endothelin-1 and Hyperaldosteronism

Although human association studies suggest a link between polymorphisms in the gene encoding transforming growth factor (TGF) β1 and differing blood pressure levels, a causative mechanism for this correlation remains elusive. Recently we have generated a series of mice with graded expression of TGFβ1, ranging from approximately 10% to 300% compared to normal. We have found that blood pressure and plasma volume are negatively regulated by TGFβ1. Of note, the 10% hypomorph exhibits primary aldosteronism and markedly impaired urinary excretion of water and electrolytes. We here review previous literature highlighting the importance of TGFβ signaling as a natriuretic system, which we postulate is a causative mechanism explaining how polymorphisms in TGFβ1 could influence blood pressure levels.

Topics: Adrenal Cortex Hormones; Animals; Blood Pressure; Electrolytes; Endothelin-1; Humans; Hyperaldosteronism; Hypertension; Mice; Nitric Oxide; Plasma Volume; Renin-Angiotensin System; Sodium; Transforming Growth Factor beta1

Essential hypertension probably results from combinations of small genetic variations that are partly normal variations and may not be appreciably harmful individually. Strategies to identify genes contributing to hypertension are discussed in this review. Gene targeting approaches, especially gene titration, have been used in these studies of hypertension. Gene titration experiments vary the expression of a chosen gene product by generating animals having different numbers of copies of the gene coding for the product. Gene titration is powerful for analyzing quantitative variations seen in common polygenic disorders, such as kidney diseases, diabetes mellitus, and atherosclerosis, as well as hypertension, because it allows tests of causation by determining the effects on a phenotype by changes in expression of the altered gene and because it matches normal quantitative variations more closely than is possible with classic transgenic mice. The use of zero-copy (gene "knockout") animals generated by gene disruption for studies of qualitative gene effects is also discussed. These various gene targeting experiments help identify genes regulating BP, promote a better understanding of the pathophysiology of the condition, and help identify potential targets for therapies.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Endothelin-1; Gene Targeting; Humans; Hyperaldosteronism; Hypertension; Mice; Mice, Knockout; Models, Genetic; Mutation; Nitric Oxide Synthase; Receptor, Bradykinin B2; Receptors, Bradykinin; Renin-Angiotensin System; Syndrome

We asked whether plasma concentrations of endothelin-1 (ET-1) or adrenomedullin (ADM) are altered by different activity states of the renin-angiotensin-aldosterone system (RAAS). Levels of ET-1 and ADM were studied in patients with primary aldosteronism (n = 15), essential hypertension (n = 15), and adrenal insufficiency (n = 7). Effects of fludrocortisone, dexamethasone, or spironolactone treatment on ET-1 and ADM levels were also analyzed. Plasma ET-1 and ADM concentrations did not differ significantly between the patient groups. After fludrocortisone, dexamethasone, or spironolactone treatment, both ET-1 and ADM did not change significantly. The data support the hypothesis that the RAAS is not directly linked with the ET-1/ADM system.

Topics: Adrenal Insufficiency; Adrenomedullin; Adult; Anti-Inflammatory Agents; Biomarkers; Dexamethasone; Diuretics; Endothelin-1; Female; Fludrocortisone; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Renin-Angiotensin System; Spironolactone

Visceral adiposity and insulin resistance are common pathophysiological denominators in patients with primary aldosteronism. Although we recently reported the antidiabetic effects of heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX) deoxycorticosterone acetate (DOCA-salt) hypertensive rats, a model of human primary aldosteronism characterized by elevated endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer heme arginate and the HO blocker chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX DOCA-salt rats. UnX DOCA-salt rats were hypertensive but normoglycemic. Heme arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor κB (NF-κB), activating-protein (AP-1), c-Jun-NH2-terminal kinase (JNK), macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and 8-isoprostane. These were associated with reduced glycemia, increased insulin, and the insulin-sensitizing protein adiponectin, with corresponding reduction in insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of heme arginate, aggravating insulin resistance, suggesting a role for the HO system in insulin signaling. Importantly, the effects of the HO system on ET-1, NF-κB, AP-1, JNK, MCP-1, and ICAM-1 in visceral or retroperitoneal adiposity in UnX-DOCA-salt rats have not been reported. Because 8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete adiponectin and insulin levels, the suppression of oxidative/inflammatory mediators such as 8-isoprostane, NF-κB, AP-1, MCP-1, ICAM-1, and JNK, an inhibitor of insulin biosynthesis, may account for the potentiation of insulin signaling/glucose metabolism by heme arginate. These data indicate that although UnX DOCA-salt rats were normoglycemic, insulin signaling was impaired, suggesting that dysfunctional insulin signaling may be a forerunner to overt diabetes in primary aldosteronism.

Topics: Adiposity; Animals; Arginine; Chemokine CCL2; Disease Models, Animal; Endothelin-1; Enzyme Activators; Gene Expression; Glucose; Heme; Heme Oxygenase (Decyclizing); Humans; Hyperaldosteronism; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Intra-Abdominal Fat; JNK Mitogen-Activated Protein Kinases; Male; Mesoporphyrins; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcription Factor AP-1

Endothelin-1 (ET-1) may function as an aldosterone secretagogue and, in turn, aldosterone can upregulate ET-1 expression. Hence, the existence of a feedforward loop involving ETs and aldosterone has been speculated in primary aldosteronism (PA). In the present study, we sought to examine ET-1 secretion from the adrenal glands in patients with PA.. We determined ET-1 levels in blood samples obtained during adrenal venous sampling of patients affected by PA (n=17). Furthermore, we examined the mRNA expression of the ET system in tissue samples from aldosterone-producing adenomas (APAs, n=9) and control normal adrenals (n=3).. Blood ET-1 levels were determined by RIA. Tissue mRNA expression of the ET system was assayed with Affymetrix microarrays.. ET-1 levels did not differ between inferior vena cava and adrenal vein blood in both bilateral adrenal hyperplasia and APA patients. Moreover, cortisol-normalized ET-1 levels did not show lateralized adrenal ET-1 secretion in APAs. Through gene expression profiling with microarray performed in a distinct set of APA individuals (n=9), we confirmed the adrenal expression of a complete ET system, but we did not detect a significant upregulation of ET components within the APA tissue compared with normal adrenals.. The present data argue against the hypothesis of increased ET-1 secretion from APAs and do not support a general role for adrenal ET-1 in the vascular pathophysiology of PA.

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenal Glands; Aged; Aldosterone; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Female; Humans; Hyperaldosteronism; Male; Metalloendopeptidases; Middle Aged; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (> or = 7.1 + or - 2.6 microg ANG I.ml(-1).h(-1) vs. < or = 0.07 + or - 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 + or - 0.02 vs. 0.2 + or - 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 + or - 51 vs. 160 + or - 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 + or - 0.04 vs. 3.1 + or - 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 + or - 0.08 vs. 0.75 + or - 0.007; P < 0.001), NADP oxidase-2 (1.03 + or - 0.006 vs. 0.76 + or - 0.04; P < 0.001), transforming growth factor-beta (0.99 + or - 0.06 vs. 0.84 + or - 0.04; P < 0.05), collagen type I (1.32 + or - 0.32 vs. 0.94 + or - 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 + or - 0.12 vs. 0.84 + or - 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.

Topics: Administration, Oral; Aldosterone; Animals; Cardiomegaly; Collagen Type I; Cytochrome P-450 CYP1A1; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Hyperaldosteronism; Hypertension; Indoles; Intercellular Adhesion Molecule-1; Magnetic Resonance Imaging; Membrane Glycoproteins; Mice; Myocardium; NADPH Oxidase 2; NADPH Oxidases; Phosphorylation; Promoter Regions, Genetic; Rats; Rats, Inbred F344; Rats, Transgenic; Renin; RNA, Messenger; Time Factors; Transforming Growth Factor beta

The aim of the study was to evaluate possible changes of plasma endothelin-1 levels (ET-1) in patients with hypertension secondary to primary aldosteronism and pheochromocytoma. We enrolled in the study: 12 patients affected by aldosterone-producing adenoma (5 M and 7 W; mean age 42.1 +/- 17.2 years); 8 patients with pheochromocytoma (5 M, 3 W; mean age 36.2 +/- 17.1 years); 15 patients with essential hypertension (9 M, 6 W; mean age 48.5 +/- 10 years). We also enrolled a normal control group (8 M, 12 W; mean age 34.2 +/- 11 years). The mean plasma ET-1 concentrations in patients with pheochromocytoma were significantly higher (23.9 +/- 5.2 pg/ml) than those in normal subjects (7.3 +/- 1.9 pg/ml), in patients with primary aldosteronism (12.1 +/- 3.8 pg/ml) and in patients with essential hypertension (9.2 +/- 3 pg/ml); p < 0.001, respectively. The present investigation demonstrates that in human adrenal hypertension patients with pheochromocytoma have increased circulating ET-1 levels respect to patients with aldosterone-producing adenoma.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Biomarkers; Endothelin-1; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Pheochromocytoma