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Desensitization of AT₁ Receptor-Mediated Cellular Responses Requires Long Term Receptor Down-Regulation in Bovine Adrenal Glomerulosa Cells¹

Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

Address all correspondence and requests for reprints to: Dr. Gaétan Guillemette, Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, 3001 12^e Avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4.

Angiotensin II (Ang II) regulates aldosterone production in bovine adrenal glomerulosa cells by interacting with the AT₁ receptor. This receptor is coupled to a G protein that controls the activity of phospholipase C. With a primary culture of bovine adrenal glomerulosa cells, we evaluated the desensitization of cellular responses after pretreatment with Ang II. When cells were pretreated for 30 min with 1 µM Ang II at 37 C, we observed a 48% loss of [¹²⁵I]Ang II-binding activity. Scatchard analysis revealed that this decreased binding activity corresponded to a 53% loss of the total number of binding sites. This phenomenon was time dependent, with a t_1/2 of 20 min, and a maximal loss of 76% of the total binding sites was observed after 14 h. A time-dependent decrease in AT₁ receptor messenger RNA levels was also observed after pretreatment with 1 µM Ang II for 12–24 h. Taken together, these results are interpreted as a down-regulation of the AT₁ receptor. Desensitization of phospholipase C activity under similar conditions was, however, a slower process, with a t_1/2 of 9 h and a maximal response reduction of 83% observed after 24 h. Dose-response experiments indicated that maximal phospholipase C desensitization was obtained in the presence of 1 µM Ang II, with an EC₅₀ of 90 nM. The desensitization was of a homologous nature, as a 24-h pretreatment with Ang II did not affect bradykinin-induced inositol phosphate production. A 24-h pretreatment with 1 µM Ang II also significantly desensitized the steroidogenic effect of Ang II and the potentiating effect of Ang II on ACTH-induced cAMP production. Lower concentrations of Ang II (10 nM) did not produce any desensitizing effect on these two parameters. This study provides evidence that glomerulosa cells are functionally resistant to short term desensitization of the AT₁ receptor and that long term down-regulation with high concentrations of Ang II is needed to desensitize AT₁-mediated cellular responses.

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