Chronic activation of 3-adrenergic receptors leads to tissue water and electrolyte retention

3-Adrenergic receptors (3-ARs) are expressed on the membranes of various cell types, and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function, and metabolic processes. However, 3-AR-associated body fluid imbalance has not been well characterized. In the present study, we hypothesized that chronic 3-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a nonselective 3-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart; increased the total body sodium, potassium, and water contents at the tissue level; and increased the water intake and blood pressure of mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a nonselective 3 receptor inhibitor. Isoproterenol-treated mice, even without excessive water intake, had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that 3-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that 3-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterization of 3-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of 3-AR inhibitors. Significance Statement: This study has shown that chronic 3-adrenergic receptor (3-AR) stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium, and water at the tissue level. This characterization of the 3-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of 3-AR in physiology and pathophysiology and the pharmacological effects of 3-AR inhibitors. (c) 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.