PI3-Kinase Upregulation and Involvement in Spontaneous Tone in Arteries From DOCA-Salt Rats

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Abstract
Increased expression of phosphoinositide 3-kinase (PI3-kinase) mediates elevated tone in the aorta from hypertensive deoxycorticosterone acetate (DOCA)-salt rats. In this article, we hypothesized that (1) alterations observed with respect to PI3-kinase observed in the aorta would also occur in mesenteric resistance arteries responsible for determining total peripheral resistance (TPR) and (2) p110δ activity was increased and localized to vascular smooth muscle cells (VSMCs), and was responsible for the increase in spontaneous tone in aortae from DOCA-salt rats. Mesenteric resistance arteries and aorta were isolated from DOCA-salt (190±3 mm Hg) and sham (121±2 mm Hg) rats. Myograph experiments revealed LY294002 (20 μmol/L), a PI3-kinase inhibitor, significantly decreased tone in mesenteric resistance arteries from DOCA-salt rats as compared with sham (−49±12 mg versus −10±7 mg). Western analyses of resistance artery protein homogenate revealed p85α and p110δ subunit protein, with significantly elevated levels of p110δ protein in the DOCA-salt compared with sham rats (0.30±0.07 versus 0.16±0.04% smooth muscle alpha-actin arbitrary units). Immunohistochemistry revealed p110δ-specific staining in VSMCs, with more intense staining in aortae from DOCA-salt rats. Compared with aortae from sham, p110δ-associated PI3-kinase activity was increased in DOCA-salt (158% of sham) and likely responsible for spontaneous tone because the p110δ specific inhibitor IC87114 decreased spontaneous tone in a concentration-dependent manner. Collectively, these data further implicate the p110δ isoform of PI3-kinase in arterial hyperresponsiveness in hypertension at the level of both large and small arteries.