Neuropeptide Y (NPY) is co-released with norepinephrine, and stimulates vasoconstriction, vascular and cardiomyocyte hypertrophy via Y1 receptors (R), and angiogenesis via Y2R. Although circulating NPY is elevated in heart failure, NPY's role remains unclear. Activation of the NPY system was determined in Wistar rats with the aortocaval (AV) fistula model of high-output heart failure. Plasma NPY levels were elevated in AV fistula animals (115.7±15. 3 vs 63.1±17.4 pM in sham, P<0.04). Animals either compensated (urinary Na+ excretion returning to normal with moderate disease (COMP)); or remained decompensated with severe cardiac and renal failure (urinary Na+ excretion <0.5 mEq/day), increased heart weight, decreased mean arterial pressure and renal blood flow (RBF), and death within 5-7 days (DECOMP). Cardiac and renal tissue NPY decreased with heart failure, proportionate to the severity of renal complications. Cardiac and renal Y1R mRNA expression also decreased (1.5-fold, P<0.005) in rats with heart failure. In contrast, Y2R expression increased up to 72-fold in the heart and 5.7-fold in the kidney (P<0.001) proportionate to severity of heart failure and cardiac hypertrophy. Changes in receptor expression were confirmed since the Y1R agonist, [Leu31, Pro34]-NPY, had no effect on RBF, while the Y2R agonist (13-36)-NPY increased RBF to compensate for disease. Thus, in this model of heart failure, cardiac and renal NPY Y1 receptors decrease and Y2 receptors increase, suggesting an increased effect of NPY on the receptors involved in cardiac remodeling and angiogenesis, and highlighting an important regulatory role of NPY in congestive heart failure.