Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats

Carrie A. Northcott, Matthew N. Poy, Sonia M. Najjar, Stephanie W. Watts

Research output: Contribution to journalArticlepeer-review

Abstract

Arteries from deoxycorticosterone acetate (DOCA)-salt and Nω-nitro-L-arginine (L-NNA) hypertensive but not normotensive rats develop spontaneous tone. LY294002 and wortmannin, phosphoinositide 3-kinase (PI3-kinase) inhibitors, eliminate spontaneous tone. We hypothesized that PI3-kinase protein and/or activity was increased in hypertension and contributed to the observed enhanced contractility. PI3-kinase activity assays revealed 2-fold higher activity in thoracic aorta from DOCA-salt [systolic blood pressure (SBP) = 184±5 mm Hg] compared with sham rats (SBP=111±2 mm Hg). Western analyses of aortic homogenates revealed the presence of p85α, p110α, p110β, and p110δ but not p110γ PI3-kinase subunits; p110δ protein was elevated in aorta of hypertensive rats as compared with sham. Aortic homogenates from L-NNA rats also had elevated p110β protein density, but neither L-NNA nor DOCA-salt had differences in p85α and p110α. Total Akt density was unaltered, but pAkt was significantly lower in homogenates from DOCA-salt rats. LY294002 (20 μmol/L) and nifedipine (50 nmol/L) abolished Ca2+-induced spontaneous tone in aorta from DOCA-salt rats. However, LY294002 did not alter BayK8644-induced contraction, indicating that LY294002 does not inhibit L-type Ca2+ channels directly. PTEN (phosphatase and tensin homolog) and pPTEN were expressed but not different in aorta from DOCA-salt and sham rats. LY294002 corrected the enhanced contraction to KCl and norepinephrine in aorta from DOCA-salt rats. These data support an increase in PI3-kinase activity and p110δ density in aorta from L-NNA and DOCA-salt rats. Importantly, this increase contributes to the enhanced contractility observed in two models of hypertension.

Original languageEnglish (US)
Pages (from-to)360-369
Number of pages10
JournalCirculation research
Volume91
Issue number4
DOIs
StatePublished - Aug 23 2002
Externally publishedYes

Keywords

  • Artery
  • Deoxycorticosterone acetate-salt hypertension
  • N-nitro-L-arginine hypertension
  • Phosphatase and tensin homolog
  • Phosphoinositide 3-kinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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