Abstract
Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an α1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that α1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the α1B and α1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein–coupled receptor kinase 2–dependent α1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of α1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native α1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that this property of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed α1A-AR regulation. OXY shows functional selectivity relative to NE and PE at α1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by α1A-ARs.
Footnotes
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) [Grant 08/50423-7], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior CAPES [Grant 9150/11-0], Dirección General de Asuntos de Personal Académico-Universidad Nacional Autónoma de México DGAPA-UNAM [Grant IN200812], and Consejo Nacional de Ciencia y Tecnología CONACYT [Grant 177556].
- Received September 10, 2012.
- Accepted January 30, 2013.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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