Abstract |
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.
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Authors | R E Chatelain, M J Manniello, B N Dardik, M Rizzo, K B Brosnihan |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 252
Issue 1
Pg. 117-25
(Jan 1990)
ISSN: 0022-3565 [Print] United States |
PMID | 2153796
(Publication Type: Journal Article)
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Chemical References |
- Antihypertensive Agents
- Carbolines
- Catecholamines
- Isoquinolines
- Receptors, Adrenergic, alpha
- Tetrahydroisoquinolines
- 4,9-dihydro-7-methoxy-3H-pyrido(3,4b)indole
- Desoxycorticosterone
- 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline
- Phenylethanolamine N-Methyltransferase
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Topics |
- Animals
- Antihypertensive Agents
(pharmacology)
- Blood Pressure
(drug effects)
- Carbolines
(pharmacology)
- Catecholamines
(analysis)
- Desoxycorticosterone
- Dose-Response Relationship, Drug
- Isoquinolines
(pharmacology)
- Phenylethanolamine N-Methyltransferase
(antagonists & inhibitors)
- Rabbits
- Rats
- Rats, Inbred SHR
- Rats, Inbred Strains
- Receptors, Adrenergic, alpha
(drug effects, metabolism)
- Tetrahydroisoquinolines
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