angiotensin-iii--ile(7)- and ubenimex

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.

Topics: Aminopeptidases; Angiotensin III; Angiotensin Receptor Antagonists; Animals; Dose-Response Relationship, Drug; In Vitro Techniques; Leucine; Male; Neurons; Prosencephalon; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; Subfornical Organ

We evaluated the participation of endogenous brain angiotensin III (AIII) in central cardiovascular regulation, using the intracerebroventricular injection technique in Sprague-Dawley rats anesthetized with pentobarbital sodium (50 mg/kg, i.p.). AIII (100 pmol) promoted an elevation in systemic arterial pressure and a reduction in the baroreceptor reflex (BRR) response. Its specific antagonist, Ile7-AIII (100 nmol), and the aminopeptidase inhibitor, bestatin (200 nmol), on the other hand, augmented the response of the same reflex. The suppressive action of AIII (100 pmol) on the BRR was attenuated, and the enhancing effect of Ile7-AIII (100 nmol) was potentiated, however, when these two peptides were administered simultaneously with bestatin (200 nmol). All these events were significantly different from their controls during the first 10-15 min following injection, parallel to the time course of a discernible action of AIII on systemic arterial pressure. We discussed that the endogenous AIII in the central nervous system may participate in cardiovascular control by tonically inhibiting the BRR, in concert with other brain neuropeptides.

Topics: Angiotensin II; Angiotensin III; Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cardiovascular System; Injections, Intraventricular; Leucine; Male; Phenylephrine; Pressoreceptors; Rats; Rats, Inbred Strains; Time Factors