Kinetics of endothelin-1 and effect selective ET_A antagonism on ET_B activation: a mathematical modeling analysis

Endothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ET_A receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ET_B receptor, either through increased ET-1 or non-selective ET_B.

A mathematical model of ET-1 kinetics was developed to quantify effects of ET_A antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ET_A and ET_B receptors. The model describes ET-1 production, tissue and plasma distribution, ET_A and ET_B receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies.

The model confirmed the significant role of ET_B in ET-1 clearance. By varying both drug ET_A selectivity (K_ib/K_ia) and concentration over a wide range, simulations predicted that while selective ET_A antagonist (selectivity >1) always decreased [ET1-ET_A], the change in [ET1-ET_B] was more complex. It increased up to 45% as drug concentrations approached and exceeded K_ia, but the increase was diminished as drug concentration increased further and fell below baseline at high concentrations. The drug concentration required to cause a decrease in [ET1-ET_B] was lower as ET_A selectivity decreased.

This is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ET_B blockade on ET-1 concentrations. It provides a useful tool that can coupled with experimental studies to quantitively understand and investigate this complex and dynamic system.