title: Binding of losartan to angiotensin AT1 receptors increases dopamine D1 receptor activation.
abstract: 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.
authors.affiliation: Department of Women's and Children's Health, Karolinska University Hospital, Q2:09, S-171 76 Stockholm, Sweden.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Lena
authors.initials: L
authors.lastname: Scott
authors.forename: Susanne
authors.initials: S
authors.lastname: Crambert
authors.forename: Sergey
authors.initials: S
authors.lastname: Zelenin
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Eklöf
authors.forename: Luis
authors.initials: L
authors.lastname: Di Ciano
authors.forename: Fernando
authors.initials: F
authors.lastname: Ibarra
authors.forename: Anita
authors.initials: A
authors.lastname: Aperia
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001017:Aortic Coarctation / Q000150:complications; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001552:Benzazepines; D044140:Receptor, Angiotensin, Type 1; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D000242:Cyclic AMP; D019808:Losartan