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.
Chatelain
R E
RE
Research Department, Ciba-Geigy Corporation, Summit, New Jersey.
Manniello
M J
MJ
Dardik
B N
BN
Rizzo
M
M
Brosnihan
K B
KB
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002395:Catecholamines / Q000032:analysis; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines
D000959:Antihypertensive Agents; D002243:Carbolines; D002395:Catecholamines; D007546:Isoquinolines; D011942:Receptors, Adrenergic, alpha; D044005:Tetrahydroisoquinolines; C062736:4,9-dihydro-7-methoxy-3H-pyrido(3,4b)indole; D003900:Desoxycorticosterone; C012153:7,8-dichloro-1,2,3,4-tetrahydroisoquinoline; D010625:Phenylethanolamine N-Methyltransferase