Neuropeptide Y (NPY) is a 36-residue peptide amide produced by cleavage from a large precursor, preproNPY, that is widely distributed in the central and peripheral nervous system. In the periphery, NPY is co-stored and co-released with noradrenaline in sympathetic nerve fibres. Its actions are mediated through G protein-coupled receptors denoted Y1-Y6. In the rat heart, NPY mRNA is expressed in the cell bodies of intrinsic neurons and endothelial cells. The actions of NPY in the heart are extensive and include practically every cardiac cell type. The Y1 receptor induces vasoconstriction and regulates protein turnover and constitutive gene expression in hypertrophying cardiomyocytes. Investigations to date have implicated the role of NPY in the pathology of a number of diseases including diabetes (Pons et al. 2004). Here, we investigated the involvement of this system in the events underlying development of diabetic cardiomyopathy in the rat model of streptozotocin (STZ)-induced diabetes by real-time RT-PCR, and immunohistochemistry. Wistar rats were humanely killed 6 and 9 months after intravenous application of STZ (65 mg/kg body weight). The quantitative RT-PCR reactions were carried out in a iCycler (BioRad). Relative gene expression was expressed as a ratio of target gene concentration to housekeeping gene. Statistical analysis of relative gene expression was done by Kruskal-Wallis test followed by Mann-Whitney test. Throughout, the results were considered significantly different when p<0.05. Expression of preproNPY mRNA was significantly lower in the left atrium 6 months after induction of the diabetes (n=5; mean=0.42; p=0.008), and it returns to control or slightly elevated levels 9 month of the duration of the disease (n=5; mean=1.39). The difference between STZ and vehicle-treated animals was not statistically significant. These changes were accompanied by initial up-regulation of Y1 receptor mRNA level at 6 month after application of STZ; however, statistical significance was not reached (n=5; p=0.16). Indirect immunofluorescence show NPY-immunoreactive (IR) nerve fibres distributed in myocardium and in the vicinity of coronary vessels in animals treated with vehicle. Some of these fibres displayed simultaneously dopamine beta-hydroxylase (DBH) immunolabelling indicating their sympathetic origin. In the hearts of animals both 6 and 9 months after STZ application, there were very few NPY-IR nerve fibres. Most of the fibres labelled by DBH antibody did not show NPY-IR. The persistence of Y1 receptors might contribute to the putative cardioprotective role of the NPY signalling system.