Plasma Aldosterone Response Research Articles

Plasma aldosterone response to ACTH stimulation test for diagnosis of primary aldosteronism: a cross-sectional study

BackgroundThe diagnosis of primary aldosteronism (PA) requires screening and confirmation testing. The present study examined whether the 1 µg ACTH stimulation test for plasma aldosterone concentration (PAC) can accurately diagnose PA by bypassing the regular confirmatory steps of PA diagnosis.MethodsA cross-sectional study with a total of 36 patients with an aldosterone-renin ratio (ARR) > 20 ng/dL per ng/m/hr were included. The confirmation test for PA was performed by saline infusion and the patients were categorized into PA and non-PA. PAC was collected at 20 and 40 min after 1 µg ACTH stimulation test. Multivariable logistic regression analysis was performed, and the associations are presented as odds ratios (OR) and 95% confidence intervals (CI). Diagnostic accuracy is presented as AuROC.ResultsMultivariable analysis found only PAC at 20 min after ACTH stimulation showed significant association with a diagnosis of PA (OR 1.18, 95%CI (0.99, 1.31), p = 0.040). AuROC for this value was 0.95 and the proposed cut-off was 52 ng/dL with a sensitivity of 71.4% and a specificity of 96.6%.ConclusionsDiagnosing PA may be aided by PAC at 20 min following 1 µg ACTH stimulation. This value may be used with patients for whom the confirmation test for PA cannot be conducted.

FRI167 Implication Of Serotonin In The Physiopathology Of Aldosterone-Producing Adenoma

Abstract Disclosure: C. Duparc: None. M. D'agostino: None. A. Lopez: None. S. Renouf: None. E. Louiset: None. H. Lefebvre: None. In the human adrenal gland, serotonin (5-HT), released by subcapsular mast cells strongly stimulates expression of CYP11B2, encoding aldosterone-synthase and aldosterone production. The effect of 5-HT on adrenocortical cells is mediated by activation of type 4 serotonin receptor (5-HT4R) positively coupled to cAMP/protein kinase A (PKA) signaling pathway and calcium influx. Consistently, administration of cisapride, a 5-HT4R agonist, to healthy volunteers induces a significant increase in plasma aldosterone levels. In aldosterone producing adenomas (APA), the density of mast cells is enhanced in comparison with normal adrenals. Moreover, molecular studies have shown overexpression of HTR4 gene, encoding 5-HT4R, in APA tissues. Administration of cisapride to patients with APA induced more robust plasma aldosterone responses than in healthy voluntaries. These results suggest that 5-HT could play a role in physiopathology of APA. The aim of our study was to examine expression of genes and proteins involved in aldosterone production and actors of the serotonergic pathway in a series of 31 adenomas removed from patients with primary aldosteronism. We have also investigated the in vitro effect of various 5-HT4R ligands on aldosterone production by explants or cultured cells derived from adenoma tissues collected at surgery. Firstly, aldosterone synthase (AS) immunostaining allowed identification of adenoma phenotypes accordingly to the new international histopathology consensus for unilateral Primary aldosteronism. Among the 31 tissues studied, 20 were classified as classical APAs, i.e. presenting with homogenous or heterogenous AS distribution, remaining being considered as 11 non-classical APA. Expression of the gene encoding the 5-HT-synthesizing enzyme tryptophan hydroxylase was similar in APA and normal adrenals. HTR4 overexpression was more robust in classical than non-classical APAs. HTR4 mRNA levels were positively correlated to those encoding CYP11B2. In addition, 5-HT4R immunostaining was widely distributed in most APA tissues, a pattern which was not exclusively noticed in AS-positive adenomas. BIMU-8, a potent 5-HT4R agonist, strongly increased aldosterone production by perifused APA explants. This effect was blocked by administration of GR-113808, a 5-HT4R antagonist. In cultured APA cells, BIMU-8 stimulated aldosterone synthesis in a dose-dependent manner with a higher efficiency than that observed in normal adrenocortical cells. Aldosterone secretion was less strongly stimulated by prucalopride, a partial 5-HT4R agonist used in the treatment of chronic constipation. These data reveal an enhancement of the 5-HT signaling pathway in APAs in comparison with normal adrenals, suggesting that 5-HT and the 5-HT4R may participate in the pathophysiology of primary aldosteronism. Presentation: Friday, June 16, 2023

Collecting duct renin regulates potassium homeostasis in mice.

The kaliuretic action of the renin-angiotensin-aldosterone system (RAAS) is well established as highlighted by hyperkalemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study addresses the involvement of intrarenal RAAS in K+ homeostasis with emphasis on locally generated renin within the collecting duct (CD). Wild-type (Floxed) and CD-specific deletion of renin (CD renin KO) mice were treated for 7 days with a high K+ (HK) diet to investigate the role of CD renin in kaliuresis regulation and further define the underlying mechanism with emphasis on analysis of intrarenal aldosterone biosynthesis. In floxed mice, renin levels were elevated in the renal medulla and urine following a 1-week HK diet, indicating activation of the intrarenal renin. CD renin KO mice had blunted HK-induced intrarenal renin response and developed impaired kaliuresis and elevated plasma K+ level (4.45 ± 0.14 vs. 3.89 ± 0.04 mM, p < 0.01). In parallel, HK-induced intrarenal aldosterone and CYP11B2 expression along with expression of renal outer medullary K+ channel (ROMK), calcium-activated potassium channel subunit alpha-1 (α-BK), α-Na+ -K+ -ATPase, and epithelial sodium channel (β-ENaC and cleaved-γ-ENaC) expression were all significantly blunted in CD renin KO mice in contrast to the unaltered responses of plasma aldosterone and adrenal CYP11B2. Taken together, these results support a kaliuretic action of CD renin during HK intake.

A quantitative systems pharmacology model of plasma potassium regulation by the kidney and aldosterone.

Plasma potassium regulation within a narrow range is vital for life. The risk for hyperkalemia increases when kidney function is impaired and with therapeutic interventions such as mineralocorticoid receptor antagonists (MRAs). The kidney maintains potassium homeostasis by matching potassium intake and excretion, in part through the action of aldosterone. A mechanistic mathematical model was developed and used to investigate the effect of renal impairment and MRAs on plasma potassium levels. The model describes renal potassium filtration, reabsorption, and secretion along the nephron; potassium-aldosterone regulatory feedbacks; whole body potassium balance; and the pharmacologic effects of MRAs. The model was calibrated by fitting (1) the plasma potassium and aldosterone response to potassium infusion in humans on high/low potassium diets, and (2) the acute potassium excretion response to spironolactone. The model was validated by predicting steady-state plasma potassium with sustained spironolactone treatment in hyperaldosteronism patients. The model was then used to demonstrate that (1) declining renal function alone has a small effect on plasma potassium for GFR > 30ml/min, but an increasing effect as GFR approaches end stage renal disease (GFR ~ 15ml/min) (2) the effect of increasing potassium intake has minimal effect at normal GFRs but increasing effect on plasma potassium as GFR declines, and 3) MRAs have a minor effect on plasma potassium when GFR is normal, but cause larger increases as GFR falls below 60ml/min. This model provides a quantitative framework for investigating integrated impacts of diseases and therapies in this complex system.

PENDRIN REDUCTION IS ASSOCIATED WITH ACUTE INTRAVENOUS SODIUM CHLORIDE LOADING IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA) is a common, potentially curable form of hypertension characterised by excessive, autonomous aldosterone production. In the distal renal tubule, aldosterone is involved in volume homeostasis by modulation of NaCl reabsorption via the epithelial Na+ channel (ENaC), the NaCl cotransporter (NCC) and the Cl-/HCO3- exchanger (pendrin). Na+ loading suppresses plasma aldosterone but its effects on these proteins in humans remain unclear. Design and method: Urine samples were collected before and 1 h after a 4 h 2L 0.9% saline infusion from 13 (F9/M5) subjects including 10 confirmed with PA and 3 in which PA was excluded [herein designated low renin hypertension (LRH)]. Urinary exosomes were harvested by ultracentrifugation and analysed by LC-MS/MS. Results: Plasma aldosterone decreased (P &lt; 0.05) from 623 [312, 2210] (median [range]) to 338 [197, 2330] pmol/L in confirmed PA and from 223 [180, 256] to 117 [110, 133] pmol/L in LRH. There were no changes in plasma K+ (pre 3.4 [2.6, 4.3] vs post 3.6 [2.6, 3.9] mmol/L in PA; pre 4.1 [3.6, 4.1] vs post 4.0 [3.9, 4.0] mmol/L in LRH). LC-MS/MS demonstrated decreases in abundance of pendrin (21.5%, P &lt; 0.01) and aquaporin-2 (AQP2) (42.9%, P &lt; 0.01) in urinary exosomes and a trend towards a decrease in NCC (20%, P = 0.07) in patients with PA. No changes were seen in those with LRH. PA patients had higher baseline pendrin abundance (1.2 [1.0, 2.1]) than LRH patients (0.7 [0.5, 1.0]) (P &lt; 0.05), but there was no difference in baseline AQP2. In all 13 subjects combined, baseline pendrin correlated positively with plasma aldosterone (P = 0.02, r2 = 0.32) and negatively with plasma K+ (P = 0.02, r2 = 0.35), whilst no correlations were observed between AQP2 and aldosterone or K+. Delta Pendrin (P = 0.04, r2 = 0.3) and delta AQP2 (P = 0.01, r2 = 0.58) positively correlated with delta plasma aldosterone. Conclusions: In PA, reduction in pendrin during saline infusion may be due to falling plasma aldosterone in response to NaCl loading. Although also correlating with reduction in aldosterone, a more likely explanation for the reduction in AQP2 may be a fall in plasma vasopressin induced by water loading. Different observations in LRH require validation with larger numbers.

Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways.

BackgroundDuring high sodium intake, the renin‐angiotensin‐aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid‐electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin‐angiotensin‐aldosterone system–epithelial sodium channel axis.Methods and ResultsMale control and collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in CDNOS1KO mice. CDNOS1KO mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal AT1R expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore, CDNOS1KO mice had significantly higher intrarenal angiotensin II with high sodium diet, although intrarenal angiotensinogen levels and angiotensin‐converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin‐angiotensin‐aldosterone system activation in the CDNOS1KO mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls.ConclusionsThese data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin‐angiotensin‐aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis.

Abstract P313: Age and Response of Plasma Aldosterone to Saline Infusion in Primary Hypertension

Objective: In patients with primary hypertension, plasma aldosterone levels are significantly decreased by an intravenous saline load (IVSL), but this response is variable among patients and related to the ability of salt to modulate aldosterone production. Previous studies have reported that activity of the renin-angiotensin-aldosterone system is related with age. The aim of this study was to investigate whether age might affect the aldosterone response to an IVSL. Design and Method: In 124 hypertensive patients (48±13 y, 71 males) who were washed-out of antihypertensive drugs for 2 weeks, we measured renin and PA levels before and after an IVSL (2 lt. saline in 4 h). In all patients secondary causes of hypertension were excluded. For statistical purposes patients were subdivided into two groups based on age (&lt; or &gt; 60 y). Results: Twenty-three of 124 patients (18%) were had 60 y of age or more (range 61-77) and the remaining were younger than 60 y (19-60 y). No differences were found between the two groups for gender, body mass index, serum potassium and creatinine clearance. Urinary sodium excretion was comparable in patients older (159±83) or younger (159±66) than 60 y. Baseline PA (76 [49-121] pg/ml) and renin (5.0 [1.9-9.8] mcIU/ml) levels were significantly lower in patients older than 60 y than in those younger than 60 y (115 [77-162] pg/ml, P=0.019; 10.7 [5.1-20.8] mcIU/ml, P=0.026). As expected IVSL decreased significantly (P&lt;0.001) both plasma renin and aldosterone levels. Post IVSL renin was 3.0 [1.1-4.9] mcIU/ml in patients older than 60 y and 6.2 [3.0-12.5] mcIU/ml younger than 60 y. Following IVSL, PA decreased by 87% (10 [10-13] pg/ml) in patients older than 60 y and by 76% (28 [10-49] pg/ml; P=0.003) in patients younger than 60 y. The change in PA induced by IVSL was significantly and inversely related to age (r=-0.185, P=0.039). Conclusions: PA levels are lower in hypertensive patients older than 60 y. This difference becomes more relevant after IVSL suggesting greater response of the renin-angiotensin system to volume expansion. This should be taken into account in the diagnostic work-out of hypertensive patients.

Plasma cortisol and aldosterone responses to insulin tolerance test and sodium depletion in women with non classic 21-hydroxylase deficiency caused by bi-allelic CYP21A2 mutations (NC-CAH)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Changes in Plasma Aldosterone and Electrolytes Following High-Volume and High-Intensity Resistance Exercise Protocols in Trained Men.

Boone, CH, Hoffman, JR, Gonzalez, AM, Jajtner, AR, Townsend, JR, Baker, KM, Fukuda, DH, and Stout, JR. Changes in plasma aldosterone and electrolytes following high-volume and high-intensity resistance exercise protocols in trained men. J Strength Cond Res 30(7): 1917-1923, 2016-Program variables such as training intensity, volume, and rest interval length are known to elicit distinct hormonal, metabolic, and physical responses. However, little is known regarding resistance exercise (RE) program design and the fluid regulatory response. This investigation aimed to compare the plasma aldosterone (ALD), electrolyte, plasma volume (PV), and osmolality (Posm) responses following high-volume (HV; 4-6 × 10-12 reps, 70% 1 repetition maximum [1RM], 60-s rest) and high-intensity (HI; 6 × 3-5 reps, 90% 1RM, 180-second rest) RE protocols. Ten experienced, resistance-trained men (24.7 ± 3.4 years; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) performed each protocol in a random, counterbalanced order. Blood samples were obtained at baseline (BL), immediately (IP), 30 minutes (30P), and 1 hour (1H) postexercise. Significant trial × time interactions (p < 0.01) were observed in Posm, sodium (Na), and potassium (K), whereas a trend (p = 0.06) was observed for ALD. The PV shift from BL-30P was greater than BL-IP and BL-1H (p ≤ 0.05), but no significant between-trial differences were noted. Comparisons between RE protocols revealed significantly greater (p ≤ 0.05) elevations during HV vs. HI in Posm at IP, 30P, and 1H; and Na at IP and 30P. During HV, significant reductions (p ≤ 0.05) were noted in K at IP compared with HI. Area under the curve analysis indicates a trend (p = 0.07) toward a higher ALD response following HV compared with HI. Results of this study indicate that high-volume, moderate-intensity resistance exercise seems to augment the fluid regulatory response to a greater extent than low-volume, high-intensity training.

Stress and hypertensive disease: adrenals as a link. Experimental study on hypertensive ISIAH rat strain

ABSTRACTObjective: Association between stress and hypertensive disease is still a matter of debate. Can stress be the cause of hypertensive disease and, if so, what mechanisms are involved? To clarify this question, the Inherited stress-induced arterial hypertensive rat strain (ISIAH rat strain) with a stress related arterial hypertension was developed by selection for the enhanced blood pressure response to 0.5 h restraint stress. The main intention of this work is to confirm that the adrenals are a main link between stress and hypertensive disease. Methods: Hypertensive ISIAH and normotensive WAG rats have been studied. The in vivo secretion rate of corticosterone, aldosterone, 11-Deoxycorticosterone (DOC), and 11-dehydrocorticosterone was measured in anesthetized rats by adrenal vein cannulation. The Dexamethasone/Adrenocorticotropic hormone (DEX/ACTH) test was performed and mRNA expression of Cyp11b1 and Cyp11b2 genes in adrenals was evaluated by real-time PCR. Results: An increased secretion rate of corticosterone and DOC and higher peripheral plasma aldosterone concentration in ISIAH rats were revealed. Response of plasma aldosterone to the surgical stress (adrenal vein cannulation) in the ISIAH rats was significantly higher. The increase of corticosterone and aldosterone in response to ACTH was also higher in hypertensive rats. The basal mRNA expression of both Cyp11b1 and Cyp11b2 genes was increased in the ISIAH rats. The ratio 11-dehydrocorticosterone/corticosterone in ISIAH rats was low which indicates the weakening of 11-beta-Hydroxysteroid dehydrogenase (11-beta-HSD) type 2 converting corticosterone to cortisone. Conclusion: ISIAH rats may serve as a living proof that stress may produce sustained hypertension, and genetically determined enhanced stress responsiveness of corticosterone and, especially, aldosterone may play a crucial role in the mechanism of hypertension development.

Primary aldosteronism and potassium channel mutations

To summarize and discuss data from recent studies implicating mutations in potassium channel genes in the pathogenesis of primary aldosteronism. Potassium channel gene variants are associated with the primary aldosteronism phenotype in animals (Kcnma1, TASK-1, and TASK-3) and humans (HERG and KCNJ5). Germline KCNJ5 mutations cause bilateral, familial primary aldosteronism with variable severity and genotype:phenotype correlations. Somatic KCNJ5 mutations occur in approximately 40% of aldosterone-producing adenomas, and are associated with younger age, female sex, more severe primary aldosteronism, lack of responsiveness of plasma aldosterone to upright posture, and zona fasciculata histology. Of five so far described, G151R and L168R are by far the most common. KCNJ5 mutations lead to reduced K⁺/Na⁺ channel selectivity and Na⁺ influx, predisposing to cell membrane depolarization, increased calcium influx, increased expression of genes promoting aldosterone synthesis, and increased aldosterone production by adrenocortical cells. How they lead to adrenal cell proliferation and tumor development is less well understood. These findings shed considerable light on the pathophysiology of primary aldosteronism with the potential to lead to new diagnostic approaches and treatments.

Adrenomedullin 2 attenuates the pressor but not adrenal responses to angiotensin II in conscious sheep

Biological actions attributed to the adrenomedullin (AM) peptides, AM and AM2, include reduction of arterial pressure and peripheral resistance. While AM has been shown to reduce aldosterone secretion from the adrenal, little information is available regarding possible actions of AM2 on aldosterone. Evidence suggests that AM may act as a functional antagonist to angiotensin II (Ang II) but such a role has not been investigated for AM2. Accordingly, we have examined hemodynamic and adrenal responses to stepped Ang II infusions with or without co-infusions of AM2 (33 ng/(kg min)) in conscious sheep under controlled conditions of a low sodium intake. The dose-dependent pressor response (5–50 mmHg) of Ang II was both delayed and attenuated ( p < 0.001) by AM2 which also stimulated heart rate ( p < 0.001) and cardiac output ( p < 0.001). AM2 prevented Ang II-induced increases in peripheral resistance ( p < 0.001). In contrast, plasma aldosterone responses to Ang II were not significantly altered by concomitant AM2 infusion. In conclusion, low dose infusion of AM2 administered to conscious sheep on a low salt diet clearly antagonized the vasopressor action of administered Ang II while stimulating cardiac output and heart rate. In contrast to AM, AM2 had no restraining influence on the aldosterone response to Ang II. The data suggest a possible role for AM2 in cardiovascular homeostasis in part through antagonism of the vasopressor action of Ang II.

Effect of Sodium Depletion on the Renin-Angiotensin-Aldosterone System and Renal Prostaglandins in Acromegalic Patients

The effects of 5 days low sodium diet and diuretic were studied in 7 normotensive acromegalics, 8 hypertensive acromegalics and 12 normal subjects. Plasma renin activity was significantly lower in both groups acromegalics, compared with that of normal subjects. Plasma aldosterone was similar in normotensive acromegalics and healthy controls. The hypertensive acromegalics showed increased plasma aldosterone levels and blunted responses of plasma renin activity and plasma aldosterone to sodium depletion. Urinary prostaglandin E2 was significantly lower in hypertensive acromegalics before and after sodium depletion in comparison with normal subjects. Urinary 6-keto prostaglandin F1 alpha and thromboxane B2 were similar in all groups studied. The decreased production of PGE2 could contribute to the development of arterial hypertension in actomegaly.

Effect of metoclopramide on orthostatic hypotension in diabetes mellitus: failure to demonstrate the role of vasoconstrictive hormones.

Effect of metoclopramide (MCP), a dopaminergic antagonist, on orthostatic hypotension associated with diabetes mellitus, was investigated to prove its plausible role of renin-angiotensin-aldosterone and catecholamine activation by comparative study in 6 diabetics with orthostatic hypotension (OH) and 9 diabetics without OH. With MCP treatment, drop of systolic blood pressure (SBP) on standing was significantly improved. However, the postural responses of plasma renin activity (PRA), plasma aldosterone and norepinephrine were not enhanced by MCP treatment. Moreover, MCP treatment did not modify the vascular reactivity to the exogenously infused angiotensin II and norepinephrine. Thus, it would be interesting to speculate that MCP can improve SBP through its suppressive effect on some depressor substance(s) such as bradykinin which liberates exaggeratively in diabetic OH.

Plasma aldosterone response to metoclopramide in patients with Cushing's disease.

The acute effect of metoclopramide on aldosterone and prolactin levels were studied in 8 control subjects and 11 patients with Cushing's disease. Metoclopramide (10 mg i.v.) induced a similar plasma prolactin response in control subjects and patients. No difference was found in basal aldosterone levels between the two groups. Apart from a more delayed aldosterone response to metoclopramide in the Cushing's disease group, no significant difference in the peak aldosterone values was found between the patients and controls. The short-term treatment with DA2-receptor agonist bromocriptine was without effect on aldosterone response to metoclopramide in the Cushing's disease group. These results argue against an altered dopaminergic control of aldosterone secretion in patients with Cushing's disease. The lack of a bromocriptine effect on aldosterone response to metoclopramide is in accordance with the concept that the dopamine receptors involved in aldosterone regulation differ from classical DA2 receptors.

Zona fasciculata-like histotype and aldosterone response to upright posture are not related in aldosterone-producing adenomas.

Two distinct subtypes of patients with primary aldosteronism due to aldosterone-producing adenomas (APA), based on different aldosterone responses to angiotensin, have been identified. We evaluated the relationship between adrenal zona fasciculata-like histotype and response of plasma aldosterone to upright posture in a series of patients with APA. Twenty-five patients were retrospectively divided in two groups according to aldosterone response to posture, i.e., a first group without postural change of aldosterone (n = 19) and a second group with at least 30% aldosterone increase after standing (n = 6). The percentage of zona fasciculata-like cells was calculated at histology in all adenoma tissues removed at adrenalectomy. The two groups of patients were similar in sex, age, systolic/diastolic blood pressure, supine/upright plasma renin activity, supine/upright aldosterone, tumor size. No differences between the two groups were observed as to zona fasciculata-like (84 +/- 3% vs 71 +/- 9%, P NS) and non-zona fasciculata-like cells percentage in adenoma tissues. No inverse correlation was found in either group between the percentage change from supine to upright aldosterone and the percentage of zona fasciculata-like cells. Aldosterone and cortisol responses to ACTH testing were similar in the two groups. Our results indicate that the two subtypes of primary aldosteronism based on different postural responses of aldosterone are not due to a different prevalence of zona fasciculata-like histotype in APA.

The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock

Impaired renal microcirculation has been suggested as a factor contributing to the development of renal dysfunction in sepsis. This study was conducted to elucidate the role of endothelin-1 (ET-1)in mediating reductions in renal microcirculatory blood flow during endotoxemic shock. A prospective, randomized, and experimental study was performed with 16 anesthetized and mechanically ventilated pigs. After 2 h of lipopolysaccaride-induced endotoxemia, eight animals received a bolus dose of the dual endothelin receptor antagonist tezosentan (1 mg/kg), followed by a continuous infusion of 1 mg/kg/h throughout the experiment. Eight animals served as the control group. Renal microcirculation, total renal blood flow, plasma creatinine levels, cardiac index, and mean arterial pressure were measured. Plasma samples were collected for the measurement of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), ET-1, angiotensin II, and aldosterone. Endotoxin infusion resulted in a state of circulatory shock with impairment of renal microcirculation. An increase in the plasma levels of TNF-alpha, IL-6, IL-10, ET-1, angiotensin II, and aldosterone was also observed. Tezosentan attenuated the decrease in renal microcirculation and renal blood flow, and attenuated the increase in plasma creatinine. Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia. These results indicate that treatment with the dual endothelin receptor tezosentan in endotoxemic shock attenuates the reduction of renal microcirculation and total renal blood flow independently of plasma changes in the renin-angiotensin-aldosterone system or early plasma cytokine response.

A possible association between aldosterone response to vasopressin and circadian change of aldosterone in the patients with aldosterone-producing adenoma

Vasopressin was reported to stimulate secretion of both cortisol and aldosterone through eutopic V1a receptors in adrenal gland. Recently, adrenal hyper-responsiveness of plasma cortisol to vasopressin with eutopic overexpession of V1a receptors has been reported in Cushing’s syndrome, such as a majority of cases of ACTH-independent macronodular adrenal hyperplasia and some cases of Cushing’s adenomas. There were a few reports regarding the aldosterone response to vasopressin in aldosterone-producing adenoma. The aim of our study was to investigate the aldosterone response to vasopressin and its pathophysiological roles in the patients with aldosterone-producing adenoma. Vasopressin-loading test was performed in 10 patients with aldosterone-producing adenoma, and in 16 patients with non-functioning adrenal tumors. The roles of the aldosterone response to vasopressin were analyzed in terms of hormonal secretion and the expression of V1a receptor mRNA on the operated adrenal gland in aldosterone-producing adenoma. We found that (1) a varying aldosterone response to vasopressin was observed, (2) absolute response of plasma aldosterone in aldosterone-producing adenoma was significantly higher than that in non-functioning tumor, (3) aldosterone response rate to vasopressin was significantly and negatively correlated with the decline rate (%) in plasma aldosterone from morning to evening in aldosterone-producing adenoma, (4) V1a receptor mRNA was expressed at various values in aldosterone-producing adenoma, and (5) surgical removal of aldosterone-producing adenoma eliminated the aldosterone response to vasopressin observed in patients with aldosterone-producing adenoma. These findings indicated that vasopressin might be involved in the coordination of aldosterone secretion through eutopic expression of V1a receptor in aldosterone-producing adenoma.

Nesiritide Appears To Inhibit the Rise in Plasma Aldosterone Associated with Furosemide Diuresis

Background: Diuretics and natriuretic peptides, both agents used in the management of heart failure (HF), elicit fundamentally different neurohormonal responses, despite the fact that both can acutely reduce filling pressures. As such, we investigated the plasma aldosterone (aldo) and diuretic response to nesiritide (nes) infusion alone, furosemide (fur) alone, and fur on a background of nes infusion. Objective: To compare the effects of nes, fur, and nes + fur on urinary sodium excretion (UNaV), urine output (UO), and plasma aldosterone (aldo) levels.

Evidence for a Role of Vasopressin in the Control of Aldosterone Secretion in Primary Aldosteronism:in Vitroandin VivoStudies

Arginine vasopressin (AVP) stimulates steroid secretion from the normal human adrenal gland and some cortisol-producing adrenocortical tumors or hyperplasia through activation of the V(1a) receptor. The objective of the study was to investigate in vitro and in vivo the possible involvement of AVP in the physiopathology of primary aldosteronism. The design of the study included immunohistochemical, pharmacological, and molecular studies on aldosterone-producing adenoma (APA), followed by a monocentric, crossover trial of the orally active V(1a) receptor antagonist, SR 49059, in a double blind, randomized, and placebo-controlled fashion. The study was conducted at a university hospital and research laboratory. The study population included eight untreated patients with primary aldosteronism, four with APA and four with idiopathic hyperaldosteronism. Aldosterone secretion of APA cells in vitro and plasma aldosterone, renin, and ACTH were measured. SR 49059 (200 mg once daily) or placebo was administered during two 1-wk treatment periods separated by a 2-wk washout. We observed the occurrence of AVP-containing cells in APA tissues. Administration of AVP to perifused APA cells induced an increase in aldosterone production, which was inhibited by a specific V(1a) antagonist. RT-PCR analysis showed the expression of V(1a) receptor mRNA in most APAs studied. In APA patients, SR 49059 did not induce any effect on basal aldosterone secretion but provoked a plasma aldosterone response to orthostatism (P < 0.03) and strengthened the positive correlation between plasma aldosterone and ACTH. The present study indicates that functional V(1a) receptors are present in APA and suggests that AVP may exert an autocrine/paracrine control of aldosterone secretion in APA tissues.