Both leptin (LEP) and amylin (AMN) are putative weight-reducing factors of clinical relevance to the treatment of obesity. First, we examined the possibility that chronic peripheral LEP infusion at physiological levels would inhibit food intake but decrease blood pressure. Male rats were instrumented for telemetry, housed in metabolic chambers, and given LEP or saline (SAL) via a subcutaneous mini-osmotic pump for 7 days. LEP infusion reduced food intake, reversibly decreased mean arterial pressure (MAP) from baseline ( SAL: -3.6±2.1 LEP: -7.8±1.5 PF: -4.0±1.0 mmHg), and prevented the bradycardia ( SAL: 20±4 LEP: 32±4 PF:-25±6 bpm) associated with pair-feeding. On the other hand, acute, central LEP infusion produced hypertension and tachycardia suggesting competing peripheral and central mechanisms. To test the hypothesis that leptin stimulates nitric oxide production to induce vasodilation, we administered LEP along with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME). LNAME prevented the depressor effect of chronic leptin suggesting a role of nitric oxide leptin-induced reductions in blood pressure. Second, we examined the effects of AMN+LEP on cardiovascular and metabolic physiology. Compared to controls, LEP infusion reduced food intake and visceral fat mass by 21% in lean rats but had no effect in obese rats. AMN infusion reduced food intake in lean and obese rats (LEAN:24% OBESE :30%) but reduced fat mass by 25% in lean rats only. In lean and obese rats, AMN+LEP synergistically reduced food intake (LEAN:57% OBESE:59%) and fat mass (LEAN:56% OBESE:41%) while LEP-induced reductions in MAP were not altered in AMN+LEP treatment. Collectively, these observations highlight the importance of studying the cardiovascular role of LEP at physiological doses and studying AMN+LEP in the amelioration of obesity. We conclude that physiological leptin reduces blood pressure via nitric oxide-dependent pathways. Further, amylin may restore leptin sensitivity in leptin resistant obese rats, which has clinical relevance to obesity treatment.