Increased PI3-kinase in presympathetic brain areas of the spontaneously hypertensive rat.
Existing evidence led us to hypothesize that increases in p85alpha, a regulatory subunit of PI3-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85alpha, p110alpha, and p110delta 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 p85alpha/p110delta 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), p110delta mRNA was approximately 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 p85alpha mRNA and PI3-kinase activity. Expression of a p85 dominant-negative mutant decreased norepinephrine (NE) transporter mRNA and [3H]NE uptake by approximately 60% selectively in SHR neurons. In summary, increased p85alpha/p110delta expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PI3-kinase p85alpha/p110delta expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.
Veerasingham
Shereeni J
SJ
Department of Physiology and Functional Genomics, University of Florida, Gainesville 32610, USA.
Yamazato
Masanobu
M
Berecek
Kathleen H
KH
Wyss
J Michael
JM
Raizada
Mohan K
MK
D000818:Animals; D001921:Brain / Q000201:enzymology*; D058534:Class I Phosphatidylinositol 3-Kinases; D019586:Intracranial Hypertension / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017384:Sequence Deletion / Q000235:genetics / Q000502:physiology; D013564:Sympathetic Nervous System / Q000201:enzymology*; D027981:Symporters / Q000378:metabolism
D007527:Isoenzymes; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; D009638:Norepinephrine