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(Hypertension. 2003;41:898.)
© 2003 American Heart Association, Inc.

Scientific Contributions

PI3-Kinase–Induced Hyperreactivity in DOCA-Salt Hypertension Is Independent of GSK-3 Activity

Robert D. Loberg; Carrie A. Northcott; Stephanie W. Watts; Frank C. Brosius, III

From the Departments of Internal Medicine and Physiology, University of Michigan (R.D.L., F.C.B.), Ann Arbor, Mich; and Department of Pharmacology and Toxicology, Michigan State University (C.A.N., S.W.W.), East Lansing, Mich.

Correspondence to Frank C. Brosius, University of Michigan, 1560 MSRB2, 1150 W. Medical Center Dr, Ann Arbor, MI 48109-0676. E-mail fbrosius{at}umich.edu

Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 µmol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.

Key Words: muscle, smooth, vascular • glycogen synthase kinase 3 • deoxycorticosterone • hypertension, sodium-dependent

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