Angiotensin IV enhances LTP in rat dentate gyrus in vivo

Angiotensins have been shown to play a significant role in a variety of physiological functions including learning and memory processes, Relatively recent evidence supports the increasing importance of angiotensin IV (Ana IV), in many of these functions previously associated only with Ana II, including learning and memory, An interesting hypothesis generated by these results has been that Ana II is a precursor for the production of a more active peptide fragment, Ana IV. Since Ana II impairs learning and memory, when administered directly or released into the hippocampal dentate gyrus, and inhibits long term potentiation (LTP) in medial perforant path-dentate granule cell synapses, as well, it remained to be seen what effects Ana IV had on LTP in these same synapses. Results of this study show clearly that Ana IV significantly enhances LTP, and the enhancement is both dose and time dependent. The following solutions of Ana IV were administered over a five min period, at the end of baseline and before the first tetanus was applied: 2.39, 4.78. and 9.56 nM. An inverted U-type dose related effect was observed. A complex time related effect was observed with a maximum at 5 min, a return to normal LTP at 30 min and a minimum below normal at 90 min, and a return to normal LTP at 120 min. The effects of the 4.78 nM solution were determined at the following intervals between administration and the first tetanus: 5, 15, 30, 60, 90, and 120 min. The enhancement of LTP can be prevented by pretreatment with Divalinal, an Ana IV antagonist, without any effect on normal LTP. Two solutions of Divalinal were used; 5 nM and 5 AM, and the 5 AM was more effective and completely blocked the enhancement of normal LTP. Results were also obtained with 4.78 nM Nle(1)-Ang IV (Norleucine), an Ana IV agonist. Norleucine was less effective than Ana IV in the enhancement of normal LTP and displayed a similar time course of activity. Both Ana IV and Norleucine produced a significant suppression of normal LTP at 90 min; that remains to be explained. However, the inhibition by Ana TV was dose dependent and was blocked by Divalinal. The fact that the Ana IV enhancement of normal LTP was blocked by losartan, an Ana II AT, receptor antagonist, is puzzling since Divalinal had no effect on the inhibition of LTP by Ana II. (C) 2001 Elsevier Science Inc. All rights reserved.