Binding of Losartan to Angiotensin AT1 Receptors Increases Dopamine D1 Receptor Activation

• Published in: Journal of the American Society of Nephrology 2012-03, Vol.23 (3), p.421-428
• Main Authors: DONG LI, SCOTT, Lena, CRAMBERT, Susanne, ZELENIN, Sergey, EKLÖF, Ann-Christine, LUIS DI CIANO, IBARRA, Fernando, APERIA, Anita
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Aortic Coarctation - complications; Basic Research; Benzazepines - pharmacology; Benzazepines - therapeutic use; Biological and medical sciences; Cell Membrane - drug effects; Cell Membrane - metabolism; Cyclic AMP - metabolism; Disease Models, Animal; HEK293 Cells; Humans; Hypertension - drug therapy; Hypertension - etiology; In Vitro Techniques; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Losartan - metabolism; Losartan - pharmacology; Losartan - therapeutic use; Male; Medical sciences; Medicin och hälsovetenskap; Nephrology. Urinary tract diseases; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1 - drug effects; Receptor, Angiotensin, Type 1 - metabolism; Receptors, Dopamine D1 - antagonists & inhibitors; Receptors, Dopamine D1 - drug effects; Receptors, Dopamine D1 - metabolism; Signal Transduction - drug effects
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2011040344

Signaling through both angiotensin AT1 receptors (AT1R) and dopamine D1 receptors (D1R) modulates renal sodium excretion and arterial BP. AT1R and D1R form heterodimers, but whether treatment with AT1R antagonists functionally modifies D1R via allosterism is unknown. In this study, the AT1R antagonist losartan strengthened the interaction between AT1R and D1R and increased expression of D1R on the plasma membrane in vitro. In rat proximal tubule cells that express endogenous AT1R and D1R, losartan increased cAMP generation. Losartan increased cAMP in HEK 293a cells transfected with both AT1R and D1R, but it did not increase cAMP in cells transfected with either receptor alone, suggesting that losartan induces D1R activation. Furthermore, losartan did not increase cAMP in HEK 293a cells expressing AT1R and mutant S397/S398A D1R, which disrupts the physical interaction between AT1R and D1R. In vivo, administration of a D1R antagonist significantly attenuated the antihypertensive effect of losartan in rats with renal hypertension. Taken together, these data imply that losartan might exert its antihypertensive effect both by inhibiting AT1R signaling and by enhancing D1R signaling.