Brain Angiotensin In Hypertensive Neurons in Culture

$622,096R37FY2010HLNIH

University Of Florida, Gainesville FL

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Abstract

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 the brain rennin-angiotensin system is illustrated by observations 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 cellular and molecular basis of this hyperactivity. Our studies during the last grant period have led to a significant advancement towards our understanding of the cellular mechanism of an hyperactivity Ang II in the SHR brain. We discovered that a greater stimulation of NE neuromodulation and neuronal activity by Ang II is a result of an exclusive recruitment of the PIS kinase signaling system by the AT1 receptor in the SHR neurons. Microarrayprofiling analysis demonstrated that the increase in PIS kinase in the SHR neuron is due to an increased expression of p85a, a regulatory subunit of this enzyme. In vivo validation of these findings has been established. These observations have led us to hypothesize that an increased expression of p85a in the RVLM of the SHR brain is responsible for the development and establishment of hypertension. Present proposal is designed to support/refute this hypothesis by investigating the following four specific aims: (1) Investigate cardiovascular effects of p85a knockdown in the RVLM of the SHR, (2) determine roles of PVN and NTS p85a and PIS kinase on hypertension in the SHR (3) investigate the role of the AT1R in neural control of cardiovascular functions and (4) validate or refute the hypothesis that genetic blocking of PIS kinase hyperactivity in the RVLM attenuates hypertension in non-genetic neurogenic rat model of hypertension. Outcomes of this study will not only be a major advancement towards the molecular/cellular basis but would also be critical in the exploration of its therapeutic potential in the control of neurogenic hypertension.

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