ANGIOTENSIN-II DECREASES INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION IN RAT ASTROGLIAL CULTURES

Consistent with stimulation of expression of an inducible form of nitr ic oxide synthase (iNOS), exposure of rat astroglial cultures to lipop olysaccharide (LPS) caused a time-dependent increase in the accumulati on of nitrite in the culture media. Addition of the peptide angiotensi n II (ANG II) with LPS decreased subsequent formation of nitrite in a concentration-dependent manner (concentration inhibiting 50% of maxima l response similar to 1 nM). The ANG II effect could be blocked by the ANG II type 1 (AT(1)) receptor antagonist losartan but not by the ANG II type 2 (AT(2)) receptor antagonist PD-123177. ANG II had no effect on nitrite formation stimulated by a combination of inflammatory cyto kines (interleukin-1 beta, tumor necrosis factor-alpha, and interferon -gamma). A brief 10-min exposure to ANG II was sufficient to cause an similar to 30% inhibition of the LPS response, with maximal inhibition of similar to 65% after 3 h, and occurred only when ANG II was added during the iNOS induction phase. Consistent with partial inhibition of LPS-stimulated expression of iNOS, ANG II reduced the levels of both iNOS mRNA and iNOS protein. These results demonstrate that ANG II can decrease LPS-stimulated NO production in astroglia by inhibiting induc tion of iNOS expression.