Adrenal adaptation in potassium-depleted men: role of progesterone?

BACKGROUND: In rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy. METHODS: Twelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test. RESULTS: The potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin. CONCLUSION: The increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.

P-glycoprotein influences urinary excretion of aldosterone in healthy individuals.

OBJECTIVES: P-glycoprotein (P-gp), the product of the ABCB1 gene, is involved in the transport of aldosterone and cortisol in adrenal cells in vitro but its physiological role in humans remains controversial. Our objective was to test the influence of P-gp polymorphisms on aldosterone. METHODS: We evaluated plasma aldosterone concentration (PAC), urinary aldosterone, and blood pressure in a cohort of white normotensive men at baseline on diets unrestricted for sodium and potassium and after a 5-day treatment with 500 mg b.i.d. clarithromycin, a P-gp inhibitor. Included were 20 homozygous wild-type (P-gp0), 20 heterozygous (P-gp1), and 20 individuals with combined 2677G>T/A-3435C>T loss-of-function polymorphism of the ABCB1 gene (P-gp2). RESULTS: At baseline, PAC, urinary aldosterone, urinary free cortisol to urine creatinine ratios, and blood pressure did not differ in the three genotypes. After clarithromycin administration, the urinary aldosterone to creatinine ratio increased by an average of 30% in the entire cohort (P < 0.001, n = 60). Increases were pronounced in P-gp1 (+40%; P = 0.014) and P-gp2 individuals (+50%; P = 0.020) but lesser and were NS in P-gp0 individuals (+10%; P = 0.259). PAC also increased from baseline after clarithromycin treatment in all individuals (+19%, P = 0.050); however, the increase in PAC was NS when the three genotypes were analyzed separately. CONCLUSION: In our experimental conditions, the interaction between P-gp inhibition and the ABCB1 genotype, suggests that aldosterone is indeed a physiological endogenous substrate of P-gp in humans and that P-gp interferes with the net equilibrium between aldosterone secretion and elimination processes in humans.Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01627665.

A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension.

OBJECTIVES: We conducted a pilot multicenter double-blind randomized placebo-controlled crossover pharmacodynamic study to evaluate the blood pressure (BP) and the hormonal effects of firibastat, a first-in-class aminopeptidase A inhibitor prodrug, in patients with hypertension. METHODS: Thirty-four patients with daytime ambulatory BP of at least 135/85 mmHg and less than 170/105 mmHg, after a 2-week run-in period were randomly assigned to receive either firibastat (250 mg b.i.d. for 1 week uptitrated to 500 mg b.i.d. for 3 weeks) and then placebo for 4 weeks each or vice versa, with a 2-week washout period on placebo. RESULTS: At 4 weeks, daytime ambulatory systolic BP (SBP) decreased by 2.7 mmHg (95% confidence interval -6.5 to +1.1 mmHg) with firibastat versus placebo (P = 0.157). Office SBP decreased by 4.7 mmHg (95% confidence interval -11.1 to +1.8 mmHg) with firibastat versus placebo (P = 0.151). However, more the basal daytime ambulatory SBP was elevated, more the firibastat-induced BP decrease was marked. Firibastat did not influence 24h-ambulatory heart rate. Firibastat had no effect on plasma renin, aldosterone, apelin and copeptin concentrations. No major adverse events occurred. There was one episode of reversible skin allergy with facial edema. CONCLUSION: In patients with hypertension, a 4-week treatment with firibastat, tended to decrease daytime SBP relative to placebo. Firibastat did not modify the activity of the systemic renin-angiotensin system These results have justified designing a larger, powered trial of longer duration to fully assess its safety and effectiveness. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. NCT02322450.

New estimate of valvuloarterial impedance in aortic valve stenosis: A cardiac magnetic resonance study.

PURPOSE: Valvuloarterial impedance (ZVA ), estimating left ventricle (LV) afterload, has been proposed in transthoracic echocardiography (TTE) as a predictor of mortality in aortic valve stenosis (AVS). However, its calculation differs from arterial characteristic impedance (ZC ). Our aim was to apply the concept of ZC calculation to estimate ZVA from MR with carotid tonometry and to evaluate these indices through their associations with symptoms, LV diastolic function and aortic stiffness. MATERIALS AND METHODS: In 40 patients with AVS (76 ± 13 years), ZVA-TI derived from velocity time integral and E/Ea were estimated by TTE. ZVA-INS , based on ZC formula, calculated as the instantaneous pressure gradient to peak flow ratio and aortic compliance were estimated by using MRI at 1.5 Tesla. RESULTS: Both ZVA estimates were higher in symptomatic than asymptomatic patients (707 ± 22 versus 579 ± 53 dyne.s/cm5 , P = 0.031 for ZVA-INS and 4.35 ± 0.16 versus 3.33 ± 0.38 mmHg.m2 /mL, P = 0.018 for ZVA-TI ). Although they were both associated with aortic compliance (r = -0.45; P = 0.006 for ZVA-INS and r = -0.43; P = 0.008 for ZVA-TI ) only ZVA-INS was associated with E/Ea (r = 0.50; P < 0.001). In multivariate analysis to identify determinants of E/Ea, a model including age, mean blood pressure, LV ejection fraction, LV mass, and aortic valve area was performed (R2 = 0.41; P < 0.01). When ZVA-INS was added to the model, its overall significance was higher R2 = 0.56 (P < 0.01) and ZVA-INS and LV mass were the only significant determinants. CONCLUSION: ZVA-INS was more strongly associated with diastolic dysfunction than usual parameters quantifying AVS severity. This new ZVA estimate could improve LV afterload evaluation. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:795-803.

Dose-effect relationship of perindopril 10, 14 and 20mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers.

BACKGROUND: We describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure. METHODS: This randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements. RESULTS: There were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3-82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9-106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects. CONCLUSIONS: Administration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.

Deciphering the Role of Vasopressin in Primary Aldosteronism.

CONTEXT: The role of vasopressin (AVP) in the pathophysiology of primary aldosteronism (PA) remains unclear. OBJECTIVES: The primary aim of this study was to investigate AVP secretion in PA by measuring the plasma concentration of copeptin (PCop), the C-terminal portion of provasopressin. The secondary aim was to assess renal sensitivity to AVP. DESIGN AND SETTING: This was a cross-sectional study in a tertiary-care hospital. PROTOCOL: We recruited 115 patients with PA, 48 patients with essential hypertension (EH), and 108 normotensive healthy subjects (HS). Blood was sampled for biochemical and hormonal evaluations in fasting condition after 1-h rest in supine position. Osmolality was determined in 24-h urine. PCop was determined by immunoassay. MAIN OUTCOME MEASURE: The main outcome measure was adjusted difference in PCop between groups. RESULTS: After adjustment for sex, body mass index, systolic blood pressure, natremia, and kalemia, PCop was significantly higher in patients with PA than in HS (geometric mean ratio, 1.61; 95% confidence interval [CI], 1.26-2.06; P < .0001) and patients with EH (1.40; 95% CI, 1.08-1.82; P = .0070) PCop was positively correlated with natremia (P = .0094). Urine osmolality was significantly lower in patients with PA than in HS (0.82; 95% CI, 0.74-0.92; P = .0002) and 24-h urinary output was significantly higher in patients with PA than in HS (1.32; 95% CI, 1.11-1.56; P = .0005). The relationship between urine osmolality and PCop was shifted downward in patients with PA but was similar in patients with EH and HS, indicating peripheral resistance to AVP. CONCLUSION: PCop increases in patients with PA in response to an increase in natremia and a renal resistance phenomenon, indicating that AVP release is chronically stimulated in PA.