Abstract 11591: Mechanism of Finerenone-Induced Vasorelaxation in Arteries From Human Visceral Adipose Tissue

Abstract

Introduction: Inadequate perfusion has emerged as a main determinant of adipose tissue (AT) dysfunction in obesity, sparking interest about possible ways to improve it. Among several mechanisms, mineralcorticoid receptor (MR) signaling has been shown to play a key role in the cross-talk between AT and the vasculature. Hypothesis: This study, therefore, tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries harvested from human AT. Methods: Small arteries (<1 mm in diameter) were isolated from visceral AT and studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone were determined under different experimental conditions. Results: Finerenone elicited a concentration-dependent relaxation in arteries of obese individuals contracted with the thromboxane A2 analogue U46619 (n=9; P<0001 vs. baseline); the steroidal MR antagonist potassium canrenoate, by contrast, did not induce any vasorelaxation (n=3; P>0.05). The relaxing effect of finerenone on U46619-induced constriction was not different in arteries from lean (n=3) and obese subjects (P=0.155). Mechanistically, the vasorelaxing response to finerenone was not influenced by pre-incubation with the nitric oxide (NO) synthase inhibitor L-NAME (n=4; P=0.19 vs. saline), hence ruling out an involvement of NO. Interestingly, finerenone was also able to relax arteries contracted with endothelin-1 (n=7; P<0.001) or with high-K + solution (n=4; P<0001), as well as those contracted with the L-type Ca 2+ -channel agonist BayK8644 (n=5; P=0.007); similarly, the calcium-channel blocker nifedipine induced relaxation of arteries contracted with BayK8644 (n=3; P<0.001). Conclusions: Finerenone induces NO-independent vasorelaxation in arterioles from human visceral AT, likely through antagonism of L-type Ca2 + -channels. This finding identifies a novel action of finerenone to improve AT perfusion, thereby potentially expanding the emerging observations about the cardiovascular benefits of this agent.