Effects of Direct Renin Blockade on Renal & Systemic Hemodynamics and on RAAS Activity, in Weight Excess and Hypertension: A Randomized Clinical Trial

Abstract

AimThe combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension.MethodsA randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15).ResultsMean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9–42] mg/d) was reduced by DRI only (12 [5–28] mg/d, P = 0.030).ConclusionsIn men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension.Trial RegistrationDutch trial register, registration number: 2532 www.trialregister.nl

An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection

“…Both angiotensinogen-specific antisense oligonucleotides and small interfering RNA (siRNA) lowered blood pressure in rat models of hypertension ( Mullick et al, 2017 ; Uijl et al, 2019 ). In humans with weight excess and hypertension, renin inhibitors (e.g., aliskiren) and ACEi (e.g., ramipril), improve renal and systemic hemodynamics and reduce arterial pressure ( Kwakernaak et al, 2017 ). Thus, therapeutic solutions for reducing COVID-19 severity could be found in the pharmacopeia used by cardiologists to intervene on the RAS.…”

Mathematical modeling of antihypertensive therapy

“…For the pharmacodynamics of aliskiren, we used the kinetic parameters from the study by Hallow et al (2014). Since aliskiren does not affect HR (Stanton et al 2003) and glomerular filtration rate (GFR) (Kwakernaak et al, 2017;Bokuda et al, 2018;Siddiqi et al, 2011), we reproduced the similar behavior of these variables in the model. For this purpose, we generated a test population of 100 virtual hypertensive patients with varying values of SBP, DBP, HR, body weight, and BMI (as described in the current section above).…”

Mathematical Modeling of the Antihypertensive Drugs Action

“…Для принятия решения на основе компьютерного анализа по оптимальному выбору антигипертензивных препаратов мы планируем в дальнейшем внести в программу исследования данные о поражениях органов-мишений и наличии особых клинических ситуаций у пациентов с АГ (например, пожилой возраст, метаболический синдром, сахарный диабет, поражение почек и т.п.). Например, алискирен в виде монотерапии 150 мг/д более эффективен при лечении пациентов с избыточным весом [53].…”