We provide the first report of direct effects of resistin upon haemodynamic and neurohumoral parameters in isolated perfused rat heart preparations. Pre-conditioning with 1 nmol L-1 recombinant human resistin prior to ischaemia significantly impaired contractile recovery during reperfusion, compared with vehicle-infused hearts (P<0.05, n=12). This was accompanied by a significant increase in both A-type and B-type natriuretic peptides (P<0.05, n=12 both ANP and BNP vs vehicle), creatine kinase, and tumour necrosis factor-alpha (TNF-alpha) release in resistin-infused hearts. Resistin had no significant effect on myocardial glucose uptake. Co-infusion of resistin with Bay 11 7082 (an NF-kappaB inhibitor) improved contractile recovery following ischaemia and reduced both natriuretic peptide and creatine kinase release. This is the first evidence indicating resistin impairs cardiac recovery following ischaemia, stimulates cardiac TNF-alpha secretion, and modulates reperfusion release of natriuretic peptides and biochemical markers of myocardial damage. A TNF-alpha signalling related mechanism is suggested as one component underlying these effects.