Brain angiotensin (Ang II) is important in the central control of blood pressure and plays a critical role in the development and establishment of hypertension. Furthermore, the spontaneously hypertensive rat (SHR) also exhibits increased brain Ang II activity. Although the physiology of the cardiovascular actions of brain Ang II is well established, little is known about the cellular and molecular bases of these actions or the hyperactivity of the brain Ang II in the SHR. The P.I. began studies to discover these mechanisms during the last grant period. The P.I. has revealed that Ang II, via AT receptor subtype (AT1R) stimulates an acute (Evoked) release of neuronal norepinephrine (NE), and a chronic (Enhanced) increase in NE synthesis and uptake, the latter via NE transporter (NET). While the intracellular signaling that mediates Evoked NE responses have not been established, the Enhanced stimulation involves Ras-Raf-1- MAP kinase signaling system and transcription of NET, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DbH) genes. In addition, increased expression of AT1R in the SHR is associated with a parallel stimulation of both Evoked and Enhanced effects on NE. The P.I. has hypothesized that (i) the Evoked NE release is associated with increased neuronal activity and involves activation of Ca2+-calmodulin-CAM kinase II signaling pathway; (ii) the Enhanced NE neuromodulation is associated with increased transcriptional activity and involves phosphorylation of a nuclear pore complex nucleoporin, p62, activation of protein kinase Cb and phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS); and (iii) stimulation of P13 kinase by Ang II is linked with the Enhanced NE neuromodulation in the SHR and not in normotensive rat brain neurons. The objective of this proposal is to provide evidence in support of these hypotheses by investigating the following four aims: The mechanism of Ang II regulation of Evoked NE neuromodulation, especially the roles of phospholipase C, PKC, CAM kinase II and K+ and Ca2+ channels. The involvement of p62 and MARCKS phosphorylation on Ang II regulation of Enhanced NE neuromodulation. The role of Ang II in regulation of P13 kinase and its role in NE neuromodulation in SHR neurons. Finally, in vivo experiments will validate the intracellular signaling mechanisms developed from in vitro experiments. The P.I. hopes to establish a unifying intracellular signal transduction mechanism of Ang II neuromodulation of NE. The studies will pinpoint the cellular basis of an altered brain Ang II in hypertension and thus, would be important towards improved therapies for hypertension.
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