The novel cyclic undecapeptide human urotensin-II (hU-II) and its high-affinity G-protein-coupled receptor, GPR14, are both expressed within the human cardiovasculature (vascular smooth muscle, endothelium, myocardium, coronary atheroma, etc.) and may, therefore, contribute to the (patho)physiological regulation of cardiovascular homeostasis in humans. Indeed, hU-II is an efficacious, sustained spasmogen of mammalian isolated blood vessels including those from rats, rabbits, dogs, pigs, non-human primates and humans (where it is one to two orders of magnitude more potent than endothelin(ET)-1). In vivo, hU-II markedly alters systemic hemodynamics in the anesthetized primate (increase cardiac contractility [dP/dt], increase stroke volume, decrease total peripheral resistance) ultimately resulting in fatal cardiovascular collapse. As such, the development of selective hU-II receptor antagonists may be of utility in the management of cardiovascular disorders characterized by aberrant vasoconstriction, myocardial dysfunction and/or cardiac remodeling (e.g., myocardial infarction, congestive heart failure).