the antihypertensive effects of canrenone in a rat model of volume expansion and hypertension (RRM-salt).
- To explore the potential role of endogenous digitalis-like compounds in the observed antihypertensive action of canrenone.
Main Methods:
- Rats underwent renal mass reduction and were fed a high-sodium diet to induce RRM-salt hypertension.
- Canrenone was administered as a single oral dose (60 mg/kg) and chronically (60 mg/kg/day).
- Measurements included systolic blood pressure, plasma digitalis-like compounds, kidney Na+, K+-ATPase activity, erythrocyte Na+, K+-pump activity, erythrocyte Na+ content, and plasma renin activity.
Main Results:
- A single dose of canrenone significantly reduced systolic blood pressure in RRM-salt rats.
- Chronic canrenone administration normalized volume expansion, decreased plasma digitalis-like compounds, and partially restored erythrocyte Na+, K+-pump activity and Na+ content.
- Canrenone's antihypertensive effect correlated with a reduction in endogenous digitalis-like compounds.
Conclusions:
- Canrenone exhibits a marked antihypertensive effect in RRM-salt rats, associated with correction of volume expansion.
- The study suggests that canrenone's antihypertensive action is, at least partly, mediated by antagonism of endogenous digitalis-like compounds.
- Canrenone represents a potential therapeutic agent for hypertension linked to volume expansion and altered digitalis-like compound levels.