The central nervous system plays a major role in the regulation of the cardiovascular system and there is a great deal of evidence that indicate that neurogenic mechanisms may contribute to the development of hypertension. An increase in the activity of the brain angiotensin II (Ang II) system has been implicated as a possible causative factor in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The present experiments are designed to utilize high resolution quantitative imaging technique to monitor the activity of the brain Ang II system in hypertensive rats in order to determine whether an alteration in the regulation of this system can be linked to the development or maintenance of hypertension. We propose to: 1) Identify putative angiotensinergic neurons in CNS by localizing angiotensinogen A-ogen) mRNA by in situ hybridization; co- localizing A-ogen mRNA with either immunoreactive A-ogen or Ang II; and correlating the distribution of these neurons with the distribution of Ang II receptors by receptor autoradiography. 2) Quantitate the neuronal levels of Ang II by radioimmunohistochemistry and monitor the level of Ang II and Ang I following central angiotensin-converting enzyme inhibition in order to estimate the neuronal turnover of Ang II. 3) Having established these quantitative procedures to focus on specific angiotensinergic systems in areas of central autonomic control, we will then monitor the activity of the brain Ang II system by correlating changes in the neuronal levels of Ang II and/or A-ogen mRNA with changes in Ang II receptors in the following hypertensive models: SHR and Wistar Kyoto rats at various stages from fetal to adult; DOCA-salt rats; and Dahl salt-sensitive and salt-resistant rats on high and low salt diets. The brain areas that we will focus on contain angiotensinergic nerve elements and are physiologically linked to cardiovascular control; including the paraventricular n., supraoptic n., circumventricular organs, perifornical area, and solitary-vagal area. The simultaneous examination of these variables of neurotransmission (i.e. peptide synthesis, storage, turnover and postsynaptic receptors) should provide important new insights into the regulation of the brain Ang II system in hypertension.
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