Summary
A bioRxiv preprint reports that BCKDK inhibitors relax blood vessels by antagonising the angiotensin II type 1 receptor (AT1R), independently of BCKDK and branched-chain amino-acid breakdown. The experimental findings raise the possibility that some effects of these inhibitors arise from this separate receptor action.
A bioRxiv preprint reports that inhibitors developed to affect branched-chain amino-acid breakdown can also act directly on a blood-pressure receptor. In experiments involving explanted vessels, in-vivo measurements and genetically modified mice, the researchers found that the drugs’ vasodilatory effect came from antagonising the angiotensin II type 1 receptor (AT1R), rather than from inhibiting BCKDK or changing branched-chain amino-acid (BCAA) catabolism.
The result identifies a separate mechanism that could matter as BCKDK inhibitors are studied for conditions including diabetes and heart failure. The authors say the receptor action may help explain reported cardioprotective effects, while raising a question about how those effects would combine with existing AT1R-blocking medicines.
A second action beyond BCAA metabolism
BCKDK is a regulator of the breakdown of branched-chain amino acids. Interest in inhibiting it has grown because BCAAs have been implicated in diabetes and heart failure, and the preprint notes that BCKDK inhibitors are being examined in clinical trials.
The new work focuses on vasodilation: the widening of blood vessels, which can reduce the resistance against which the heart pumps. The researchers report that this effect was rapid and independent of nitric oxide, BCAA catabolism and BCKDK itself. Instead, structural and biochemical studies indicated that the inhibitors directly antagonised AT1R.
AT1R responds to angiotensin II, a signalling molecule that promotes blood-vessel constriction. Blocking this receptor therefore offers a direct explanation for the vessel-relaxing effect described in the preprint. The findings distinguish the drugs’ action at AT1R from their intended role in regulating BCAA metabolism.
What the finding could mean for drug studies
The evidence comes from experimental studies using explanted vessels, measurements of haemodynamics and telemetry in living animals, genetically modified mice, and structural and biochemical analyses. It is preclinical research, not a clinical study showing that BCKDK inhibitors lower blood pressure or improve outcomes in people.
The proposed mechanism matters when interpreting future studies of these inhibitors: an effect attributed to altered BCAA metabolism could also involve AT1R blockade. Since medicines that block AT1R are already used, the authors identify whether BCKDK inhibitors provide additional protection alongside them as an open research question. The work is posted as a bioRxiv preprint.