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PubMed1995

[Acetylation of spironolactone, canrenone and 2-methyl-canrenone].

Reaction of the title compounds with acetic anhydride and acetyl chloride yields the 3,5-dien-3-yl acetate 2, the isomeric 2,4,6- and 3,5,7-trien-3-yl acetates 3 and 4 as well as the 2,4,6,8(14)-tetraen-3-yl acetate 7. The 2 alpha-methyl-8,14-didehydro-canrenone (9) is obtained by hydrolysis of 7. Binding affinities of 7 and 9 to hormone receptors as well as serum proteins (SHBG, CBG) are investigated. The compounds are inactive.

Acetylation↗

PubMed1998

Small doses of canrenone block the effects of ouabain on the mechanical activity of the heart and vessels of the rat.

Canrenone has been described as an antihypertensive drug that blocks endogenous ouabain effects in volume-dependent hypertensive models. Considering that some canrenone metabolites may be putative mutagenic factors, therapeutic dose reduction might be advantageous if the blockade of ouabain effects is maintained. In this study, the effects of low doses or concentrations of canrenone were investigated in rats by using isolated papillary muscles, Langendorff-perfused hearts, perfused rat-tail vascular bed, and anesthetized animals. Canrenone (0.5, 1, 2, and 5 mg/ml) produced a dose-dependent negative inotropic effect in papillary muscles contracting isometrically and blocked the positive inotropic effect produced by 660 microM ouabain. In Langendorff-perfused hearts beating spontaneously, a low concentration of canrenone (10 microg/ml) increased the isovolumic systolic pressure obtained at several diastolic pressures. Higher concentrations of canrenone (20, 30 microg/ml) brought the isovolumic pressure toward control values, and 100 microg/ml canrenone produced an isovolumic pressure reduction. In these preparations, 20 microg/ml canrenone reduced significantly the positive inotropic effects of 100 microM ouabain. Investigating the vascular smooth muscle reactivity to phenylephrine (PE; 0.5, 1, and 2 microg bolus injections) in the perfused rat-tail vascular bed, it was observed that canrenone blocked completely the enhancement of PE pressor effect produced by 1-h treatment with 100 microM ouabain. Similar results were obtained with the arterial blood pressure reactivity to PE in anesthetized rats. In these animals, canrenone (1 mg/kg) blocked the sensitizing effect of 18 microg/kg ouabain on PE reactivity. In conclusion, results presented here suggest that canrenone may block ouabain effects at very low concentrations. It blocked myocardial positive inotropic effects of ouabain on both papillary muscle and perfused hearts, and the sensitization of PE pressor effects. The results also suggest that canrenone at very small doses might be used to reduce arterial blood pressure in hypertensive conditions accompanied by increased ouabain plasma levels as the main therapeutic procedure or as an adjunct treatment to prevent ouabain sensitizing effects on pressor responses.

Animals↗

PubMed2003

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells.

BACKGROUND & AIMS: Several lines of evidence indicate that aldosterone antagonists may exert direct antifibrogenic effects. The aim of this study was to evaluate the possible direct antifibrogenic effects of canrenone, the active metabolite of spironolactone, in activated human hepatic stellate cells. METHODS: The effects of canrenone were assessed on platelet-derived growth factor-induced mitogenic and chemotactic effects and the increased de novo synthesis of different extracellular matrix components induced by transforming growth factor-beta1. RESULTS: Canrenone dose-dependently reduced platelet-derived growth factor-induced cell proliferation and motility. This effect was not associated with either changes in the phosphorylation of platelet-derived growth factor receptor and phospholipase C gamma or in the activation of the Ras/extracellular signal-regulated kinase pathway, whereas it was accompanied by a dose-dependent inhibition of platelet-derived growth factor-induced phosphatidylinositol 3-kinase activity. In addition, canrenone inhibited the activity of the Na(+)/H(+) exchanger 1 induced by platelet-derived growth factor. The effect of canrenone on Na(+)/H(+) exchanger 1 activity was reproduced by phosphatidylinositol 3-kinase inhibitors, thus supporting an inhibitory action of canrenone on phosphatidylinositol 3-kinase activity. To further address this possibility, the action of canrenone was compared with that of 2 established Na(+)/H(+) exchanger 1 inhibitors: ethylisopropylamiloride and cariporide. Whereas ethylisopropylamiloride was able to inhibit platelet-derived growth factor-induced phosphatidylinositol 3-kinase activity, cariporide was without any effect. Both compounds reproduced the effects of canrenone on platelet-derived growth factor-induced mitogenesis and chemotaxis. Finally, canrenone was able to reduce transforming growth factor-beta1-induced de novo synthesis of procollagen type I/IV and fibronectin and thrombin-induced hepatic stellate cell contraction. CONCLUSIONS: These results indicate that canrenone may be active as an antifibrogenic drug.

Aldosterone↗

PubMed1988

Do canrenone and 6,7-dihydroxylated derivatives compete with ouabain at the same site on Na,K-ATPase?

Canrenone is the major metabolic product of the synthetic steroids spironolactone and K+-canrenoate, used in antihypertensive therapy. Canrenone can competitively displace [3H]ouabain from Na,K-ATPase [Na+- and K+-activated, Mg2+-dependent adenosine triphosphatase (E.C.3.6.1.3)] and partially inhibit enzymatic activity. These features have led to a hypothesis that competition between canrenone and endogenous digitalis-like materials, suggested to be involved in etiology of essential hypertension, could underly the antihypertensive effect of canrenone. Surprisingly, three derivatives of canrenone (6 beta,7 alpha-,6 beta,7 beta-, and 6 alpha,7 alpha-dihydroxy-6,7-dihydrocanrenone) reportedly occur in normal human and rat urine. This paper characterizes the interactions with partially purified renal Na,K-ATPase of canrenone, the three 6,7-dihydroxylated derivatives, and one epoxide intermediate, synthesized from K+-canrenoate. Canrenone and all the 6,7-substituted derivatives partially inhibited Na,K-ATPase activity (39-45%), with approximately the same apparent affinity, 100-200 microM. Canrenone displaced [3H]ouabain in an apparently competitive fashion (Ki = 100-300 microM) but none of the tested derivatives significantly displaced ouabain even at very high concentrations. The ability to differentiate the ATPase inhibition and [3H]ouabain displacement by modification of the 6,7-double bond indicates that inhibition of ATPase activity does not occur from within the ouabain binding site. We suggest that neither canrenone nor the 6,7-derivatives bind to the ouabain site, but rather interact with it 'allosterically.' Our findings do not support the proposed mechanisms for the antihypertensive action of canrenone.

Antihypertensive Agents↗

PubMed1983

The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.

1 Canrenone, the major active metabolite of spironolactone, decreased [3H]-progesterone binding to isolated uterine cytosolic progesterone receptors. The inhibition was concentration-dependent. 2 Canrenone did not alter [3H]-oestradiol binding to isolated uterine cytosolic oestrogen receptors. 3 Canrenone inhibition of progesterone binding to isolated cytosolic receptors was strictly competitive: Kd (apparent dissociation constant for progesterone binding) was increased in a concentration-dependent manner by canrenone, whereas Bmax (maximal number of progesterone binding sites/mg cytosolic protein) was unaltered. There was marked cooperativity in progesterone binding at high canrenone and low progesterone concentrations. The implication is that canrenone alters the subunit interaction of the receptor protein. 4 Kd for progesterone was 3.2 X 10(-9)M. Ki (the inhibition constant for canrenone with respect to progesterone binding) was 300 X 10(-9)M. Reports in the literature suggest that, following spironolactone administration, canrenone may rise to concentrations sufficiently high to inhibit progesterone binding. This action may contribute to the effect of spironolactone in inducing menstrual disturbances in female patients.

Canrenone↗

PubMed1985

Hypotensive action of canrenone in a model of hypertension where ouabain-like factors are present.

It has been proposed that peripheral resistance can be increased by ouabain-like factors that are able to increase cell sodium and thereby cell calcium. Canrenone has been reported to be a partial agonist of ouabain. The effect of canrenone was investigated in rats with reduced renal mass (RRM) showing evidence of excess circulating ouabain-like factors. Wistar rats were uninephrectomized, 30% of the other kidney was removed, and they were given a 0.8% NaCl solution to drink. Half of them received 60 mg/kg per day of canrenone orally for 26 days. In RRM, the following indices of a ouabain-like activity were found: erythrocyte Na+K(+)-pump activity was decreased by 39% (P < 0.001), sodium content increased by 12% (P < 0.01), net erythrocyte sodium extrusion in plasma decreased by 20% (P < 0.01), and plasma digoxin equivalents increased by 62% (P < 0.02). Canrenone increased the IC50 for ouabain from 1.05 to 2.16 x 10(-4) mol/l (P < 0.05) in erythrocytes. In RRM with systolic blood pressure of 165 mmHg, acute administration of canrenone decreased blood pressure by 36 mmHg. Chronic administration blunted the blood pressure rise by 12, 26 and 21 mmHg at days 5, 14 and 26, respectively (P < 0.05). Haematocrit was markedly reduced in RRM (33%) and much less when treated with canrenone (37.5%). In conclusion, in contrast with spontaneously hypertensive rats, RRM hypertension is a model where a ouabain-like factor is present and in which canrenone reduces blood pressure. The hypotensive effect of canrenone may be related to a competition with ouabain-like factors.

Animals↗

PubMed1976

Effect of aldosterone antagonist canrenone on plasma aldosterone concentration and plasma renin activity, and on the excretion of aldosterone and electrolytes by man.

Canrenone was administered in doses of 2 x 82 mg and 2 x 164 mg per day over a period of 10 days to diabetic patients without cardiovascular, liver or kidney involvement. Aldosterone excretion and plasma aldosterone increased only slightly during both regimes. There was a clear-cut increase in aldosterone excretion only after discontinuation of canrenone. Excretion of sodium, potassium and fluid was not significantly changed either during or after treatment. The lack of effect of canrenone on the kidney was in contrast to the significant decrease in serum sodium and increase in serum potassium, and the significant, dose-dependent rise in plasma renin activity following canrenone administration. The increased plasma renin activity persisted for some days after discontinuation of canrenone. It is suggested that canrenone primarily exerted its effect in the distal part of the large intestine where ionic movements are most affected by aldosterone. The disproportionately slight increase in plasma aldosterone concentration and aldosterone excretion, in spite of the greatly elevated plasma renin activity and serum potassium level, is considered to be due to a direct inhibitory effect of canrenone on aldosterone production in the adrenals.

Aldosterone↗

PubMed2001

Effects of canrenone on aorta and right ventricle of the rat.

Canrenone is a major active metabolite of spironolactone and, in addition to the antimineralocorticoid effect, shares with the parent compound the action as a partial agonist with respect to ouabain on the Na+-K+ ATPase. We have investigated whether canrenone, through its action on Na+-K+ ATPase, reverses rat aorta contractions induced by ouabain and has vasorelaxant properties unrelated to its interaction with ouabain. Contractile responses of endothelium-deprived aorta to 1 mM ouabain, 0.1 microM phenylephrine, 10 microM serotonin, and 60 mM K+ were relaxed by canrenone (50-250 microM), with maximum inhibitions of 85.3%, 55.3%, 56.7%, and 64.2%, respectively. Canrenone shifted to the right the concentration-response curve for Ca2+ in depolarized aorta and did not affect the response to 10 mM caffeine. In rat right ventricular strips driven at 0.1 Hz, canrenone exerted negative inotropic effect. The relaxation of ouabain-induced contraction may be due, at least in part, to an interaction between canrenone and ouabain on the Na+-K+ ATPase. Inhibition of calcium entry through calcium channels either in aorta or ventricles is the most parsimonious hypothesis of mechanism underlying the effect of canrenone on contractile responses of rat aorta to agonists and high K+ and the negative inotropic effect on ventricular strips.

Animals↗

PubMed2003

Effect of canrenone on the digitalis site of Na+/K(+)-ATPase in human placental membranes and in erythrocytes.

It has been reported that canrenone, which is used in hypertensive therapy as an antialdosteronic drug, may also act as a blocker of ouabain effects. Several studies suggest that human plasma contains an endogenous ouabain-like factor similar to ouabain, which may be increased in hypertension, in pregnancy, and in the neonatal state. This study evaluated (1) the effect of canrenone on Na+/K(+)-ATPase in relation to ouabain in human placental membranes and erythrocytes by 3H-ouabain binding assay; (2) the capacity of canrenone (10 microM) to reverse the inhibition of Na+/K(+)-ATPase by ouabain and by ouabain-like factor (from umbilical cord plasma) in human erythrocytes employing a 86Rb uptake assay. Increasing concentrations of canrenone (0-350 microM) partially competed with 3H-ouabain binding in placental membrane (40%) and erythrocytes (60%). Scatchard plot from radioreceptor assay in placental membrane showed that ouabain and canrenone compete for the same binding site. In erythrocytes, canrenone completely reversed the inhibition caused by ouabain (5 x 10(-9) M) and ouabain-like factor (2 x 10(-9) M ouabain equivalents). A reduction of inhibition of about 50% was observed with ouabain and ouabain-like factor respectively at a concentration of 5 x 10(-8) M and 2 x 10(-8) M (ouabain equivalents). Our results thus provide evidence that canrenone, at therapeutical concentrations, is a partial competitive agonist of ouabain and of ouabain-like factor in human placental membranes and erythrocytes.

Binding Sites↗

PubMed1985

The interaction of canrenone with the Na+,K+ pump in human red blood cells.

Canrenone inhibits 30-40% of ouabain-sensitive Na+ efflux in human red cells. Half-maximal inhibition was obtained with a canrenone concentration = 86 +/- 37 mumol/l (mean +/- SD of 13 experiments). The partial inhibition of the Na+,K+ pump appears to be mediated at the digitalis receptor site with an apparent dissociation constant (Kc) = 200 +/- 130 mumol/l (mean +/- SD). Further evidence suggesting that canrenone is a partial agonist at the digitalis receptor site was obtained by the observation that it decreases the apparent affinity of the Na+,K+ pump for external K+. However, in contrast to ouabain, canrenone decreases the apparent pump affinity for internal Na+. Our results show that, at physiological cell Na+ levels canrenone is able to enhance the inhibition of the Na+,K+ pump by low doses of ouabain. Conversely, in cells treated with high concentrations of cardiac glycosides (in which cell Na+ content increases), canrenone is able to restimulate the blocked pumps.

Canrenone↗

PubMed1984

Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone.

Plasma levels of canrenone and 'total metabolites' after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and 'total metabolites' were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and 'total metabolites'. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state pre-dose plasma levels of canrenone and 'total metabolites' were significantly higher in the elderly subjects. The accumulation ratios of canrenone and 'total metabolites' were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as a proportionate shift in metabolism with age; impaired oral absorption of the parent compound; and/or altered volume of distribution of the drug.

Adult↗

PubMedDate not supplied

Canrenone formation via general-base-catalyzed elimination of 7 alpha-(methylthio)spironolactone S-oxide.

The preparation of the two diastereomeric S-oxides of 7 alpha-(methylthio)spironolactone, the major metabolite of spironolactone in humans, is described. When placed in aqueous solution, these diastereomers undergo elimination reactions to give canrenone. The rate of canrenone formation from 7 alpha-(methylthio)spironolactone S-oxide was carefully investigated spectrophotometrically. In weakly acidic media, canrenone formation was found to proceed at significant rates, and the reaction was catalyzed by basic buffer species. At strongly acidic or basic pH only, specific-acid or specific-base catalysis of sulfoxide elimination, respectively, was observed. The observation that formation of canrenone could occur from nonenzymatic elimination of 7 alpha-(methylthio)spironolactone S-oxide may have toxicological significance since it has been determined that canrenone can be metabolized to mutagenic epoxides in vitro. Our studies demonstrate a novel chemical pathway leading from a major metabolite of spironolactone, 7 alpha-(methylthio)spironolactone S-oxide, to canrenone.

Buffers↗

PubMed2002

Cardiovascular effects of canrenone in patients with preascitic cirrhosis.

In patients with cirrhosis and portal hypertension, standing induces a reduction in cardiac index (CI) and an increase in systemic vascular resistance index. Our previous studies indicate that this abnormal hemodynamic response to standing is due to an altered myocardial function, because cirrhotic patients are unable to compensate for the reduced preload with an increase in left ventricular (LV) ejection fraction (EF) and stroke volume. To evaluate whether the cardiac dysfunction in cirrhosis is influenced by canrenone, an aldosterone antagonist, 8 patients with preascitic, nonalcoholic cirrhosis, and portal hypertension underwent echocardiographic assessment of LV function and systemic hemodynamics and determinations of plasma volume, urinary sodium excretion, and plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (PNE) when on a 150-mmol/d-sodium diet (baseline), after 1 month on canrenone (100 mg/d) plus a 40-mmol/d-sodium diet and after 1 month on canrenone plus a 150-mmol/d-sodium diet. Echocardiographic evaluation was performed with the patient in the supine position and during active standing. At baseline, patients had high plasma volume and normal renal function, PRA, PAC, and PNE. CI, LVEF, and stroke volume index were also normal. Standing caused a significant reduction in CI and LVEF. After canrenone and either sodium diet, CI significantly decreased, and PRA and PNE increased in the supine position. On standing, LVEF and CI did not decrease further. Plasma volume significantly decreased only after low-sodium diet plus canrenone. In conclusion, canrenone normalizes the cardiac response to the postural challenge in patients with preascitic cirrhosis.

Aged↗

PubMed1981

Canrenone as a partial agonist at the digitalis receptor site of sodium-potassium-activated adenosine triphosphatase.

Canrenone, a spironolactone metabolite, was tested for its possible effects on (Na+-K+) adenosine triphosphatase (ATPase) activity [Mg++-dependent, (Na+-K+)-activated ATP phosphohydrolase (E.C.3.6.1.3) and ouabain interaction with the enzyme. Canrenone competitively antagonized the binding of [3H]ouabain to (Na+-K+)ATPase and inhibited (Na+-K+)ATPase activity. The multiple inhibition technique was used to demonstrate that canrenone is a partial inhibitor of (Na+-K+)ATPase, mutually exclusive with respect to ouabain. Comparative studies of the effects of ouabain and canrenone on potassium-dependent p-nitrophenylphosphatase activity (E.C.9.6.1.7) and potassium activation of (Na+-K+)ATPase confirmed that ouabain and canrenone interacted with the same receptor site. The finding that canrenone is a partial agonist may explain the results of previous in vivo studies showing that spironolactone and the allied drug to potassium conrenoate have either a positive inotropic action or an antagonistic effect against digitalis toxicity.

4-Nitrophenylphosphatase↗

PubMed1984

Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone.

The pharmacokinetics of canrenone and 'total metabolites' after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and 'total metabolites' were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2 alpha) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2 beta) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of 'total metabolites' after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of 'total metabolites' was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and 'total metabolites' were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.

Administration, Oral↗

PubMed1989

Erythrocyte Na+, K+ pump inhibition after saline infusion in essentially hypertensive subjects: effects of canrenone administration.

The effects of a 2-litre isotonic saline infusion, with and without prior oral canrenone (150 mg) administration, on erythrocyte Na+, K+ pump, urinary sodium excretion and arterial pressure were evaluated in nine patients with essential hypertension. Ouabain-sensitive Na+ efflux in fresh erythrocytes was used as an index of Na+, K+ pump activity, and the inhibitory effect on this ion efflux of preincubation of erythrocytes in plasma was used to test the presence of a circulating ouabain-like substance. Erythrocyte Na+, K+ pump activity decreased significantly (P less than 0.01) after saline infusion; canrenone administration was able to prevent this inhibition. Plasma from hypertensive patients obtained before saline infusion significantly (P less than 0.01) inhibited the Na+, K+ pump of erythrocytes from normal subjects, while plasma taken after the saline infusion plus canrenone was unable to produce any significant inhibition. Both systolic and diastolic arterial pressure fell significantly (P less than 0.05) only at the end of saline infusion with prior canrenone administration. This study supports the hypothesis that protection of Na+, K+ pump against endogenous inhibitors, other than exogenous, seems to be a pharmacological effect of canrenone, and may partly explain its antihypertensive activity.

Adult↗

PubMed2002

Effects of canrenone on myocardial reactive fibrosis in a rat model of postinfarction heart failure.

BACKGROUND: Spironolactone reduces overall mortality by 30% in advanced congestive heart failure. Nevertheless, few data are available with regard to the effects of mineral corticoid inhibition in postinfarction heart failure. MATERIALS AND METHODS: Experimental myocardial infarction was induced by left coronary ligation in 70 male rats with body weights ranging from 180 to 200 gr. The day after surgery, animals were randomized to either placebo or canrenone-gamma-cyclodestrin 8 mg/kg/die or canrenone-gamma-cyclodestrin 18 mg/kg/die. Twelve animals served as the control group. After two weeks, the rats underwent closed chest left ventricular catheterization. The heart was the rapidly excised for subsequent histological analysis. RESULTS: Compared with controls, infarcted rats had reduced left ventricular systolic pressures (-6%) and higher left ventricular end-diastolic pressures (+600%), associated with a marked increase of mean collagen fraction (+446%) and perivascular fibrosis (+72%). Compared with placebo-infarcted rats, in the group treated with high canrenone dose there was a significant reduction of left ventricular systolic and end-diastolic pressures (-6.5% and -23%, respectively) and an attenuation of interstitial and perivascular fibrosis (-47% and -34%, respectively). The low-dose canrenone group did not show differences compared with the placebo infarcted rats, except for a slight reduction of mean collagen fraction (-21%). CONCLUSIONS: Canrenone attenuates LV interstitial remodeling and reduces filling pressures in rats with postinfarction heart failure.

Administration, Oral↗

PubMed1989

Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy.

Plasma levels of canrenone and androgen receptor-active materials (ARM) were determined during long-term oral K-canrenoate or spironolactone therapy in cirrhotics with chronic recurrent ascites. Mean plasma canrenone level was approximately 3 times higher under K-canrenoate than under spironolactone treatment; moreover, the levels were not dose related. Either type of treatment did not affect plasma aldosterone and testosterone concentrations. Plasma ARM during K-canrenoate treatment did not change, whereas in the spironolactone group a 3-fold increase of ARM occurred (p less than 0.05). No dose-related effect was evident with the latter treatment. The lower incidence of gynecomastia in the K-canrenoate group was not correlated with values of plasma canrenone or ARM (p greater than 0.05). Our study questions the traditional view that the mode of action of spironolactone is via its metabolite canrenone. The two antialdosterone drugs, although equally effective in clearing ascites from cirrhotics, appear to act through partially different metabolites. The lower incidence of antiandrogenic or estrogen-like side effects during K-canrenoate seems to be related to metabolites other than canrenone itself.

Adult↗