RESUMO
BACKGROUND AND PURPOSE: Adding spironolactone to standard therapy in heart failure reduces morbidity and mortality, but the underlying mechanisms are not fully understood. We analysed the effect of canrenone, the major active metabolite of spironolactone, on myocardial contractility and intracellular calcium homeostasis. EXPERIMENTAL APPROACH: Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca(2+) transients by fluorescence and Ca(2+) fluxes by electrophysiological techniques. KEY RESULTS: Canrenone (300-600 micromol L(-1)) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 micromol L(-1)) reduced cell shortening and L-type Ca(2+) channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca(2+) content of the sarcoplasmic reticulum, intracellular Ca(2+) transient amplitude and intracellular diastolic Ca(2+) concentration. However, the time course of [Ca(2+)](i) decline during transients evoked by caffeine was not affected by canrenone. CONCLUSION AND IMPLICATIONS: Canrenone reduced L-type Ca(2+) channel current, amplitude of intracellular Ca(2+) transients and Ca(2+) content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.
Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Cálcio/metabolismo , Canrenona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Animais , Cafeína/farmacologia , Canais de Cálcio Tipo L/metabolismo , Canrenona/administração & dosagem , Relação Dose-Resposta a Droga , Homeostase , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/metabolismo , Ratos , Ratos Wistar , Retículo Sarcoplasmático/metabolismo , Espironolactona/metabolismoRESUMO
Apos uma avaliacao inicial, 25 pacientes com sindrome dos ovarios policisticos (SOP) foram submetidas a teste de tolerancia a glicose oral com dosagens de glicose e insulina. Treze pacientes foram tratadas com espironolactona, 200 mg/dia por 6 meses e reavaliadas aos 3 e 6 meses. Concluimos que : 1- a SOP esta associada com a resistencia a insulina; 2- insulinemia de jejum nao e suficiente para o diagnostico; 3- mulheres obesas com acanthosis nigricans sao mais resistentes a insulina e 4- o uso de um antiandrogenio melhora a...
Assuntos
Humanos , Feminino , Resistência à Insulina , Insulina/metabolismo , Síndrome do Ovário Policístico/metabolismo , Diagnóstico Diferencial , Hiperandrogenismo/metabolismo , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/metabolismo , Síndrome do Ovário Policístico/diagnóstico , Espironolactona/análise , Espironolactona/metabolismoRESUMO
In the rat, the conformationally highly bent steroid 21-hydroxy-6, 19-oxidoprogesterone efficiently displaces [3H]corticosterone from thymus-glucocorticoid receptors and blocks type II receptors in kidney cytosols but competes with neither [3H]aldosterone for kidney-mineralocorticoid receptors nor [3H]progesterone for uterus-progesterone receptors. It evokes Na+ retention only at very high doses (approximately 100 microg/100 g of rat weight) and is unable to induce tyrosine aminotransferase or to increase glycogen deposits in rat liver. When coincubated with corticosterone or dexamethasone, 2.5 microM 21OH-6OP inhibits 80% of tyrosine aminotransferase induction. It may therefore be used experimentally as an antiglucocorticoid virtually lacking mineralocorticoid or glucocorticoid properties as well as affinity for mineralocorticoid or progesterone receptors.
Assuntos
Progesterona/análogos & derivados , Receptores de Glucocorticoides/antagonistas & inibidores , Aldosterona/metabolismo , Androstanóis/metabolismo , Animais , Rim/metabolismo , Masculino , Progesterona/química , Progesterona/metabolismo , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espironolactona/análogos & derivados , Espironolactona/metabolismo , Relação Estrutura-Atividade , Timo/metabolismo , Transcortina/metabolismo , TrítioRESUMO
Spironolactone (SL) is a mineralocorticoid antagonist used clinically to treat hypertension and congestive heart failure. Its mechanism of action involves competitive binding to aldosterone receptors in the kidneys, resulting in diuresis. It is known that the actions of SL are mediated by metabolites of the drug, but the active metabolites have not been definitively identified. Accordingly, studies were done to determine which metabolites bind to renal mineralocorticoid receptors after SL administration to guinea pigs. The major metabolite found in the steroid receptor fraction of kidney cytosol was 7 alpha-thiomethyl-SL (TM). Incubation of kidney cytosol with varying concentrations (0-100 pmol/l) of aldosterone resulted in the concentration-dependent displacement of TM from the steroid receptor fraction. The steroid receptor fraction from renal nuclei of SL-treated animals contained approximately equal concentrations of TM, 7 alpha-thio-SL (TH), and canrenone (CAN). Incubation of kidney nuclei with aldosterone caused a concentration-dependent displacement of all three metabolites. The results indicate that TM is the major SL metabolite that interacts with cytosolic mineralocorticoid receptors in kidneys, but that TH and CAN may contribute to nuclear receptor binding.
Assuntos
Aldosterona/metabolismo , Rim/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espironolactona/metabolismo , Animais , Ligação Competitiva , Canrenona/metabolismo , Cobaias , Masculino , Espironolactona/administração & dosagem , Espironolactona/análogos & derivadosRESUMO
Type I corticosteroid receptors were determined in cytosol from hippocampus (HIPPO) and amygdala (AMYG), using [3H]aldosterone (ALDO), [3H]dexamethasone (DEX) or the mineralocorticoid antagonist [3H]ZK 91587 as ligands. Incubations with the first two compounds also contained the pure glucocorticoid RU 28362 to block type II receptors. Binding of the three ligands was comparable in cytosol from HIPPO and it was slightly higher for [3H]DEX in AMYG. However, after heat-induced receptor transformation, binding to DNA-cellulose was observed for [3H]ALDO-receptor complex obtained from HIPPO or AMYG, whereas it was negligible for [3H]ZK 91587. Receptors charged with [3H]DEX or [3H]ALDO showed similar retention on DNA-cellulose columns in the case of the AMYG, while binding to the polynucleotide was higher for [3H]ALDO in the HIPPO. Finally, only [3H]ALDO was taken up to a significant extent in purified cell nuclei prepared from slices of HIPPO and AMYG previously incubated with the three ligands. It is concluded that binding of a natural agonist steroid may be a prerequisite for type I receptor transformation and translocation from the cytoplasm into the nuclear fraction. DEX binding to type I receptors resembles a partial agonist with antagonist properties, whereas antagonists such as ZK 91587 are bound and retained in cytoplasm, without further translocation.
Assuntos
Tonsila do Cerebelo/metabolismo , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Aldosterona/química , Aldosterona/metabolismo , Animais , Núcleo Celular/metabolismo , Celulose/análogos & derivados , Celulose/metabolismo , Técnicas de Cultura , DNA/metabolismo , Dexametasona/química , Dexametasona/metabolismo , Masculino , Mineralocorticoides/antagonistas & inibidores , Ratos , Ratos Endogâmicos , Espironolactona/análogos & derivados , Espironolactona/química , Espironolactona/metabolismoRESUMO
We have studied type I and type II adrenal cortical steroid receptors in the anterior (AL), intermediate (IL) and posterior (PL) lobes of the pituitary and in the hippocampus of ovariectomized-adrenalectomized female rats and in castrated-adrenalectomized male animals, with or without oestrogen treatment. Using [3H]dexamethasone as ligand and conditions suitable for determination of its binding to type I and type II receptors, we found that 4 or 15 days of oestrogen reduced type I receptors in AL by 50-60% without changes in IL, PL or hippocampus, or in type II sites in any of the four neuroendocrine tissues studied. This down-regulatory effect was seen only in female rats and no change was found for males. The reduction in type I sites in AL in oestrogenized female rats was confirmed by labelling type I sites with the synthetic antimineralocorticoid [3H]ZK 91587. Saturation analysis with [3H]ZK 91587 demonstrated that the reduction was due to a reduction in Bmax without change in Kd. We conclude that: (a) type I receptors in the anterior pituitary are under oestrogenic control; (b) there is a sex difference in the response to oestrogen of AL type I sites; and (c) this demonstration may be useful in determining the role of type I receptors in neuroendocrine regulation of the anterior pituitary by hormones derived from the adrenal cortex, and the participation of sex hormones in this process.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estradiol/farmacologia , Adeno-Hipófise/efeitos dos fármacos , Receptores do Hormônio Hipofisário/efeitos dos fármacos , Adrenalectomia , Animais , Castração , Dexametasona/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Mineralocorticoides/antagonistas & inibidores , Adeno-Hipófise/metabolismo , Neuro-Hipófise/efeitos dos fármacos , Neuro-Hipófise/metabolismo , Ratos , Ratos Endogâmicos , Receptores da Corticotropina , Receptores do Hormônio Hipofisário/classificação , Receptores do Hormônio Hipofisário/metabolismo , Fatores Sexuais , Espironolactona/análogos & derivados , Espironolactona/metabolismoRESUMO
We have studied the binding of the synthetic antimineralocorticoid [3H]ZK 91587 to soluble receptors in brain of adrenalectomized rats. It was observed that [3H]ZK 91587 labeled a single receptor class with high affinity (Kd 1.3 nM) and low capacity (51.1 fmol/mg prot.) in cytosol of hippocampus (HIPPO). The ligand was efficiently displaced in vitro from the receptor by aldosterone (IC50 2.0 nM) and corticosterone (2.3), while dexamethasone showed less potency (IC50 5.1 nM) and the pure antiglucocorticoid RU 28362 competed weakly (161 nM). Furthermore, there was a widespread distribution of binding sites all over the brain for this compound, but with CA1 and CA3 regions of HIPPO, some amygdaloid nuclei and lateral septum containing most of the binding sites, as revealed by binding assays employing 16 different microdissected brain regions. Finally, the receptor labeled with [3H]ZK 91587 was readily displaced by administration of aldosterone in vivo in physiological amounts, from 5 whole brain regions examined, but preferentially from preoptic area, amygdala and HIPPO. It is concluded that [3H]ZK 91587 is a useful ligand for further studies on putative mineralocorticoid responsive cells in brain, due to its high affinity, stability and lack of cross reactivity with glucocorticoid receptors. Its brain distribution is similar to that previously obtained using [3H]aldosterone in the presence of RU 28362 to block ligand binding to the glucocorticoid receptor.
Assuntos
Encéfalo/metabolismo , Mineralocorticoides/antagonistas & inibidores , Receptores de Esteroides/metabolismo , Espironolactona/análogos & derivados , Adrenalectomia , Aldosterona/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Ligação Competitiva , Corticosterona/metabolismo , Hipocampo/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides , Ratos , Ratos Endogâmicos , Receptores de Mineralocorticoides , Receptores de Esteroides/antagonistas & inibidores , Septo Pelúcido/metabolismo , Espironolactona/metabolismo , Distribuição TecidualAssuntos
Insuficiência Cardíaca/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Receptores de Esteroides/metabolismo , Espironolactona/efeitos adversos , Adolescente , Adulto , Arritmias Cardíacas/etiologia , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Humanos , Hiperaldosteronismo/etiologia , Hiperpotassemia/etiologia , Hiponatremia/etiologia , Masculino , Pessoa de Meia-Idade , Receptores de Mineralocorticoides , Renina/sangue , Espironolactona/metabolismo , Espironolactona/uso terapêuticoRESUMO
It is presented a case with mitral and tricuspid rheumatic valvulopathy and refractory chronic congestive heart failure, which developed two episodes of severe hyponatremia and hyperkalemia, accompanied in at least one occasion of hyperpreninemia and hyperaldosteronism, after administration of 50 and 100 mg of sprionolactone for 2 and 3 weeks. It is believed that this severe effect of spironolactone was due to the presence of an alteration of aldosterone receptors acquired during the large period of congestive failure suffered by the patient. In as much as we have studied 4 similar cases in the last few months, a note of warning is done in the use of this drug in the treatment of this type of cardiac condition.