It is now established that the brain contains a renin-angiotensin system which plays an important role in the central regulation of blood pressure. Considerable evidence exists that this role of central angiotensin (Ang) is mediated by catecholamines (CA). These observations taken together with the evidence that the central Ang system is hyperactive in certain types of experimental hypertension, suggest that central Ang-CA interactions may be important in the development and/or maintenance of hypertension. The objective of this research is to elucidate the mechanism of this interaction. We propose to investigate this in a novel way with the use of neuron-enriched co-cultures from hypothalamus and brain stem. Preliminary results have shown that neuronal cultures from the brains of spontaneously hypertensive (SH) rats possess lower Ang II levels, higher numbers of Ang II specific receptors and altered norepinephrine re-uptake compared with their normotensive, Wistar Kyoto (WKY) rats. In addition, we have formulated the hypothesis that Ang and CA interact in a negative feedback manner in WKY brain cultures whereas cultures from SH rat brains lack such a negative feedback control. The significance of these observations is that alterations in central Ang-CA interactions in hypertensive animals are expressed at a very early age which may be associated with the development and not as a result of hypertension. Neurons will be cultured from the hypothalamus and brain stem of one day old rats, i.e., areas which contain CA and Ang neurons and are imporant in cardiovascular regulation. Characterization of Ang II receptors, Ang II synthesis, CA receptors and the turnover of CA in co-cultures of WKY and SH rats will be carried out. The mechanism of central Ang II-CA interactions will be compared in WKY and SH brain cultures. This will include effects of CA on Ang II receptors and synthesis, and the regulation of CA metabolism and receptors by Ang II. Finally, the hypothesis developed in cell cultures describing possible alterations in the mechanism of Ang II-CA interactions from SH rat brains will be validated by in vivo experiments. Such a neurobiological approach at the cellular level will provide new information towards the understanding of the role of central Ang II-CA interactions in the hypertensive state, and may lead to new strategies for the management and prevention of this disease.
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