The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynamic homeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD2s ≥9) approximately an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the most, if not the most, potent mammalian vasoconstrictor identified to date. However, in vitro responses exhibited significant anatomical and/or species-dependency, that is, human U-II was a selective ‘aorto-coronary’ vasoconstrictor in rats and dogs, inactive in mice and contracted all primate arteries studied. In vivo, this peptide evoked a complex, dose-dependent hemodynamic response in the anesthetized primate, culminating in severe myocardial depression and fatal circulatory collapse. As such, U-II may represent a novel neurohumoral regulator of mammalian cardiovascular physiology and pathology in particular disorders characterized by aberrant vascular smooth muscle and/or myocardial function.
Departments of Cardiovascular Pharmacology and *Laboratory Animal Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
Address correspondence and reprint requests to Dr Stephen A. Douglas, Senior Investigator, Department of Cardiovascular Pharmacology (UW2510), SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406-0939, U.S.A. E-mail: email@example.com
© 2000 Lippincott Williams & Wilkins, Inc.