title: Chronic blockade of phosphatidylinositol 3-kinase in the nucleus tractus solitarii is prohypertensive in the spontaneously hypertensive rat.
abstract: Phosphatidylinositol 3-kinase (PI3K) within brain stem neurons has been implicated in hypertension in the spontaneously hypertensive rat (SHR). Previously, we demonstrated elevated expression of PI3K subunits in rostral ventrolateral medulla and paraventricular nucleus of SHRs compared with Wistar-Kyoto rats. Here, we considered expression levels of PI3K in the nucleus tractus solitarii, a pivotal region in reflex regulation of arterial pressure, and determined its functional role for arterial pressure homeostasis in SHRs and Wistar-Kyoto rats. We found elevated mRNA levels of p110beta and p110delta catalytic PI3K subunits in the nucleus tractus solitarii of adult (12 to 14 weeks old) SHRs relative to the age-matched Wistar-Kyoto rats (fold differences relative to beta-actin: 1.7+/-0.2 versus 1.01+/-0.08 for p110beta, n=6, P<0.05; 1.62+/-0.15 versus 1.02+/-0.1 for p110delta, n=6, P<0.05). After chronic blockade of PI3K signaling in the nucleus tractus solitarii by lentiviral-mediated expression of a mutant form of p85alpha, systolic pressure increased from 175+/-3 mm Hg to 191+/-6 mm Hg (P<0.01) in SHRs but not in Wistar-Kyoto rats. In addition, heart rate increased (from 331+/-6 to 342+/-6 bpm; P<0.05) and spontaneous baroreflex gain decreased (from 0.7+/-0.07 to 0.5+/-0.04 ms/mm Hg; P<0.001) in the SHRs. Thus, PI3K signaling in the nucleus tractus solitarii of SHR restrains arterial pressure in this animal model of neurogenic hypertension.
authors.affiliation: Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Waki
authors.forename: Carlos
authors.initials: C
authors.lastname: Diez-Freire
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gampel
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006339:Heart Rate / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000201:enzymology*
chemical_list: D021122:Protein Subunits; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases