Endothelin and the role of venous capacitance in fluid retention with endothelin antagonists -- a mathematical modeling analysis

Abstract

Background and objectives: Selective endothelin-1 (ET1) receptor A (ETA) antagonists have been evaluated for the treatment of chronic kidney disease and cancer. However, the investigation has been challenged due to the increased safety concern of fluid retention, which can increase the risk of heart failure. The mechanisms responsible for the fluid retention remain incompletely understood, in part because of the complexity of the endothelin system. The objective of this study was to incorporate the physiology of ET1, its receptors ETA and ETB, and their mechanisms of action into an existing model of cardiorenal function, and to investigate physiological mechanisms that may explain fluid retention observed with endothelin receptor antagonists. Methodology: Processes of ET1 production from BigET-1, distribution between peripheral compartments (kidney/lung) and blood, binding to ETA/ETB, and clearance were modeled. Parameters were estimated by fitting to experimental studies of ET-1 kinetics following ET-1 or BigET-1 infusion. A minimal set of physiological effects of ET1-bound ETA and ETB were estimated by fitting published experimental data of ET1 infusion with and without ETA or ETB antagonism in healthy subjects. The model was then used to simulate changes in eGFR, mean arterial pressure (MAP), urinary albumin creatinine ratio (UACR), and hematocrit with the ETA antagonist atrasentan in the RADAR clinical trial. Results and Conclusions: The model describes ET-1 kinetics well, and reproduces responses to ET1 infusion in healthy subjects, including changes in GFR, renal blood flow, renal vascular resistance, urinary sodium/water excretion, and mean arterial pressure. It was also able to differentiate the response to ETA and ETB antagonism. The determined minimal set of necessary mechanisms were: systemic, afferent, and efferent vasoconstriction and proximal tubule sodium retention through ETB; efferent dilatation and reduced collecting duct sodium and water reabsorption through ETB. While these mechanisms described the response in healthy subjects well and reproduced the reduction in MAP with atrasentan in the RADAR study, the the model initially underpredicted the change in UACR and predicted hematocrit would decrease, when in fact the study showed an increase, reflecting fluid retention and increased blood volume. We hypothesized that the changes in MAP and blood volume in opposite directions in RADAR indicate increased venous capacitance with ETA antagonism due to venodilation. Adding this single mechanistic effect (i.e. ET-1 induced vasoconstriction) into the model allowed it to fully reproduce the MAP, UACR, and hematocrit response in RADAR. In addition, simulations with the model illustrate the mechanisms by which venodilation can alter starling forces, leading to redistribution of fluid, a vasopressin response, and fluid retention with ETA antagonism. AstraZeneca Pharmaceuticals This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.