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

Autor:	Yu H; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States., Greasley P; Early Clinical Development, Research, and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden., Lambers-Heerspink H; Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands.; The George Institute for Global Health, Sydney, NSW, Australia., Boulton DW; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States., Hamrén B; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Hallow KM; School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United States.; Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Apr 05; Vol. 15, pp. 1332394. Date of Electronic Publication: 2024 Apr 05 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1332394
Abstrakt:	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. Competing Interests: This study received funding from AstraZeneca Pharmaceuticals. The funder had the following involvement in the study: Employees of AstraZeneca are co-authors on this manuscript and were involved in conceptualization, project administration, supervision, formal analysis, investigation, methodology, validation, review and editing. HY, PG, DB, and BH are employees of AstraZeneca and own AstraZeneca stock or stock options. HL-H is a consultant for and received honoraria from AbbVie, Astellas, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen and Merck. He has a policy that all honoraria are paid to his employer. KH has received research funding from AstraZeneca in the last 3 years. (Copyright © 2024 Yu, Greasley, Lambers-Heerspink, Boulton, Hamrén and Hallow.)
Databáze:	MEDLINE
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