Binding of Losartan to Angiotensin AT1 Receptors Increases Dopamine D1 Receptor Activation
Autor: | Fernando Ibarra, Dong Li, Anita Aperia, Luis A. Di Ciano, Ann-Christine Eklöf, Lena Scott, Sergey Zelenin, Susanne Crambert |
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Rok vydání: | 2012 |
Předmět: |
Male
medicine.medical_specialty In Vitro Techniques Kidney Aortic Coarctation Losartan Receptor Angiotensin Type 1 Kidney Tubules Proximal Rats Sprague-Dawley Dopamine receptor D1 Internal medicine Renin–angiotensin system Cyclic AMP medicine Animals Humans Receptor Angiotensin II receptor type 1 Chemistry Receptors Dopamine D1 Cell Membrane HEK 293 cells General Medicine Benzazepines Rats Disease Models Animal HEK293 Cells Basic Research Endocrinology Nephrology Renal sodium excretion Hypertension Signal transduction Angiotensin II Type 1 Receptor Blockers Protein Binding Signal Transduction medicine.drug |
Zdroj: | Journal of the American Society of Nephrology. 23:421-428 |
ISSN: | 1046-6673 |
Popis: | 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. |
Databáze: | OpenAIRE |
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