DIFFERENTIAL NEURONAL RESPONSES TO ANGIOTENSIN-III FROM THE SUBFORNICAL ORGAN OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

We previously reported that chronic central administration of angioten sin III (AIII) fails to produce sustained drinking behavior in spontan eously hypertensive rats (SHR), possibly because of the development of early desensitization of the angiotensin receptors. The present study extended these findings to the cellular level, using brain-slice prep aration from Wistar-Kyoto rats (WKY) and SHR, in conjunction with sing le-neuron recording in the subfornical organ (SFO), a target site for angiotensin II-induced drinking. We found that a majority of the SFO n eurons studied (13/18 in WKY, 20/28 in SHR) responded in a dose-relate d manner to AIII, given in the range of 10(-6)-10(-5) M. This excitati on was receptor-specific, since it was reversed by Ile(7)-AIII(10(-4)- 10(-3) M), the selective AIII antagonist. Bestatin (10(-5)-10(-4) M), an aminopeptidase B inhibitor, did not discernibly affect basal spike frequency when delivered alone. Nevertheless, given in combination wit h the heptapeptide, bestatin reduced the intensity and duration of SFO neuronal response in WKY to the higher dose (10(-5) M), and in SHR to both doses (10(-6) or 10(-5) M), of AIII. These data suggest that the SFO may also be a central site of action for AIII. Moreover, prolongi ng the action of AIII by protecting it from being metabolized with bes tatin may produce desensitization of the angiotensin receptors on SFO neurons. This was particularly so in the SHR, which are thought to be defective in the degradation of the heptapeptide in the brain.