Circulation Research. 2002
Published online before print July 25, 2002, doi: 10.1161/01.RES.0000030861.13850.F1
Published online before print July 25, 2002, doi: 10.1161/01.RES.0000030861.13850.F1
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Submitted on February 1, 2002
Revised on July 12, 2002
Accepted on July 15, 2002
Phosphoinositide 3-Kinase Mediates Enhanced Spontaneous and Agonist-Induced Contraction in Aorta of Deoxycorticosterone Acetate--Salt Hypertensive Rats
Carrie A. Northcott *;
From the Department of Pharmacology and Toxicology (C.A.N., S.W.W.), Michigan State University, East Lansing, Mich; and Medical College of Ohio (M.N.P., S.M.N.), Toledo, Ohio.
* To whom correspondence should be addressed. E-mail: taetscar{at}msu.edu.
Arteries from deoxycorticosterone acetate (DOCA)-salt and N
-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 p85
, p110, p110ß, and p110
but not p110
PI3-kinase subunits; p110 protein was elevated in aorta of hypertensive rats as compared with sham. Aortic homogenates from L-NNA rats also had elevated p110ß protein density, but neither L-NNA nor DOCA-salt had differences in p85 and p110. 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 p110 density in aorta from L-NNA and DOCA-salt rats. Importantly, this increase contributes to the enhanced contractility observed in two models of hypertension.
Key words: phosphoinositide 3-kinase • artery • deoxycorticosterone acetate--salt hypertension • phosphatase and tensin homolog • N
-nitro-L-arginine hypertension
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