Antihypertensive effects of CGS 19281A, an inhibitor of phenylethanolamine-N-methyltransferase.

In experimental hypertension, phenylethanolamine-N-methyltransferase (PNMT) activity and adrenaline levels are elevated in brainstem centers involved in cardiovascular regulation. Known PNMT inhibitors used to lower blood pressure have invariably shown alpha adrenergic activity as a side effect. A search for new inhibitors disclosed that CGS 19281A (4,9-dihydro-7-methoxy-3H-pyrido[3,4b]indole) inhibits PNMT (IC50, 2.7 x 10(-6) M) without interacting with the alpha-1 or alpha-2 adrenergic receptors. CGS 19281A (20 mg/kg i.v.) reduced PNMT activity (60% decrease; P less than 0.001) and adrenaline concentration (38%; P less than .025) in the brainstem of normal rats. In conscious deoxycorticosterone acetate-salt rats and spontaneously hypertensive rats, CGS 19281A (20 mg/kg i.v.) decreased blood pressure (50 mm Hg; P less than .001) and heart rate (26-36%; P less than .001) for 3 hr. Elevated brainstem adrenaline levels in deoxycorticosterone acetate-salt rats were decreased by CGS 19281A (42%; P less than .005) whereas i.c.v. administration of CGS 19281A (845 nmol/rat) to conscious spontaneously hypertensive rats decreased blood pressure (20 mm Hg; P less than .010) and heart rate (84 beats/min; P less than .001) as well. Therefore, CGS 19281A may be useful for the study of the function of PNMT and adrenaline in the central nervous system.