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
2002 Circulation Research  
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
more » ... lood pressure (SBP)ϭ184Ϯ5 mm Hg] compared with sham rats (SBPϭ111Ϯ2 mm Hg). Western analyses of aortic homogenates revealed the presence of p85␣, p110␣, p110␤, 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 p110␤ 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 mol/L) and nifedipine (50 nmol/L) abolished Ca 2ϩ -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 Ca 2ϩ 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. (Circ Res. 2002;91:360-369.) Key Words: phosphoinositide 3-kinase Ⅲ artery Ⅲ deoxycorticosterone acetate-salt hypertension Ⅲ phosphatase and tensin homolog Ⅲ N -nitro-L-arginine hypertension Original
doi:10.1161/01.res.0000030861.13850.f1 pmid:12193470 fatcat:2w5ut4qi25cfzeofcneqcwnfxa