Existing evidence led us to hypothesize that increases in p85α, a regulatory subunit of PI37-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85α, p110α, and p110δ 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 p85α/p110δ 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), p110δ 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 p85α 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 p85α/p110δ expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PD-kinase p85α/p110δ expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.