title: Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors.
abstract: Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an alpha1-adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor alpha2-adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular alpha2-adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective alpha1-adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective alpha2-adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective alpha2-adrenergic antagonist, rauwolscine (10(-7) M) but was abolished by the selective alpha1-adrenergic antagonist, prazosin (3 x 10(-7) M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential alpha2-adrenergic agonist. At low concentrations, it constricts blood vessels that express functional alpha2-adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular alpha1-adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.
authors.affiliation: DAvis Heart and Lung Research Institute, Ohio State University, Columbus OH 43210, USA. flavahan-1@medctr.osu.edu
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Flavahan
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000068438:Brimonidine Tartrate; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010665:Phenylpropanolamine / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D011810:Quinoxalines; D014662:Vasoconstrictor Agents; D010665:Phenylpropanolamine; D000068438:Brimonidine Tartrate