Monogenic forms of low-renin hypertension: clinical and molecular insights

Author(s):  
Priyanka Khandelwal ◽  
Jaap Deinum
Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Gregor Guron ◽  
Lisa Nguy ◽  
Maria Johansson ◽  
Tom Teerlink

We have shown that rats with adenine-induced chronic renal failure (A-CRF) develop modest hypertension, left ventricular hypertrophy, and a marked decrease in aortic relaxation rate. The aim of this study was to investigate mechanisms causing hypertension in this model and to assess aortic stiffness by measuring aortic pulse wave velocity (PWV). Male Sprague-Dawley rats were equipped with radiotelemetry probes and subsequently received either chow containing adenine (0.5% for 3 weeks, 0.3% for 2 w., and 0.15% thereafter) or were pair-fed with a normal control diet. At 7 to 11 weeks blood pressure responses to high NaCl diet (4%) and pharmacological interventions were performed. In separate groups aortic PWV was analyzed in isoflurane-anesthetized animals. Values are means±SD. Baseline 24-h mean arterial pressure (MAP) was 101±10 and 119±9 mmHg in controls and A-CRF animals, respectively (P < 0.01). After 5 days of 4% NaCl diet MAP had increased by 24±6 mmHg in A-CRF animals vs. 2±1 mmHg in controls (P<0.001 between groups). Administration of L-NAME in the drinking water (50 mg/kg/day) increased MAP by 37±9 and 24±4 mmHg in A-CRF animals and controls, respectively (P< 0.01 between groups). Candesartan (10 mg/kg by gavage) produced a more pronounced reduction of MAP in controls vs. A-CRF animals (-12±3 vs. -5±5 mmHg, P<0.05). Aortic PWV was elevated in A-CRF rats (5.10±0.51 vs. 4.58±0.17 m/s, P<0.05) although histological analysis did not show aortic calcifications. At sacrifice, plasma levels of creatinine (259±46 vs. 31±2 μM, P<0.001) and asymmetric dimethylarginine (ADMA, 0.65±0.04 vs. 0.45±0.02 μM, P < 0.001) were elevated in A-CRF animals whereas plasma renin activity was markedly suppressed (0.7±0.5 vs. 15.1±7.5 μg/L/h, P<0.001). Hypertension in A-CRF animals is characterized by low renin levels and is aggravated by high NaCl diet suggesting a pathogenic role for hypervolemia secondary to severe renal insufficiency. Although ADMA concentrations were elevated, A-CRF animals showed a more pronounced increase in MAP in response to L-NAME than controls, suggesting that reduced nitric oxide synthase activity was not a major cause of hypertension in this model. Finally, aortic stiffness was elevated in A-CRF animals as indicated by increased aortic PWV.


Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jeremy A Sandgren ◽  
Danny W Linggonegoro ◽  
Kristin E Claflin ◽  
Nicole A Pearson ◽  
Gary L Pierce ◽  
...  

Increased blood pressure in the deoxycorticosterone acetate (DOCA)-salt model of low-renin hypertension is correlated with increased vasopressin (AVP) secretion, and is sensitive to inhibition of the brain renin-angiotensin system (RAS). Further, AVP-deficient Brattleboro rats are largely resistant to DOCA-salt hypertension. These findings lead us to hypothesize a role for AT1A receptors localized to AVP-expressing neurons in the control of AVP secretion, specifically in low-renin hypertension. Blood pressure was assessed via tail-cuff plesthysmography and total daily AVP secretion assessed via urine copeptin in mice with specific disruption of the AT1A gene in AVP-expressing cells (AVP-Cre x AT1Aflox/flox mice, “KO”) under both baseline and DOCA-salt treatment conditions. Specific activity of Cre-recombinase within the paraventricular and supraoptic nuclei of AVP-Cre transgenic mice was confirmed by fluorescent microscopy in brain sections from mice expressing a conditional fluorescent reporter (AVP-Cre x ROSA-stopflox-tdTomato mice). At baseline, AVP secretion (via urine copeptin) trended downward with large variation (control n=17, 363±182 vs KO n=5, 33±11 pg/day; p>0.05) but there was no significant difference in blood pressure (control n=27, 107±1.3 vs KO n=12, 111±2.2 mmHg; p>0.05) compared to littermate controls. In response to DOCA-salt, blood pressure (control n=23, +10.35±2.1 vs KO n=8, +12.91±2.0; p>0.05), urine output (control n=23, +12.65±0.8 vs KO n=9, +12.73±1.5 g/day; p>0.05), and fluid intake (control n=23, +16.17±1.3 vs KO n=9, +14.83±2.5 mL/day; p>0.05) increased normally in KO mice. Preliminary findings indicate normal or possibly exaggerated urine copeptin levels in KO mice following DOCA-salt, and an exaggerated AVP release in response to increasing serum osmolality. Collectively, these data suggest that AT1A receptors on AVP expressing cells are required to mediate baseline secretion of AVP, but that these receptors are dispensable for DOCA-salt mediated increases in circulating AVP and blood pressure.


1979 ◽  
Vol 98 (5) ◽  
pp. 642-652 ◽  
Author(s):  
Arunabha Ganguly ◽  
Myron H. Weinberger

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yuta Tezuka ◽  
Adina Turcu

Abstract Background: Medical treatment with mineralocorticoid receptor antagonists (MRAs) is preferred for patients with primary aldosteronism (PA) who are not surgical candidates. Adequate mineralocorticoid receptor blockade, as suggested by renin elevation above suppression levels, has been associated with lower rates of cardiovascular and renal complications as compared with PA with sustained renin suppression. Objectives: To assess the timeline and rates of achieving target renin levels in patients with PA and low renin hypertension treated with MRAs. Patients and Methods: We conducted a retrospective cohort study of adult patients with hypertension who were treated with MRAs in an academic center between 2003-2019. Of these, we included patients who had suppressed renin at baseline, and repeated renin measurement(s) during MRAs therapy. Renin suppression was defined as plasma renin activity (PRA) 1.0 ng/mL/h or direct renin concentration (DRC) 8.0 pg/mL. We excluded patients with adrenal cancer, end-stage renal disease, exogenous glucocorticoids, and critically ill. Mann-Whitney test, Wilcoxon signed rank test, Chi-Square test and multiple logistic regression analysis were employed, as appropriate. Results: So far, 89 patients (45 men), median age 56 (range, 19-84), have been included. Of these, 46% had confirmed PA; 25% had positive PA screening, but no confirmatory tests; and 29% had other forms of low-renin hypertension. On average, patients were on 2.9 1.6 antihypertensive agents; 62% of patients were prescribed beta blockers, and 38% were on K+ supplements. Overall, renin (PRA in 69 cases, and DRC in 20 cases) increased after MRA treatment (from 0.40 [0.10, 0.60] ng/mL/h to 1.10 [0.60, 2.23] ng/mL/h; and from 2.1 [2.1, 3.7] pg/mL to 5.7 [2.9, 16.7] pg/mL, respectively, p&lt;0.0001 for both). The cumulative proportions of patients in whom renin reached target levels during MRA treatment were: 25% at 2 weeks; 38.9% at 1 month; 34.2% at 3 months; 39.5% at 6 months; and 47.2% at 1 year. Age, sex, race, blood pressure, use of beta blockers, renal function, serum K+ and aldosterone concentrations were similar between patients with target vs. suppressed renin. Multiple logistic regression analysis suggested that after adjusting for age and sex, higher MRA dose and higher BMI were associated with higher likelihood of achieving target renin during MRA therapy (odds ratio (95%CI): 1.021 (1.001-1.041) and 1.097 (1.008-1.193), respectively, p&lt;0.05 for both); conversely, beta blockers use tended to be less often associated with target renin (odds ratio, 0.37 (0.13-1.008), p=0.052). Conclusion: Although raising renin above suppression levels is important for reducing the cardiovascular risk associated with PA, this goal is achieved in less than half of patients, even after one year of treatment with MRAs, in an academic setting. Strategies for optimizing PA treatment are critically needed.


2020 ◽  
Vol 34 (3) ◽  
pp. 101399 ◽  
Author(s):  
Fabrizio Buffolo ◽  
Silvia Monticone ◽  
Alessio Pecori ◽  
Jacopo Pieroni ◽  
Isabel Losano ◽  
...  

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