Angiotensin II Regulates Anxiety and Social-Affective Top-Down and Bottom-Up Attention Control in a Sex-dependent Manner

The renin-angiotensin system (RAS), traditionally known for cardiovascular regulation, has increasingly been recognized as a modulator of cognitive and affective functions. However, whether the RAS regulates attentional control and whether such effects are sex-dependent remain unexplored. The present preregistered, randomized, double-blind, placebo-controlled pharmacological eye-tracking study (N = 79) examined the effects of transient angiotensin II type 1 receptor (AT1R) blockade via losartan (50 mg) on emotional attention control using a validated anti-saccade task with social (emotional faces) and non-social stimuli. Treatment effects on state anxiety and oculomotor responses were characterized using traditional performance metrics and a novel trial-history informed dynamic control (TIDC) framework for adaptive control. Losartan reduced state anxiety irrespective of sex and induced sexually dimorphic reconfiguration of attentional processing. In females, AT1R blockade enhanced performance by reducing endpoint error without altering latency. Conversely, in males, losartan increased endpoint error and prolonged latency of the first correct saccade. Trial-history analyses further revealed that losartan reduced error probabilities following error and repeat trials in both sexes. Yet, following correct trials, females receiving losartan maintained lower error probabilities, while males receiving losartan exhibited higher errors, potentially reflecting a failure to flexibly disengage from the effortful controlled mode. Findings indicate that the RAS modulates anxiety and attentional control, the latter in a sexdependent manner. AT1R blockade can reconfigure attentional processing and adaptive control, suggesting sex-specific therapeutic potential in disorders characterized by excessive anxiety and attentional dysregulation.