Aims Angiotensin II (Ang II) and tumour necrosis factor α (TNFα) are involved in the progression from compensated hypertrophy to heart failure. Here, we test their role in the remodelling of ATP-dependent potassium channel (KATP) in heart failure, conferring increased metabolic and diazoxide sensitivity. Methods and results We observed increased expression of both angiotensinogen and TNFα in the failing rat myocardium, with a regional gradient matching that of the KATP subunit Kir6.1 expression. Both angiotensinogen and TNFα expression correlated positively with Kir6.1 and negatively with Kir6.2 expression across the post-infarction myocardium. To further identify a causal relationship, cardiomyocytes isolated from normal rat hearts were exposed in vitro to Ang II or TNFα. We observed increased Kir6.1 and SUR subunit and reduced Kir6.2 subunit mRNA expression in cardiomyocytes cultured with Ang II or TNFα, similar to what was observed in failing hearts. In patch-clamp experiments, cardiomyocytes cultured with Ang II or TNFα exhibited responsiveness to diazoxide, in terms of both KATP current and action potential shortening. This was not observed in untreated cardiomyocytes and resembles the diazoxide sensitivity of failing cardiomyocytes that also overexpress Kir6.1. Ang II exerted its effect through induction of TNFα expression, because TNFα-neutralizing antibody abolished the effect of Ang II, and in failing hearts, regional expression of angiotensinogen matched TNFα expression. Finally, Ang II and TNFα regulated KATP subunit expression, possibly through differential expression of Forkhead box transcription factors. Conclusion This study identifies Ang II and TNFα as mediators of the remodelling of KATP channels in heart failur
