Abstract
The present study examined the modulator role of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway activated by the α-1 adrenoceptor agonist phenylephrine in ATP-sensitive K+ channel function in intact vascular smooth muscle. We evaluated the ATP-sensitive K+ channel function and the activity of the PI3K–Akt pathway in the rat thoracic aorta without endothelium. The PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) (10−5 M) augmented relaxation in response to the ATP-sensitive K+ channel opener levcromakalim (10−8 to 3 × 10−6 M) in aortic rings contracted with phenylephrine (3 × 10−7 M) but not with 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α (U46619; 3 × 10−8 M), although those agents induced similar contraction. ATP-sensitive K+ channel currents induced by levcromakalim (10−6 M) in the presence of phenylephrine (3 × 10−7 M) were enhanced by the nonselective α-adrenoceptor antagonist phentolamine (10−7 M) and LY294002 (10−5 M). Levels of the regulatory subunits of PI3K p85-α and p55-γ increased in the membrane fraction from aortas without endothelium treated with phenylephrine (3 × 10−7 M) but not with U46619 (3 × 10−8 M). Phenylephrine simultaneously augmented Akt phosphorylation at Ser473 and Thr308. Therefore, activation of the PI3K–Akt pathway seems to play a role in the impairment of ATP-sensitive K+ channel function in vascular smooth muscle exposed to α-1 adrenergic stimuli.
Footnotes
This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [Grants 19390409, 18659462].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167775.
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ABBREVIATIONS:
- PI3K
- phosphatidylinositol 3-kinase
- LY294002
- 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
- U46619
- 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α
- PSS
- physiological salt solution
- PBS
- phosphate-buffered saline.
- Received March 2, 2010.
- Accepted June 1, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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