Background Sympathetic overactivity and catecholamine accumulation are important characteristic findings in heart failure, which contribute to its pathophysiology. However, the mechanism underlying circulating catecholamine accumulation remains largely unclear.

Objective To identify a novel mechanism underlying norepinephrine accumulation in a rat model of heart failure.

Methods and results Initially, we constructed a rat model of unilateral renal artery stenosis and found that the expression of renalase, a previously identified secreted amine oxidase, was markedly reduced in the ischaemic compared to the non-ischaemic kidney. Subsequently, we utilised an isolated perfused rat kidney model to demonstrate that the clearance rate of norepinephrine decreased with reduction of either perfusion flow or pressure. On the basis of these findings, we hypothesised that the reduced renal blood supply which occurs in heart failure would result in impaired synthesis of renalase by the kidney and consequently reduced degradation of circulating norepinephrine. To verify this, we used a rat model of infarction-induced heart failure caused by ligation of the left anterior descending coronary artery. In these rats, renal expression of renalase, when measured at 4 weeks, was reduced, and this was associated with an increase in circulating norepinephrine.

Conclusions We conclude that impaired synthesis of renalase by the kidney may represent a novel mechanism underlying circulating norepinephrine accumulation in heart failure.