Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating α2-adrenoceptors

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 α₁-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 α₂-adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular α₂-adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective α₁-adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective α₂-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 α₂- adrenergic antagonist, rauwolscine (10^-7 M) but was abolished by the selective α₁-adrenergic antagonist, prazosin (3 × 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 α₂-adrenergic agonist. At low concentrations, it constricts blood vessels that express functional α₂-adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular α₁- adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.