Various studies have confused the norephedrine and norpseudoephedrine isomers with phenylpropanolamine (PPA, d,l-norephedrine). This confusion has led us to investigate the pharmacological activity of the norephedrine (NOR) and norpseudoephedrine (NORP) isomers in the cardiovascular system of the urethane:chloralose anesthetized rat. Following intravenous administration, in a cumulative-dose fashion, l-NOR and PPA were the most potent compounds at increasing arterial blood pressure, while d-NOR, d-NORP, and l-NORP were relatively inactive at the doses tested (0.31-10 mg/kg). Prior reserpinization did not significantly shift the cumulative dose-response curves for l-NOR and PPA. Repetitive injections of PPA and l-NOR (1 mg/kg, 4 doses at 5-min intervals) failed to produce tachyphylaxis to the pressor response. On the other hand, when d-NORP was administered in a similar fashion, tachyphylaxis to the second and subsequent doses was observed. These studies demonstrate that significant mechanistic differences exist between these norephedrine isomers.