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(Circulation Research. 2005;96:277.)
© 2005 American Heart Association, Inc.

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Increased PI3-Kinase in Presympathetic Brain Areas of the Spontaneously Hypertensive Rat

Shereeni J. Veerasingham, Masanobu Yamazato, Kathleen H. Berecek, J. Michael Wyss, Mohan K. Raizada

From the Department of Physiology and Functional Genomics (S.J.V., M.Y., M.K.R.), University of Florida, Gainesville; and the Departments of Physiology (K.H.B.) and Cell Biology (M.W.), University of Alabama, Birmingham.

Correspondence to Prof Mohan K. Raizada, PhD, Department of Physiology and Functional Genomics, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu

Existing evidence led us to hypothesize that increases in p85, a regulatory subunit of PI3-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85, p110, and p110 mRNA was 1.5- to 2-fold higher in the paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHR) compared with their controls, Wistar Kyoto rats (WKY). The increase in p85/p110 was attenuated in SHR treated with captopril, an angiotensin (Ang)-converting enzyme inhibitor, from in utero to 6 months of age. In the rostral ventrolateral medulla (RVLM), p110 mRNA was 2-fold higher in SHR than in WKY. Moreover, the increases in mRNA were associated with higher PI3-kinase activity in both nuclei. The functional relevance was studied in neuronal cultures because SHR neurons reflect the augmented p85 mRNA and PI3-kinase activity. Expression of a p85 dominant-negative mutant decreased norepinephrine (NE) transporter mRNA and [³H]NE uptake by 60% selectively in SHR neurons. In summary, increased p85/p110 expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PI3-kinase p85/p110 expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.

Key Words: PI3-kinase • spontaneously hypertensive rats • norepinephrine transporter • paraventricular nucleus • rostral ventrolateral medulla

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