Quantifying the integrated physiological effects of endothelin-1 on cardiovascular and renal function in healthy subjects: a mathematical modeling analysis

• Published in: Frontiers in pharmacology Vol. 15; p. 1332394
• Main Authors: Yu, Hongtao, Greasley, Peter, Lambers-Heerspink, Hiddo, Boulton, David W., Hamrén, Bengt, Hallow, K. Melissa
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2024
• Subjects: cardiovascular and renal function; endothelin-1; ETA receptor antagonist; ETB receptor antagonist; mathematical modeling; natriuresis and diuresis; mathematical modeling; cardiovascular and renal function; ETB receptor antagonist; ETA receptor antagonist; natriuresis and diuresis; endothelin-1
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1332394

Endothelin-1 (ET-1) is a potent vasoconstrictor with strong anti-natriuretic and anti-diuretic effects. While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ET A and ET B , the complexity of responses and sometimes conflicting data make it challenging to understand the effects of ET-1, as well as potential therapeutic antagonism of ET-1 receptors, on human physiology. In this study, we aimed to develop an integrated and quantitative description of ET-1 effects on cardiovascular and renal function in healthy humans by coupling existing experimental data with a mathematical model of ET-1 kinetics and an existing mathematical model of cardiorenal function. Using a novel agnostic and iterative approach to incorporating and testing potential mechanisms, we identified a minimal set of physiological actions of endothelin-1 through ET A and ET B receptors by fitting the physiological responses (changes in blood pressure, renal blood flow, glomerular filtration rate (GFR), and sodium/water excretion) to ET-1 infusion, with and without ET A /ET B antagonism. The identified mechanisms align with previous experimental studies on ET-1 and offer novel insights into the relative magnitude and significance of endothelin’s effects. This model serves as a foundation for further investigating the mechanisms of ET-1 and its antagonists.