Phosphoinositide 3-Kinase Mediates Enhanced Spontaneous and Agonist-Induced Contraction in Aorta of Deoxycorticosterone Acetate-Salt Hypertensive Rats

• Published in: Circulation research 2002-08, Vol.91 (4), p.360-369
• Main Authors: Northcott, Carrie A, Poy, Matthew N, Najjar, Sonia M, Watts, Stephanie W
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - chemistry; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Calcium - metabolism; Calcium Channel Agonists - pharmacology; Calcium Channel Blockers - pharmacology; Cardiology. Vascular system; Desoxycorticosterone; Disease Models, Animal; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Experimental diseases; Hypertension - chemically induced; Hypertension - physiopathology; In Vitro Techniques; Male; Medical sciences; Nitroarginine; Phosphatidylinositol 3-Kinases - analysis; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Phosphoric Monoester Hydrolases - analysis; Phosphoric Monoester Hydrolases - biosynthesis; Protein Subunits; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; Tumor Suppressor Proteins - analysis; Tumor Suppressor Proteins - biosynthesis; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000030861.13850.F1

ABSTRACT—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 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 Ca-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 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.