Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the extent to which dietary sodium modulates aldosterone-induced cardiovascular damage, and to determine whether increased dietary potassium can prevent this damage, we used the Nomega-nitro-L-arginine methyl ester (L-NAME)/angiotensin II (Ang II) rat model of cardiac injury. This model is dependent on the presence of aldosterone for the occurrence of myocardial damage. Two sets of experiments were performed. In the first set, the following groups were studied: (1) 1% NaCl to drink (control group); (2) L-NAME/Ang II with water to drink (low salt group); (3) L-NAME/Ang II/1% NaCl (high salt group); (4) L-NAME/Ang II/1% NaCl/eplerenone (eplerenone group). Systolic blood pressure increased similarly in all groups compared with controls. Compared with the controls, the high salt group, but not the low salt or eplerenone groups, developed significant myocardial damage. In the second set of experiments three groups of animals were studied: (1) L-NAME/Ang II/1%NaCl (high salt group) (2) L-NAME/Ang II/1%NaCl/eplerenone (eplerenone group), and (3) L-NAME/Ang II/1%NaCl with an extra 1% KCl in food (high dietary potassium group). Eplerenone, but not dietary potassium supplementation, prevented the development of cardiac damage. Thus, mineralocorticoid receptor antagonist treatment and low sodium diet were effective in preventing cardiac damage, which suggests that a minimal level of aldosterone and a moderately high sodium diet are both required for the development of the cardiovascular damage in the L-NAME/Ang II model. The inability of potassium supplementation to reduce myocardial damage suggests that eplerenone's protective effect is not due to its potassium-sparing ability, but is rather related to some other feature of its selective aldosterone antagonism.
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PMID:Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. 1188 18

Aldosterone has been suggested to elicit vessel contraction via a nongenomic mechanism. We tested this proposal in microdissected, perfused rabbit renal afferent arterioles. Aldosterone had no effect on internal diameter in concentrations from 10(-10) to 10(-5) mol/L, but aldosterone abolished the ability of 100 mmol/L KCl to induce vascular contraction. The inhibitory effect of aldosterone was observed from 1 pmol/L. The inhibitory effect was significant after 5 minutes and maximal after 20 minutes and was fully reversible. Actinomycin D (10(-6) mol/L) prolonged the effect of aldosterone. The effect was abolished by the mineralocorticoid receptor antagonist spironolactone (10(-7) mol/L) but not by the glucocorticoid receptor antagonist mifepristone (10(-6) mol/L). The K+-mediated increase of intracellular calcium concentration in afferent arterioles was not affected by aldosterone. Mineralocorticoid receptor was detected by reverse transcription-polymerase chain reaction and immunohistochemistry in rat renal vasculature and rabbit endothelial cells. Inhibition of phosphatidylinositol (PI)-3 kinase with LY 294002 (3x10(-6) mol/L) restored sensitivity to K+ in the presence of aldosterone, and afferent arterioles were immunopositive for PI-3 kinase subunit p110alpha. Inhibition of NO formation by L-NAME (10(-4) mol/L) or inhibition of soluble guanylyl cyclase with 1H-(1,2,4)Oxadiazolo[4,3-a]quinoxaline-1-one restored K+-induced vasoreactivity in the presence of aldosterone. Similar to aldosterone, the NO donor sodium nitroprusside inhibited K+-induced vascular contraction. Geldanamycin (10(-6) mol/L), an inhibitor of heat shock protein 90, abolished aldosterone-induced vasorelaxation. We conclude that aldosterone inhibits depolarization-induced vasoconstriction in renal afferent arterioles by a rapid nongenomic mechanism that is initiated by mineralocorticoid receptor activation and involves PI-3 kinase, protein kinase B, and heat shock protein 90-mediated stimulation of NO generation.
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PMID:Rapid inhibition of vasoconstriction in renal afferent arterioles by aldosterone. 1461 88

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and "pill hypertension" in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin-angiotensin-aldosterone (RAAS) system. Drospirenone (DRSP: 6beta,7beta,15beta,16beta-dimethylene-3-oxo 17alpha-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1-3mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after L-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5-4 mg per day) in humans. Combined with EE (3 mg DRSP+30 microg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day+15, 20, or 30 microg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research.
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PMID:Conception and pharmacodynamic profile of drospirenone. 1466 81

There is considerable evidence in the setting of cardiovascular disease to suggest that, in addition to the classic effects of aldosterone on sodium retention, blood volume, blood pressure and potassium homeostasis, aldosterone is involved in fibrotic end-organ damage by means of intermediate mechanisms involving an interplay between the mineralocorticoid receptor, sodium intake and a variety of molecular messengers. Such processes may help to explain the reduction in mortality that can be achieved in patients with severe heart failure and post-myocardial infarction by the addition of an aldosterone receptor antagonist to standard therapy. Studies in animal models treated with the nitric oxide inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), angiotensin II and salt, with and without adrenalectomy, have demonstrated that myocardial damage can be eliminated by adrenalectomy or by administering an aldosterone receptor antagonist and is induced by adding back aldosterone to adrenalectomized animals. Importantly, at least a modest salt intake is an obligate co-factor. Other animal studies have established that an early stage in aldosterone-associated myocardial damage involves the release of proinflammatory molecules, including cyclo-oxygenase type 2, osteopontin and monocyte chemoattractant protein-1. Taken together, these findings suggest that aldosterone in the presence of salt intake is a major cardiovascular risk factor mediated by inflammatory and fibrotic processes. Thus, mineralocorticoid receptor antagonists are likely to be effective additional agents to treat a broad range of cardiovascular diseases.
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PMID:Cardiovascular benefits of aldosterone receptor antagonists. 1501 46

Although angiotensin-converting enzyme (ACE) inhibitors are well-established drugs in the treatment of hypertension, they are not supposed to be sufficient in the inhibition of aldosterone formation. The present study analyzes the effect of aldosterone receptor antagonist, spironolactone and ACE inhibitor, captopril on nitric oxide (NO) and S-nitrosothiol formation in the kidney of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Male Wistar rats were divided into six groups: (1) controls, (2) L-NAME (40 mg/kg/day), (3) spironolactone (200 mg/kg/day), (4) captopril (100 mg/kg/day), (5) L-NAME+spironolactone, and (6) L-NAME+captopril. After 4 weeks, NO synthase (NOS) activity, protein expression of endothelial NOS, inducible NOS and concentration of thiol and S-nitrosothiol groups were determined in the kidney. Besides the increase in systolic blood pressure (by 32%) and the decrease in NOS activity (by 37%), L-NAME treatment lowered the concentration of thiols (by 32%) and S-nitrosothiols (by 36%) in the renal tissue. Simultaneous treatment with spironolactone preserved NOS activity and S-nitrosothiols on the control level, whereas captopril did not affect these parameters modified by L-NAME treatment. Moreover, spironolactone increased expression of endothelial NOS protein without affecting inducible NOS protein expression. In conclusion, both captopril and spironolactone prevented L-NAME-induced hypertension and the decline of the antioxidant potential of the kidney tissue. However, only spironolactone improved NOS activity which led to the S-nitrosothiols formation. Both NO itself and S-nitrosothiols may contribute to the preventive effect of spironolactone against development of L-NAME-induced hypertension.
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PMID:Effect of spironolactone and captopril on nitric oxide and S-nitrosothiol formation in kidney of L-NAME-treated rats. 1671 Mar 50

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.
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PMID:The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats. 1676 Nov 90

N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension is associated with protein remodeling of the left ventricle. The aim of the study was to show, whether aldosterone receptor blocker spironolactone and precursor of NO-production L-arginine were able to reverse the protein rebuilding of the left ventricle. Six groups of male Wistar rats were investigated: control 4 (4 weeks placebo), L-NAME (4 weeks L-NAME), spontaneous-regression (4 weeks L-NAME + 3 weeks placebo), spironolactone-regression (4 weeks L-NAME + 3 weeks spironolactone), L-arginine-regression (4 weeks L-NAME + 3 weeks arginine), control 7 (7 weeks placebo). L-NAME administration induced hypertension, hypertrophy of the left ventricle (LV), and the increase of metabolic and contractile as well as soluble and insoluble collagenous protein concentration. The systolic blood pressure and relative weight of the LV decreased in all three groups with regression, while the most prominent attenuation of the LVH was observed after spironolactone treatment. In the spontaneous-regression and L-arginine-regression groups the concentrations of individual proteins were not significantly different from the control value. However, in the spironolactone-regression group the concentration of metabolic, contractile and insoluble collagenous proteins remained significantly increased in comparison with the control group. The persistence of the increased protein concentration in the spironolactone group may be related to the more prominent reduction of myocardial water content by spironolactone.
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PMID:Spontaneous, L-arginine-induced and spironolactone-induced regression of protein remodeling of the left ventricle in L-NAME-induced hypertension. 1782 6

Aldosterone receptor antagonist, spironolactone, has been shown to prevent remodeling of the heart in several models of left ventricular hypertrophy. The aim of the present study was to determine whether the treatment with spironolactone can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) and aortic remodeling in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Four groups of rats were investigated: control, spironolactone (200 mg/kg), L-NAME (40 mg/kg) and L-NAME + spironolactone (in corresponding dosage). Animals were studied after 5 weeks of treatment. The decrease of NO-synthase activity in the LV and kidney was associated with the development of hypertension and LV hypertrophy, with increased DNA concentration in the LV, and remodeling of the aorta in the L-NAME group. Spironolactone prevented the inhibition of NO-synthase activity in the LV and kidney and partially attenuated hypertension and LVH development and the increase in DNA concentration. However, remodeling of the aorta was not prevented by spironolactone treatment. We conclude that the aldosterone receptor antagonist spironolactone improved nitric oxide production and partially prevented hypertension and LVH development without preventing hypertrophy of the aorta in NO-deficient hypertension. The reactive growth of the heart and aorta seems to be controlled by different mechanisms in L-NAME-induced hypertension.
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PMID:Spironolactone differently influences remodeling of the left ventricle and aorta in L-NAME-induced hypertension. 1782 10

Chronic inhibition of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (L-NAME) causes progressive renal injury with systemic hypertension and interstitial macrophage infiltration. We have previously shown that there is local activation of the renin-angiotensin-aldosterone system in the renal cortex as a major pathogenic feature of macrophage infiltration. In this study, we measured the effects of the aldosterone antagonist, spironolactone, on renal injury in L-NAME-treated male Wistar rats. After 12 weeks of L-NAME-treatment, rats had increased systolic blood pressure, urinary protein excretion, and serum creatinine and histological analysis showed glomerulosclerosis, interstitial fibrosis, and macrophage infiltration. Treatment with spironolactone significantly prevented these renal changes, whereas treatment with hydralazine had no effect. The cortical expression of osteopontin was significantly elevated in L-NAME-treated rats, and expression of its mRNA significantly correlated with the number of infiltrating macrophages and degree of interstitial fibrosis. Spironolactone treatment markedly suppressed osteopontin expression. Our results suggest that reduced nitric oxide bioavailability caused renal inflammation and fibrosis through an aldosterone receptor-dependent mechanism associated with osteopontin expression independent of its systemic hemodynamic effects.
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PMID:Spironolactone suppresses inflammation and prevents L-NAME-induced renal injury in rats. 1911 42

Caveolae are the major cellular membrane structure through which extracellular mediators transmit information to intracellular signaling pathways. In vascular tissue (but not ventricular myocardium), caveolin-1 (cav-1) is the main component of caveolae; cav-1 modulates enzymes and receptors, such as the endothelial nitric oxide synthase and the angiotensin II (AngII) type 1 receptor. Evidence suggests that AngII and aldosterone (ALDO) are important mediators of ventricular injury. We have described a model of biventricular damage in rodents that relies on treatment with N-omega-nitro-l-arginine methyl ester (L-NAME (nitric oxide synthase inhibitor)) and AngII. This damage initiated at the vascular level and was observed only in the presence of ALDO and an activated mineralocorticoid receptor (MR). We hypothesize that cav-1 modulates the adverse cardiac effects mediated by ALDO in this animal model. To test this hypothesis, we assessed the ventricular damage and measures of inflammation, in wild-type (WT) and cav-1 knockout (KO) mice randomized to either placebo or L-NAME/AngII treatment. Despite displaying cardiac hypertrophy at baseline and higher blood pressure responses to L-NAME/AngII, cav-1 KO mice displayed, as compared with WT, decreased treatment-induced biventricular damage as well as decreased transcript levels of the proinflammatory marker plasminogen activator inhibitor-1. Additionally, L-NAME/AngII induced an increase in cardiac MR levels in WT but not cav-1-ablated mice. Moreover and despite similar circulating ALDO levels in both genotypes, the myocardial damage (as determined histologically and by plasminogen activator inhibitor-1 mRNA levels) was less sensitive to ALDO levels in cav-1 KO vs. WT mice, consistent with decreased MR signaling in the cav-1 KO. Thus, we conclude that the L-NAME/AngII-induced biventricular damage is mediated by a mechanism partially dependent on cav-1 and signaling via MR/ALDO.
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PMID:Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II. 2009 17


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