Differential neuronal responses to angiotensin III from the subfornical organ of normotensive and spontaneously hypertensive rats.
We previously reported that chronic central administration of angiotensin III (AIII) fails to produce sustained drinking behavior in spontaneously 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 preparation from Wistar-Kyoto rats (WKY) and SHR, in conjunction with single-neuron recording in the subfornical organ (SFO), a target site for angiotensin II-induced drinking. We found that a majority of the SFO neurons studied (13/18 in WKY, 20/28 in SHR) responded in a dose-related manner to AIII, given in the range of 10(-6)-10(-5) M. This excitation was receptor-specific, since it was reversed by Ile7-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 with 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, prolonging the action of AIII by protecting it from being metabolized with bestatin 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.
Yang
C C
CC
Institute of Pharmacology, National Yang-Ming Medical College, Taipei, Taiwan, ROC.
Chan
J Y
JY
Pan
J T
JT
Chan
S H
SH
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000805:Angiotensin III / Q000031:analogs & derivatives / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011921:Rats, Inbred WKY / Q000502:physiology; D011945:Receptors, Angiotensin / Q000502:physiology; D013356:Subfornical Organ / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology
D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D000805:Angiotensin III; C056764:angiotensin III, Ile(7)-; D000626:Aminopeptidases; C019721:aminopeptidase B; D007930:Leucine; C012211:ubenimex