In previous work we established that phenyl-2-aminoethyl sulfide (PAES) and derivatives of this basic structure are novel substrate analogs for the adrenergic synthetic enzyme, dopamine beta-monooxygenase (DBM). We examined the in vivo effects of infusions of PAES and ring-hydroxylated (HOPAES) and/or alpha-methylated derivatives (MePAES, HOMePAES) and observed antihypertensive activity in SHR with HOPAES and HOMePAES using an indirect blood pressure measuring protocol. We now wish to report that by employing a direct blood pressure measuring technique we have been able to demonstrate a potent antihypertensive activity of all these derivatives in conscious, unrestrained spontaneously hypertensive rats (SHR) that persisted beyond a 6-h testing period. We found that MePAES, which displayed only a minor antihypertensive activity in the indirect measurements, was the most potent antihypertensive in the direct measuring protocol. In addition, in this report we demonstrate a potent chronic antihypertensive effect for MePAES over a 2-week period in SHR using continuous infusion with implanted osmotic pumps. From a comparison of the effects of the hydroxylated and alpha-methylated derivatives, we conclude that: (a) the locus of the antihypertensive activity is primarily in peripheral adrenergic sites; (b) alpha-methylation of the basic structure imparts an increased affinity for peripheral adrenergic uptake sites that may be responsible for its increased antihypertensive potency; and (c) monoamine oxidase (MAO) catabolism plays a relatively unimportant role in the termination of the activity of these compounds. These results also demonstrate the importance of direct blood pressure measurements in assaying antihypertensive activity of test compounds that possess indirect sympathomimetic activity. The implications of these findings in terms of the mechanism by which these compounds exert their anti-hypertensive activity is discussed.