Circulating levels of leptin are increased in obesity and have been proposed to contribute to the development of hypertension in obese individuals. Four cardiac hormones, specifically, vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide and atrial natriuretic peptide (ANP), have blood pressure-lowering properties and correlate with the presence of hypertension in obesity. The objective of this study was to determine whether one or more of these cardiac hormones was able to decrease the levels of leptin in the hypothalamus, an area of the brain that has been demonstrated to synthesize more than 40% of leptin in the circulation. The effects of these four cardiac hormones on leptin were examined using dose-response curves in the rat hypothalamus, which synthesizes leptin. Vessel dilator, LANP, kaliuretic peptide and ANP maximally decreased the levels of leptin in hypothalamic cells by 79, 76, 80 and 62%, respectively (P<0.0001 for each). The cardiac hormones decreased leptin levels over a concentration range of 100 pM to 10 μM, with the most significant reductions in leptin levels occurring when the concentrations of the hormones were at micromolar levels. The results of the study suggest that the four cardiac hormones lead to significant reductions in hypothalamic leptin levels, which may be an important mechanism for alleviating leptin-induced hypertension in obesity.