The proposed work concerns the critical role of the circumventricular organs (CVOs) in the development and maintenance of essential hypertension in the Spontaneously Hypertensive Rat (SHR). The CVOs are regions of the brain that have relatively no blood-brain-barrier and are therefore directly accessible to blood-borne molecules of less than 70,000 MW. Fenestrated capillaries in CVOs allow filtration of small molecules into the interstitial spaces in concentrations that closely parallel their free plasma levels. Four CVOs have been shown to have cardiovascular modulatory functions. Data from this laboratory indicate that glutamate-sensitive neurons in CVOs are critically involved in mechanisms supporting SHR hypertension. A single parenteral dose of monosodium L-glutamic acid (MSG) in young adult SHRs reverses hypertension. The same treatment in the borderline hypertensive adolescent SHRs prevents the development of adult hypertension without impairing growth rate or health. Importantly, the same treatment does not affect blood pressure in either normotensive Wistar Kyoto or Sprague Dawley rats. HYPOTHESIS: Among the many neuronal elements within CVOs, THERE EXIST GLUTAMATE-SENSITIVE NEURONS THAT CAN POWERFULLY MODULATE NEURAL CONTROL OF THE CIRCULATION VIA CONNECTIONS TO BRAIN CARDIOVASCULAR REGULATORY CENTERS DISTAL TO THE CVOs. MSG TREATMENT MAY PROVIDE LONG-TERM PROTECTION FROM HYPERTENSION BECAUSE IT ELIMINATES THE SYMPATHOEXCITATORY EFFECT OF THESE CVO MODULATORY SYSTEMS WITHOUT INTERFERING WITH THE MAIN SYMPATHETIC NERVOUS SYSTEM OR BAROREFLEX CONTROL OF BLOOD PRESSURE. Functional analysis of the hemodynamic events responsible for the reversal of hypertension in the young adult SHR will be performed as blood pressure normalizes and for several days after normalization of blood pressure. Protocol are described for determination of blood pressure parameters, cardiac output, heart rate, stroke volume, total peripheral resistance and regional blood flow changes in SHR vs WKY rats. These studies will lay the groundwork for future nutritional and pharmacological exploitation of the neurochemistry of cardiovascular CVO neurons with treatments that cannot be used behind the blood-brain barrier. The location of powerful cardiovascular modulatory systems at CVOs suggests an organization ideally suited to integrate neural and humoral information. If a simple amino acid like glutamate can have this marked an effect on blood pressure in the SHR, many other blood-borne nutrients may be able to excite or inhibit CVO neurons.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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University of Georgia
Schools of Pharmacy
United States
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