RESUMEN
Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Nefropatías Diabéticas/tratamiento farmacológico , Imidazoles/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Pirroles/uso terapéutico , Sulfonas/uso terapéutico , Tetrazoles/uso terapéutico , Albuminuria/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Imidazoles/farmacología , Masculino , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides/farmacología , Pirroles/farmacología , Sulfonas/farmacología , Tetrazoles/farmacologíaRESUMEN
The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.
Asunto(s)
Acetato de Desoxicorticosterona/efectos adversos , Hipertensión/inducido químicamente , Hipertensión/prevención & control , Riñón/efectos de los fármacos , Pirroles/farmacología , Receptores de Mineralocorticoides/metabolismo , Cloruro de Sodio Dietético/efectos adversos , Sulfonas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/patología , Riñón/lesiones , Riñón/metabolismo , Riñón/patología , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacología , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , RatasRESUMEN
The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5µM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/farmacología , Pirroles/farmacología , Receptores de Mineralocorticoides/efectos de los fármacos , Sulfonas/farmacología , Administración Oral , Adrenalectomía , Aldosterona/metabolismo , Aldosterona/farmacología , Animales , Antihipertensivos/farmacología , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Acetato de Desoxicorticosterona , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Eplerenona , Femenino , Células HEK293 , Humanos , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hipertensión/prevención & control , Masculino , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Potasio/orina , Unión Proteica , Pirroles/administración & dosificación , Pirroles/farmacocinética , Conejos , Ensayo de Unión Radioligante , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Sodio/orina , Espironolactona/análogos & derivados , Espironolactona/metabolismo , Espironolactona/farmacología , Sulfonas/administración & dosificación , Sulfonas/farmacocinética , Activación Transcripcional/efectos de los fármacos , Transfección , Agentes Urológicos/farmacología , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Liver X receptors (LXRs), LXRalpha and LXRbeta, are members of the nuclear receptor superfamily and regulate the expression of genes involved in the regulation of cholesterol and fatty acid metabolism. Human plasma, unlike mouse plasma, contains cholesteryl ester transfer protein (CETP), which plays an important role in reverse cholesterol transport (RCT). LXRs induce CETP transcription via a direct repeat 4 element in the CETP promoter. However, the specific roles of the individual LXR subtypes in CETP expression and their consequences on plasma lipoprotein metabolism are still unclear. Here we showed that synthetic LXR agonist enhanced plasma CETP activity and resulted in non-high density lipoprotein (non-HDL) increase and HDL decrease in cynomolgus monkeys and human CETP transgenic mice. To address the relative importance of the two LXR subtypes, we investigated the effect of the suppression of both LXR subtypes on CETP expression in HepG2 cells. CETP expression induced by the LXR agonist was significantly reduced by LXRalpha knock-down, but not by LXRbeta. Consistent with these data, CETP promoter activity was enhanced by LXRalpha activation, whereas LXRbeta activation had only a minor effect. Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes in human CETP transgenic mice. LXRalpha deficiency abolished the augmentation of plasma CETP activity and hepatic CETP expression induced by the synthetic LXR agonist, consequently increasing HDL and decreasing non-HDL, whereas LXRbeta deficiency did not affect CETP activation. These findings indicate that LXRalpha has an essential role in the regulation of CETP expression and maintaining RCT.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Lípidos/sangre , Receptores Nucleares Huérfanos/metabolismo , Animales , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Relación Dosis-Respuesta a Droga , Ayuno/sangre , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Hidrocarburos Fluorados/farmacología , Lipoproteínas HDL/sangre , Receptores X del Hígado , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/deficiencia , Receptores Nucleares Huérfanos/genética , Regiones Promotoras Genéticas , Interferencia de ARN , ARN Mensajero/metabolismo , Sulfonamidas/farmacología , TransfecciónRESUMEN
High-density lipoprotein (HDL) has a protective effect against atherosclerosis. Therefore, a compound that elevates the plasma HDL cholesterol (HDL-C) levels is expected to be a promising anti-atherosclerotic agent. We discovered a novel compound, R-138329, that increased HDL-C by 41% in normolipidemic hamsters at a dose of 100mg/kg. To investigate the mechanism of action of R-138329, we examined the effect of R-138329 on the clearance of [(3)H]cholesterol ether ([(3)H]COE)-labeled and [(125)I]-labeled HDL in mice. R-138329 delayed the clearance of [(3)H]COE-labeled HDL and reduced accumulation of tracer HDL in the liver, whereas the clearance of [(125)I]-labeled HDL particles was unaffected by the compound. In vitro analysis showed that R-154716, a metabolite of R-138329, dramatically inhibited the uptake of [(3)H]COE-labeled HDL in McA-RH 7777 rat hepatoma cells. Furthermore, 100 nM of R-154716 completely inhibited [(3)H]COE-labeled HDL uptake induced by overexpression of scavenger receptor BI (SR-BI) in HEK293 cells. Taken together, these findings suggest that the mechanism by which R-138329 elevates HDL-C in vivo is principally involved in the inhibition of SR-BI-mediated selective lipid uptake in the liver.
Asunto(s)
Antígenos CD36/efectos de los fármacos , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , Piperazinas/farmacología , Receptores Depuradores de Clase B/antagonistas & inhibidores , Animales , Línea Celular Transformada , HDL-Colesterol/química , Cricetinae , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Mesocricetus , Ratones , Piperazinas/farmacocinética , Ratas , Receptores Depuradores de Clase B/efectos de los fármacos , Receptores Depuradores de Clase B/genéticaRESUMEN
The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Apolipoproteínas E/deficiencia , Aterosclerosis/tratamiento farmacológico , Ácidos Indolacéticos/uso terapéutico , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Anticolesterolemiantes/farmacología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Línea Celular , Humanos , Ácidos Indolacéticos/farmacología , Lípidos/sangre , Ratones , Ratones Noqueados , Monocitos/efectos de los fármacosRESUMEN
Liver X receptors (LXR alpha and LXR beta) are nuclear receptors, which are important regulators of cholesterol and lipid metabolism. LXRs control genes involved in cholesterol efflux in macrophages, bile acid synthesis in liver and intestinal cholesterol absorption. LXRs also regulate genes participating in lipogenesis. To determine whether the activation of LXR promotes or inhibits development of atherosclerosis, T-0901317, a synthetic LXR ligand, was administered to low density lipoprotein receptor (LDLR)(-/-) mice. T-0901317 significantly reduced the atherosclerotic lesions in LDLR(-/-) mice without affecting plasma total cholesterol levels. This anti-atherogenic effect correlated with the plasma concentration of T-0901317, but not with high density lipoprotein cholesterol, which was increased by T-0901317. In addition, we observed that T-0901317 increased expression of ATP binding cassette A1 in the lesions in LDLR(-/-) mice as well as in mouse peritoneal macrophages. T-0901317 also significantly induced cholesterol efflux activity in peritoneal macrophages. These results suggest that LXR ligands may be useful therapeutic agents for the treatment of atherosclerosis.