The purpose of the study was to investigate the effects of agmatine, an endogenous clonidine-displacing substance (CDS), on systemic hemodynamics in the anesthetized rat. Bolus intravenous (i.v.) injections of agmatine decreased systemic arterial pressure (SAP) and systemic vascular resistance in a dose-dependent manner. The development of acute tachyphylaxis to the systemic vasodepressor response to agmatine did not induce cross-tachyphylaxis to the systemic vasodepressor responses to bradykinin, isoproterenol and nitroglycerin. The present data demonstrate agmatine, as a CDS and agonist for imidazoline (I) receptors, possesses marked systemic vasodilator activity in the rat. The present data suggest that activation of I receptors may represent a novel mechanism of vasodilation in vivo.