Circulation Research. 2002;91:360-369
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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© 2002 American Heart Association, Inc.
Integrative Physiology |
Phosphoinositide 3-Kinase Mediates Enhanced Spontaneous and Agonist-Induced Contraction in Aorta of Deoxycorticosterone Acetate-Salt Hypertensive Rats
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.
Correspondence to Carrie A. Northcott, MS, Dept of Pharmacology and Toxicology, B445 Life Science Building, Michigan State University, East Lansing, MI 48824-1317. E-mail taetscar@ 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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