Myocardial, Smooth Muscle, Nephron, and Collecting Duct Gene Targeting Reveals the Organ Sites of Endothelin A Receptor Antagonist Fluid Retention

Endothelin-1 binding to endothelin A receptors (ETA) elicits profibrogenic, proinflammatory, and proliferative effects that can promote a wide variety of diseases. Although ETA antagonists are approved for the treatment of pulmonary hypertension, their clinical utility in several other diseases has been limited by fluid retention. ETA blocker-induced fluid retention could be due to inhibition of ETA activation in the heart, vasculature, and/or kidney; consequently, the current study was designed to define which of these sites are involved. Mice were generated with absence of ETA specifically in cardiomyocytes (heart), smooth muscle, the nephron, the collecting duct, or no deletion (control). Administration of the ETA antagonist ambrisentan or atrasentan for 2 weeks caused fluid retention in control mice on a high-salt diet as assessed by increases in body weight, total body water, and extracellular fluid volume (using impedance plethysmography), as well as decreases in hematocrit (hemodilution). Mice with heart ETA knockout retained fluid in a similar manner as controls when treated with ambrisentan or atrasentan. Mice with smooth muscle ETA knockout had substantially reduced fluid retention in response to either ETA antagonist. Mice with nephron or collecting duct ETA disruption were completely prevented from ETA blocker-induced fluid retention. Taken together, these findings suggest that ETA antagonist-induced fluid retention is due to a direct effect of this class of drug on the collecting duct, is partially related to the vascular action of the drugs, and is not due to alterations in cardiac function.