Brain angiotensin (Ang II) exerts key regulatory influences in the central control of blood pressure and thus plays a critical role in the development and establishment of hypertension. The importance of this system is illustrated by the observation that interruption of its activity using pharmacological or genetic means reverses hypertension. Although the physiology of the brain Ang II system in hypertension is well established, little is known about the cellular and molecular basis of this hyperactivity. We began studies to elucidate these mechanisms during the last grant period. We have discovered that Ang II, via the AT1 receptor subtype (AT1 R) stimulates both acute (evoked) release of norepinephine (NE) and chronic (enhanced) increase in NE synthesis, uptake and release in neurons from both normotensive (WKY) and spontaneously hypertensive rats (SHR). We have also discovered that a greater stimulation of NE neuromodulation by Ang II is the result of an exclusive coupling of the AT1R with the PI3 Kinase (PI3K) signaling system. We HYPOTHESIZE: that (1) In SHR neurons the greater AT1 R-mediated evoked Ang II response involves PI3K-L-type-Ca2 + channel signaling while the enhanced response is a result of exclusive coupling of AT1R to PI3K-AKT/PKB-GSK-3 signaling, (2) An increase in PI3K activity as a result of an increased expression of PI3Ky isoform in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to hypertension; and (3) Genetic inhibition of the RVLM PI3K would reverse hypertension on a long-term basis. Thus, our objective is to provide evidence to support/or refute the hypothesis. Combined in vitro and in vivo techniques that utilize cellular, molecular, gene transfer and physiological approaches will be used to accomplish these objectives. The studies will establish a novel central mechanism of Ang II action in the brain of hypertensive rats. In addition, the results of these studies will allow us to explore their therapeutic potential in the long-term control of centrally mediated hypertension.
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