The effects of a centrally acting phenylethanolamine N-methyl-transferase (PNMT) inhibitor, SKF 64139, and of its analog, SKF 72223, which is devoid of PNMT inhibitory activity on blood pressure and heart rate, were investigated in spontaneously hypertensive rats (SHR) and in DOCA-salt hypertensive rats. SKF 64139 lowers blood pressure and decreases pulse rate, while SKF 72223 lowers blood pressure and transiently increases pulse rate in SH-rats and in DOCA-salt hypertensive rats. SKF 72223 has no effect on blood pressure or heart rate in normotensive Wister-Kyoto rats. These results suggest that the antihypertensive action elicited by these two tetrahydroisoquinoline (TIQ) derivatives is not due to lowering of central epinephrine (E) levels. To determine whether the cardiovascular response elicited by SKF 72223 is due to stimulation of presynaptic alpha 2-adrenoreceptors, or to blockade of alpha 1-adrenoreceptors, we have examined its effect in combination with the partial alpha 2-agonist clonidine, or with the alpha 1-antagonist prazosin. The administration of clonidine slightly decreases the antihypertensive action of SKF 72223. The clonidine induced reduction in pulse rate is reversed by SKF 72223. In animals pretreated with prazosin, SKF 72223 elicits an additional decrease in blood pressure. Since SKF 64139 and SKF 72223 interact with alpha 2-adrenoreceptors, it is suggested that blockade of peripheral vascular alpha 2-adrenoreceptors might be in part responsible for their antihypertensive action. However, the antihypertensive action of these two drugs might also be due to some central mechanisms.