Functional evidence for subfornical organ-intrinsic conversion of angiotensin I to angiotensin II

Abstract

Using extracellular electrophysiological recording in an in vitro slice preparation, we investigated whether ANG I can be locally converted to the functionally active ANG II within the rat subfornical organ (SFO). ANG I and ANG II (10−8–10−7M) excited ∼75% of all neurons tested with both peptides ( n = 25); the remainder were insensitive. The increase in firing rate and the duration and the latency of the responses of identical neurons, superfused with equimolar concentrations of ANG I and ANG II, were not different. The threshold concentrations of the ANG I- and ANG II-induced excitations were both 10−9M. Inhibition of the angiotensin-converting enzyme by captopril (10−4M; n = 8) completely blocked the ANG I-induced excitation, a 10-fold lower dose was only effective in two of four neurons. The AT1-receptor antagonist losartan (10−5M; n = 6) abolished the excitation caused by ANG I and ANG II. Subcutaneous injections of equimolar doses of ANG I and ANG II (200 μl; 2 × 10−4M) in water-sated rats similarly increased water intake by 2.4 ± 0.5 ( n = 16) and 2.7 ± 0.4 ml ( n = 20) after 1 h, respectively. Control rats receiving saline drank 0.07 ± 0.06 ml under these conditions. Pretreatment with a low dose of captopril (2.3 × 10−3M) 10 min before the injection of ANG I caused a water intake of 2.8 ± 0.5 ml ( n = 10), whereas a high dose of captopril (4.6 × 10−1M) suppressed the dipsogenic response of ANG I entirely ( n = 11). These data provide direct functional evidence for an SFO-intrinsic renin-angiotensin system (RAS) and underline the importance of the SFO as a central nervous interface connecting the peripheral with the central RAS.