Abstract-Urotensin II is a small peptide whose receptor was recently identified in mammals as the orphan G protein-coupled receptor-14. The reported cardiovascular responses to systemic urotensin II administration are variable, and there is little detailed information on its central cardiovascular actions. We examined the cardiovascular and humoral actions of intracerebroventricular urotensin II (0.02 and 0.2 nmol/kg and vehicle) and intravenous urotensin II (2, 20, and 40 nmol/kg and vehicle) in conscious ewes previously surgically implanted with flow probes and intracerebroventricular guide tubes. Two hours after intracerebroventricular infusion of urotensin II (0.2 nmol/kg over 1 hour; nϭ5), heart rate (ϩ56Ϯ13 beats per minute, and cardiac output (ϩ3.4Ϯ0.4 L/min) increased significantly compared with vehicle, as did renal, mesenteric, and iliac blood flows and conductances. Plasma epinephrine, adrenocorticotropic hormone, and glucose levels also increased dramatically (ϩ753Ϯ166 pg/mL, ϩ14.3Ϯ3.5 pmol/L, and ϩ7.0Ϯ1.4 mmol/L, respectively). All of these variables remained elevated for up to 4 hours after infusion. In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; nϭ6), a sustained tachycardia (ϩ25Ϯ8 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly. In summary, this is the first study to show that urotensin II acts centrally to stimulate sympathoadrenal and pituitary-adrenal pathways, resulting in increased adrenocorticotropic hormone and epinephrine release and potent chronotropic and inotropic actions. In contrast, tachycardia was the only major response to intravenous urotensin II. These findings suggest that urotensin II is a novel stimulator of central pathways that mediate responses to alerting stimuli or stress.

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