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PubMed1987

Conversion of spironolactone to 7 alpha-thiomethylspironolactone by hepatic and renal microsomes.

Recent observations indicate that 7 alpha-thiomethylspironolactone is an important circulating metabolite of the mineralocorticoid antagonist spironolactone (SL). Studies were carried out to determine possible sites and pathways of 7 alpha-thiomethyl-SL formation and, in particular, to evaluate SL metabolism by guinea pig hepatic and renal microsomal preparations. In the absence of S-adenosylmethionine (SAM), liver and kidney microsomes rapidly converted SL to 7 alpha-thio-SL as the only metabolite. The rate of 7 alpha-thio-SL production was greater in liver than kidney. In the presence of SAM, 7 alpha-thio-SL was further converted to 7 alpha-thiomethyl-SL by liver and kidney microsomes. The rates of methylation with 7 alpha-thio-SL as substrate were three to four times greater for liver than for kidney, but the Km values were similar (approximately 30 microM) in the two issues. Maximal enzyme activity was obtained with SAM concentrations of 25-200 microM. NADPH had no effect on SL or 7 alpha-thio-SL metabolism by liver or kidney microsomes. To determine if a pathway involving the C-S lyase enzyme might contribute to circulating 7 alpha-thiomethyl-SL levels in vivo, guinea pigs were treated with SL or its dethioacetylated derivative, canrenone, and plasma metabolites were analyzed by HPLC. Both 7 alpha-thiomethyl-SL and canrenone were found to be circulating metabolites in SL-treated animals, but only canrenone was identified in the plasma of canrenone-treated guinea pigs. The results indicate that the liver and kidney are potential sites of 7 alpha-thiomethyl-SL production and that its formation probably does not involve the C-S lyase pathway.

Animals↗
PubMed1988

Adrenal mitochondrial metabolism of spironolactone. Absence of metabolic activation.

Previous investigations have established that spironolactone (SL) administration to guinea pigs decreases adrenal mitochondrial and microsomal cytochrome P-450 content, and that the latter requires microsomal activation of the drug. Studies were carried out to determine if adrenal mitochondrial metabolism (activation) of SL was similarly involved in the effects of the drug on mitochondrial cytochrome P-450 destruction. Incubation of guinea pig adrenal mitochondria with SL in the absence of NADPH resulted in the formation of 7 alpha-thio-SL as the only metabolite. In the presence of an NADPH-generating system, an unknown polar metabolite was also produced. The mass spectrum of the unknown compound suggested that it was a hydroxylated derivative of SL. Incubation of mitochondrial preparations with 7 alpha-thio-SL also resulted in the formation of a polar metabolite, but the latter had a different HPLC retention time than that of the SL metabolite. Formation of the polar SL metabolite was prevented by metyrapone, an 11 beta-hydroxylase inhibitor, and was greatest in mitochondria from the adrenal zone having the highest 11 beta-hydroxylase activity. Steroid substrates for 11 beta-hydroxylation inhibited the production of the SL metabolite. Mitochondrial incubations with SL or with 7 alpha-thio-SL in the presence or absence of an NADPH-generating system did not affect cytochrome P-450 concentrations. The results indicate that, unlike the microsomal effects of SL, local activation of SL is not responsible for the destruction of adrenal mitochondrial cytochromes P-450. The major adrenal mitochondrial metabolites of SL appear to be 11 beta-hydroxy-SL and 7 alpha-thio-SL.

Adrenal Glands↗
PubMed1992

Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites.

The intent of this study was to identify pharmacokinetic and pharmacodynamic characteristics for spironolactone (SP) and its metabolites (canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 7 alpha-thiomethylspirolactone) in cirrhotics under steady state conditions. Nine cirrhotics with ascites participated in the study. Serial blood samples were drawn and urine was collected over a 26-hour period. Using a reverse-phase high performance liquid chromatography (HPLC) method, all samples were analyzed for SP, canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and 7 alpha-thiomethylspirolactone concentrations. Parent compound and metabolite urinary excretion rates as well as maximal concentrations and time at which these are observed were calculated. The apparent median terminal elimination rate constants (associated half-lives) were 0.0767 h-1 (9.04 hours) for SP, 0.0055 h-1 (126 hours) for 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 0.029 h-1 (23.9 hours) for 7 alpha-thiomethylspirolactone and 0.012 h-1 (57.8 hours) for canrenone. SP metabolism is impaired in cirrhosis; terminal half-lives of SP and metabolites appear to be increased when compared with values reported in the literature for normals. When assuming a linear model, clearance-effect relationship estimates are best correlated with 7 alpha-thiomethylspirolactone and canrenone. Further research is required to identify specific pharmacokinetic and pharmacodynamic parameters for SP and its metabolites in this patient population.

Adult↗
PubMedDate not supplied

Functional properties of deoxycorticosterone and spironolactone: molecular characterization and effects on sleep-endocrine activity.

Adrenal steroid hormones are capable of interfering with a variety of behavioral phenomena including sleep. The mechanisms appear to involve effects at the cell membrane as well as nuclear actions mediated by intracellular mineralo- and glucocorticosteroid receptors (MR and GR). We employed the MR agonist deoxycorticosterone (DOC) and the MR antagonist spironolactone (SP) to study the role of MRs in the regulation of human sleep. We also tested whether the effects of DOC upon the sleep EEG and nocturnal hormone secretion (growth hormone and cortisol) are compatible with those predicted for its major metabolite tetrahydro-DOC (THDOC): electrophysiological and animal experiments had suggested that THDOC would act as a hypnotic via positive modulation of the GABAA receptor. Because neither DOC nor SP affected the sleep EEG substantially, the involvement of MRs in the regulation of sleep needs further study. The sleep-endocrine data showed a suppressive effect of DOC upon plasma cortisol concentrations and an earlier occurrence of nocturnal GH maxima, which can be plausibly explained by GR or sigma receptor-mediated effects. Molecular characterization of DOC and SP confirmed a relatively strong effect of DOC upon transactivation via MR and no effect of SP on the GR-mediated transcription rate. In addition, the possibility that a low dose of the mineralocorticoid DOC may serve as a prodrug for the potential hypnotic THDOC is not supported by the current data.

Adult↗
PubMed1985

The effect of spironolactone on genital skin 5 alpha-reductase activity.

The effect of spironolactone (S) on genital skin 5 alpha-reductase activity (5 alpha-RA) of hirsute women (HW) in vivo as well as in normal genital skin in vitro was evaluated. Thirteen HW (Ferriman-Gallwey score of 23.3 +/- 2.8) received S 100 mg twice a day for a month. Twenty-three non-hirsute women were selected as controls for the assessment of genital skin 5 alpha-RA. S was added to incubations of genital skin from 9 additional controls in vitro in concentrations from 1.2 X 10(-8) to 10(-5) M. HW had significantly higher conversion ratios (CR) of T to DHT compared to controls (P less than 0.05). Post treatment values for the CR T to DHT were significantly lower than prior to S (17.5 +/- 1.7 and 8.05 +/- 1.2%, P less than 0.05) and the mass of DHT produced also decreased by 37 +/- 9% (P less than 0.05). The CR T to 3 alpha-diol decreased by 30 +/- 9% (P less than 0.05). In 11 of 13 women, a significant reduction of 5 alpha-RA was demonstrated while in 2 patients the activity remained unchanged. The maximum in vitro inhibitory effect of S on the CR T to DHT occurred with a concentration of 1.2 X 10(-5) M (P less than 0.01). In conclusion, S has a direct inhibitory effect on 5 alpha-RA. The beneficial effect of S treatment in HW may be related, in part, to this inhibition of 5 alpha-RA.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1988

Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture.

A series of compounds designed to block the action of androgens in target tissues, and called antiandrogens, have been developed for the treatment of androgen-sensitive diseases, especially prostate cancer, hirsutism, precocious puberty and deviant sexual behavior. In order to further assess the androgenic activity of these compounds, we have studied their effect on the growth of an androgen-sensitive clone of the mouse mammary carcinoma Shionogi SC-115 cells in culture. Hydroxy-flutamide did not affect the doubling time (7.40 +/- 0.09 vs 7.20 +/- 0.12 days) characteristic of these cells. However, all of the other compounds tested stimulated cell growth. Thus, in the presence of cyproterone acetate, cells had an accelerated growth rate and shorter generation time of 6.28 +/- 0.06 days (P less than 0.01). In the presence of 1 microM spironolactone, the generation time was 4.96 +/- 0.04 days (P less than 0.01). With chlormadinone acetate, the doubling time was reduced to 3.79 +/- 0.08 days while for megestrol acetate, the doubling time was 3.63 +/- 0.04 days (P less than 0.01). The synthetic progestin Medroxyprogesterone acetate had the most potent androgenic effect reducing the doubling time to 1.85 +/- 0.05 days (P less than 0.01). For comparison, dihydrotestosterone gave a doubling time of 1.76 +/- 0.07 days. When hydroxy-flutamide (5 microM) was added simultaneously with each "progestin", the ED50 value of action of all the compounds was increased in a competitive manner, thus indicating that the mitogenic effect on cell growth of all compounds is mediated by the androgen receptor. Of all the compounds used, only hydroxy-Flutamide was devoid of any androgenic activity and thus meets the criteria of a pure antiandrogen.

Androgens↗
PubMed1985

Comparative diuretic, saluretic, kaliuretic, and prostaglandin synthetase inhibitory activities of a competitive inhibitor of prostaglandin synthetase and spironolactone.

A newly described in vivo and in vitro competitive inhibitor of prostaglandin synthetase, 2-methyl, 8-cis, 12-trans, 14-cis, eicosatrienoic acid, a functional and structural analog of the endogenous substrates of prostaglandin E biosynthesis, as well as an analog of a putative intermediate in PGE1 biosynthesis, was shown to increase long-term urine excretion, and decrease long-term prostaglandin metabolite excretion in a linear dose-related manner. The correlation of both responses with dose were large (0.94, and 0.91 respectively), and nearly identical, within the limits of experimental error. In parallel studies, similar properties and nearly identical correlation coefficients were demonstrated for spironolactone, a known diuretic, suggesting that both drugs may be acting on mechanisms which may be closely associated and which may be involved in regulation of water and salt.

8,11,14-Eicosatrienoic Acid↗
PubMed1991

Relationship between covalent binding to microsomal protein and the destruction of adrenal cytochrome P-450 by spironolactone.

Previous investigations have demonstrated that guinea pig adrenal microsomes catalyze an NADPH-dependent activation of spironolactone (SL) resulting in the degradation of cytochrome(s) P-450 and decreases in steroidogenic enzyme activities. Studies were done to evaluate the relationship between the destruction of cytochrome P-450 and the covalent binding to microsomal protein by SL and by 7 alpha-thiospironolactone (7 alpha-thio-SL), an obligatory intermediate in the activation pathway. NADPH-dependent irreversible binding to guinea pig adrenal microsomal protein was demonstrable with 22-14C- and with 35S-labelled SL or 7 alpha-thio-SL as substrates. In the absence of NADPH, there was relatively little binding. NADPH-dependent covalent binding was not demonstrable with hepatic microsomal preparations. The amount of covalent binding to adrenal microsomes was far greater with 7 alpha-thio-SL than with SL and also greater with 35S-labelled than with 14C-labelled substrates. The latter results suggest the possibility of more than one reactive metabolite. Time-course experiments revealed a good correlation between covalent binding and P-450 destruction by SL and by 7 alpha-thio-SL. In addition, the 17 alpha-hydroxylase inhibitor, SU-10'603, and the 17 alpha-hydroxylase substrate, progesterone, prevented both the degradation of cytochrome P-450 and the NADPH-dependent covalent binding by 7 alpha-thio-SL. Reduced glutathione also decreased covalent binding but did not diminish P-450 destruction. The latter results indicate that some of the covalent binding is unrelated to the degradation of cytochrome P-450. However, all of the data are consistent with the hypothesis that 7 alpha-thio-SL is a suicide inhibitor of adrenal cytochrome P-450 and that covalent binding to protein is involved in the degradation of cytochrome P-450.

Adrenal Glands↗
PubMed1991

Mechanism of action of spironolactone on cortisol production by guinea pig adrenocortical cells.

Studies were done to determine the mechanism(s) of action of spironolactone (SL) and of its deacetylated metabolite, 7 alpha-thio-SL, to inhibit cortisol secretion by guinea pig adrenocortical cells in vitro. Preincubation of cells at 37 degrees C with SL or with 7 alpha-thio-SL caused a time-dependent decline in subsequent ACTH-stimulated cortisol secretion. In the absence of a preincubation, neither compound affected cortisol production, indicating the need for production of an active metabolite. When the 17 alpha-hydroxylase inhibitor, SU-10'603, was included during the preincubation period, neither SL nor 7 alpha-thio-SL decreased cortisol secretion, indicating the involvement of the 17 alpha-hydroxylase in the activation of both compounds. By contrast, neither the 11 beta-hydroxylase inhibitor, metyrapone, nor the cholesterol sidechain cleavage inhibitor, aminoglutethimide, diminished the effects of SL or of 7 alpha-thio-SL on cortisol secretion. Preincubation of cells with SL or 7 alpha-thio-SL also decreased the conversion of exogenous progesterone to cortisol, but did not affect cortisol production from the 17 alpha-hydroxylated substrates, 17 alpha-hydroxyprogesterone and 11-deoxycortisol, suggesting that only 17 alpha-hydroxylation was impaired. In addition, there was a decline in 17 alpha-hydroxylase activity in microsomes isolated from cells preincubated with SL or with 7 alpha-thio-SL, but no change in microsomal 21-hydroxylase or in mitochondrial 11 beta-hydroxylase and cholesterol sidechain cleavage activities. The results indicate that the direct effects of SL and of 7 alpha-thio-SL on the adrenal cortex to decrease cortisol production result from the selective inhibition of 17 alpha-hydroxylation. Since 17 alpha-hydroxylase activity is apparently required for the activation of both compounds, suicide inhibition of the enzyme may be the mechanism of action.

Adrenal Glands↗
PubMed1980

Distribution and excretion of 203Hg2+ in rats after unitiol, spironolactone and polythiol resin treatment.

Rats were given 203HgCl2 i.v. at a dose level of 120 microgram of Hg2+ per rat. The effect of unitiol (UNI; sodium 2, 3-dimercaptopropanosulphonate) and a combined UNI, spironolactone (SPL) and polythiol resin treatment on wholebody retention, organ distribution and excretion were studied for 48 h. In both treated groups significant increases in excretion and decreases in whole-body retention of 203Hg were observed. In the combination-treated group significantly lower values of 203Hg in plasma, kidney and brain were found.

Animals↗
PubMed1993

A micellar liquid chromatographic procedure for the determination of amiloride, bendroflumethiazide, chlorthalidone, spironolactone and triamterene in pharmaceuticals.

A procedure for the determination of amiloride, bendroflumethiazide, chlorthalidone, spironolactone and triamterene in pharmaceutical preparations (tablets) by micellar liquid chromatography, using a 0.07 M SDS-0.5% pentanol mobile phase, is proposed. Recoveries were found in the 100-108% range, with relative standard deviations of 0.4-3.1%. Elution of the most retained diuretics occurred in less than 18 min (at a 1 ml min-1 flow rate). The change in the values of the solute-micelle binding constants and the partition coefficients of the diuretics between the stationary phase and water, upon addition of pentanol, was also studied.

Amiloride↗
PubMed2004

Mechanisms involved in spironolactone-induced choleresis in the rat. Role of multidrug resistance-associated protein 2.

The mechanisms involved in spironolactone (SL, 200 micromol/kg body weight, 3 days i.p.)-induced choleresis were explored in vivo by evaluating bile salt export pump (Bsep)-, multidrug resistance-associated protein 2 (Mrp2)-, and anion exchanger 2 (AE2)-mediated secretory processes in rat liver. Hepatic bile salt metabolism was also analyzed. Total bile flow was significantly increased by SL, primarily due to an increase in bile salt-independent bile flow, whereas bile salt secretion was decreased. SL did not produce any choleresis in TR(-) rats. SL decreased the de novo bile salt synthesis rate in concordance with impaired microsomal cholesterol 7 alpha-hydroxylase activity, thus leading to a decrease in endogenous bile salt pool size. In contrast, the maximum secretory rate of tauroursodeoxycholate as well as expression of Bsep protein detected by Western blotting were not affected. Thus, decreased bile salt availability for canalicular transport rather than transport capability itself likely explains reduced biliary secretion of bile salts. Biliary secretion of glutathione, an endogenous substrate of Mrp2, and HCO(3)(-), the AE2 substrate, were increased by SL, as a main factor explaining enhanced bile salt-independent bile flow. Western blot studies revealed increased expression of Mrp2 in response to SL whereas AE2 content remained unchanged. Enhanced activity and expression of Mrp2 was confirmed by analyzing the excretion rate of dinitrophenyl S-glutathione, an exogenous substrate of Mrp2, in isolated hepatocytes and by immunofluorescence microscopy, respectively. We conclude that SL increased bile flow mainly by increasing the biliary secretion of glutathione species and HCO(3)(-); increased expression of Mrp2 is also involved.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure?

BACKGROUND: Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K(+) levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects. METHODS AND RESULTS: We investigated 125 consecutive patients with CHF recruited from our heart failure clinic. Inclusion criteria were LVEF (left ventricular ejection fraction) </=45% and treatment with SPL. Blood tests were performed bimonthly or more frequently if necessary. Outcomes measures were (1) increases in serum K(+) to >5,0, 5.5, 6.0, or 6.5 mmol/L, respectively, and (2) rise in serum creatinine to 120%, 150%, and 200% of baseline, respectively. Mean age was 72.9 years (range 46.5 to 90.6 years); 27% were women. The New York Heart Association class distribution was: I, 6%; II, 44%; III, 46%; and IV, 4%. Mean LVEF was 29+/-5%. Other medication included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 86% and beta-blockers in 39%. At baseline, serum creatinine levels were 117.6+/-6.5 (mean+/-standard deviation; micromol/L, normal <130) and serum K(+) was 4.2+/-0.3 mmol/L. The mean follow-up period was 11 months, and the cumulative observation period was 73 SPL treatment years. Mean peak serum-creatinine was 167.6 micromol/L+/-11.9 (45% increase from baseline) and mean peak serum K(+) was 5.0+/-0.4 mmol/L (21% increase from baseline). Sixty patients were already on SPL when admitted to the CHF clinic. The remainder were initiated on SPL. During the follow-up period 36% of the patients developed hyperkalemia (>5 mmol/L), with 10% having serum K(+) >6 mmol/L. An increase in serum creatinine of >20% was seen in 55%, and in 24% an increase of >50% was found. These alterations in serum creatinine and serum K(+) were not significantly more frequent in patients treated with angiotensin-converting enzyme inhibitors or beta-blockers or different doses of SPL. CONCLUSION: SPL adverse effects (impaired renal function, increase in serum K(+)) are much more prevalent in our elderly CHF patient population than previously reported. The recommendations from our study are that (1) particular caution is mandated in elderly patients with an LVEF <20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise concern, and (4) a dose-adjustment of the concomitant conventional diuretic regime should be considered. Care should be given to the frequent monitoring of electrolytes and renal parameters.

Aged↗
PubMed2006

Direct effects of 3 combinations of enalapril, metoprolol, and spironolactone on cardiac remodeling in dilated cardiomyopathic hamsters.

BACKGROUND: In congestive heart failure, enalapril (E), metoprolol (M), and spironolactone (S) improve survival. Their direct effects on cardiac remodeling, when administered in combination, remain to be assessed. METHODS AND RESULTS: One hundred and five cardiomyopathic hamsters were divided into 5 groups (control, E, E-M, E-S, E-M-S) and treated from 150 to 240 days of age (E: 3 mg/kg, M: 1 mg/kg, S: 20 mg/kg). Cardiac and systemic hemodynamics, and cardiac remodeling were investigated. There was no difference between groups on blood pressure. Compared with C, both S-treated groups significantly increased cardiac index (E-S: +49%; E-M-S: +46%). Compared with C, E significantly decreased left ventricular (LV) cavity area (-10%). Compared with E, all combinations significantly decreased LV cavity area (E-M: -13%, E-S: -22%, E-M-S: -19%) and right ventricular (RV) collagen density (E-M: -18%, E-S: -30%, E-M-S: -34%), and the tri-therapy significantly decreased LV collagen density (-18%). Compared with bi-therapies, the tri-therapy significantly decreased LV (-19% vs. E-M, -16% vs. E-S) and RV (-20% vs. E-M) collagen densities. CONCLUSION: At subdepressor doses, both bi-therapies induced similar effects on myocardial remodeling, enhancing the effects of E on LV cavity area and reducing RV collagen density. Compared with bi-therapies, the tri-therapy induced additional effects on LV and RV collagen densities.

Adrenergic beta-Antagonists↗
PubMed2004

Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells.

BACKGROUND: The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF. MATERIAL AND METHODS: We examined the effect of SPIR on in vitro cytokine production by human peripheral blood mononuclear cells (PBMC). PBMC were cultured with 10-1000 microM SPIR and stimulated with lipopolysaccharide or phytohaemagglutinin-P. Tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1beta, and interferon (IFN)-gamma were measured in culture supernatants by enzyme-linked immunosorbent assay and mRNA expression of the cytokines was determined by real-time reverse transcriptase polymerase chain reaction (PCR). RESULTS: SPIR inhibited the stimulated production of TNF-alpha, IL-6, and IFN-gamma, whereas the release of IL-1beta was not significantly affected. The SPIR-induced cytokine inhibition occurred at the transcriptional level and was independent of antimineralocorticoid and antiandrogen activities. CONCLUSION: The findings suggest that inhibited production of proinflammatory cytokines may be an extrarenal mechanism that contributes to the beneficial effect of SPIR in patients with CHF.

Aldosterone↗
PubMed2005

Isolation and identification of novel impurities in spironolactone.

Three known and five new steroidal compounds as impurities in spironolactone were isolated from the enriched mother liquor by using various chromatographic methods. Their structures were elucidated by spectrometric analysis. New compounds were characterized as 3-(3,3-dimethoxy-5 alpha,7 alpha-epidithio-17beta-hydroxy-4-androstan-17 alpha-yl) propionic acid gamma-lactone (6); 3-(3-oxo-7 alpha-acetylthio-6 beta,17beta-dihydroxy-4-androsten-17 alpha-yl) propionic acid gamma-lactone (7); 7 alpha-acetylthio-17beta-20-isopropylidendioxy-21-nor-17 alpha-pregn-4-en-3-one (8); 7 alpha-acetylthio-3-oxo-pregna-4,17(20)i-dien-22-oic acid methyl ester (9) and 7 alpha-acetylthio-17-methyl-18-nor-androsta-4-en-3-one (10).

Chromatography, High Pressure Liquid↗
PubMed2004

The 45-year story of the development of an anti-aldosterone more specific than spironolactone.

At the early stage of its development in 1957, the daily dose of spironolactone necessary to improve various pathological conditions was not precisely determined and dose-dependent sexual side effects limited its long-term use. Prescription of high daily doses and absence of selectivity for the mineralocorticoid receptor explain these limitations. The 9-11alpha epoxy group added to mexrenone by the Ciba-Geigy chemists in 1984 and improved chemical synthesis at Searle, permitted the original international clinical development of a selective antagonist for high blood pressure and congestive heart failure treatment. This review deals with the main methodological issues of a 20-year biological and clinical development of eplerenone, the second antimineralocorticoid drug. The investigation of a large range of daily doses (25-400mg) initially selected in normal volunteers by the 9alpha-fluorohydrocortisone test has led to the conclusion that 50-100mg q.i.d. doses of eplerenone offer a favorable benefit/risk ratio in various patient populations by neutralization of the aldosterone effects on blood pressure and target organ damage. The absence of sexual side-effects has confirmed the clinical relevance of the initial biological hypothesis on the need for more selectivity at the androgen and progestogen receptor sites. Widening the distance between efficacy and adverse effects of an anti-mineralocorticoid drug will facilitate the long-term maintenance of a moderately negative sodium balance and a slightly positive potassium balance, while minimizing the direct effects of salt and aldosterone on the heart, vessels, brain, and kidneys. Wide use in unselected patients and additional controlled clinical trials are necessary to confirm the benefits expected from animal and clinical research given that a 45-year interval also characterizes the story of the Na-Cl cotransporter (NCC) blocker, chlorthalidone, from its initial clinical use to the demonstration of its beneficial effects on cardiovascular morbidity and mortality.

Antihypertensive Agents↗
PubMed2005

Angiotensin II, angiotensin II antagonists and spironolactone and their modulation of cardiac repolarization.

Angiotensin II and aldosterone produce pro-arrhythmic effects by several mechanisms, including the modulation of voltage-dependent K(+) channels involved in human cardiac repolarization. Drugs that inhibit the renin-angiotensin-aldosterone system exert anti-arrhythmic actions that are related to the blockade of the pro-arrhythmic actions of angiotensin II and aldosterone. These anti-arrhythmic actions include inhibition of electrical and structural cardiac remodeling, inhibition of neurohumoral activation, reduction of blood pressure and stabilization of electrolyte disturbances. In this article, several angiotensin II AT(1) receptor antagonists (candesartan, E3174, eprosartan, irbesartan and losartan) and aldosterone receptor antagonists (canrenoic acid and spironolactone) that directly modulate the activity of the voltage-dependent K(+) channels are reviewed; the effects of these antagonists might be useful in the prevention and treatment of cardiac arrhythmias.

Angiotensin II↗