Background: A hypertensive response to exercise (HRE) is associated with increased aortic stiffness. Spironolactone is thought to improve aortic stiffness via BP-independent (antifibrotic) effects, but the exact mechanisms are unknown. This study aimed to determine the underlying physiological actions of spironolactone in people with HRE.

Methods: 115 people with HRE (aged 54±9 years) were randomized to three months spironolactone (25mg/d) or placebo. Serum samples and physiological data including aortic stiffness (pulse wave velocity; PWV) and 24 hour ambulatory BP were recorded at baseline and three months. Liquid chromatography/mass spectrometry and untargeted metabolomics profiling were used to identify metabolites (endogenous and/or drug metabolites) that were significantly different after spironolactone treatment compared with placebo.

Results: Spironolactone significantly reduced aortic PWV (P=0.047), but this change was no longer significant after adjustment for the change in daytime systolic BP (P=0.132). Metabolomics profiling identified 43 features (nothing endogenous) that corresponded to downstream spironolactone metabolites, including canrenoate, but none of these correlated with the change in aortic PWV (P>0.05 for all). However, canrenoate was significantly related to the reduction in daytime systolic BP (r=−0.355, P=0.017) and 24 hour PP (r=−0.332, P=0.026). These associations remained significant on multiple regression analysis after adjustment for sex and body mass index.

Conclusions: The downstream spironolactone metabolite canrenoate appears to be an active metabolite with BP-dependent effects on the attenuation of aortic stiffness in people with HRE. This finding, together with the lack of change in endogenous metabolites relating to fibrosis, suggests that the antifibrotic effects of spironolactone could be BP-dependent.