Abstract--Neuropeptide Y is a potent inhibitory neurotransmitter expressed in the central neurons that control blood pressure. NO also serves as an inhibitory neurotransmitter, and its deficit causes sympathetic overactivity, which then contributes to hypertension. This study tested the hypothesis that neuropeptide Y functions as a central neurotransmitter to lower blood pressure, therefore its increased signaling ameliorates hypertension induced by NO deficiency. Conscious neuropeptide Y transgenic male rats, overexpressing the peptide under its natural promoter, and nontransgenic littermates (controls) were used in this study. Neuropeptide Y, Y1 receptor antagonist BIBP3226, or vehicle (saline) were administered continuously for 14 days into the cerebral lateral ventricle in unrestrained animals using osmotic pumps. Blood pressure was measured by radiotelemetry. Compared with control animals, transgenic overexpression of neuropeptide Y significantly ameliorated (by 9.7±1.5 mm Hg) NO deficiency hypertension (induced by administration of N()-nitro-L-arginine methyl ester in the drinking water). This hypotensive effect of neuropeptide Y upregulation was associated with reduced proteinuria and cardiac hypertrophy and fibrosis. Central administration of neuropeptide Y in nontransgenic rats also reduced (by 10.2±1.6 mm Hg) the NO deficiency hypertension, whereas a neuropeptide Y1 receptor antagonist centrally administered in the transgenic subjects during NO deficiency hypertension completely attenuated the depressor effect of neuropeptide Y upregulation. Thus, acting at the level of the central nervous system distinctively via a Y1 receptor-mediated mechanism, endogenous neuropeptide Y exerted a potent antihypertensive function, and its enhanced signaling ameliorated NO deficiency hypertension.