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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)898-902
Number of pages5
JournalHypertension
Volume41
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Keywords

  • Deoxycorticosterone
  • Glycogen synthase kinase 3
  • Hypertension, sodium-dependent
  • Muscle, smooth, vascular

ASJC Scopus subject areas

  • Internal Medicine

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