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.

Elevated plasma catecholamines and adrenal phenylethanolamine N-methyl transferase in experimental renal hypertension.

The participation of plasma catecholamine alterations in the development of renal hypertension is uncertain. Therefore, plasma catecholamines and phenylethanolamine N-methyl transferase (PNMT) activity in the adrenal gland were studied in rats with aortic ligation between the renal arteries. Blood pressure reached a plateau after 12 days (mean arterial pressure (MAP): 194 +/- 3 mmHg; P less than 0.001) and its elevation was accompanied by a biphasic elevation in plasma adrenaline. The first elevation (4-fold above control levels; P less than 0.001) occurred at 24 h after aortic ligation and lasted for 4 days. The second elevation commenced on day 6, reached its zenith at day 9 (16-fold increase; P less than 0.005) and lasted for 6 days. The first elevation was associated with the highest levels of plasma renin activity (PRA) (34-fold increase; P less than 0.001) and glucocorticoids (74% increase; P less than 0.001) but plasma noradrenaline, plasma dopamine and adrenal PNMT activity were minimally affected. However, a statistically significant increase in PNMT activity preceded and accompanied the second adrenaline elevation. Despite falling PRA and glucocorticoid levels, marked increases in plasma noradrenaline (5-fold increase; P less than 0.001) and plasma dopamine (2.5-fold increase; P less than 0.010) were observed. These experiments identify an early activation of the sympatho-adrenal axis in renal hypertension. Apparently there is a rapid release of the adrenaline pool followed by an elevation in PNMT activity. The results suggest that the sympatho-neuronal axis is also activated leading to increases in both plasma noradrenaline and dopamine levels.

Metabolism of tripelennamine in man.

Four polar metabolites were isolated from the urine of human subjects orally treated with tripelennamine, and their structures elucidated by various chemical and physical methods. One of the metabolites, which is a minor one, was identified as an N-oxide of tripelennamine, and the other three as glucuronide conjugates. One of the conjugates, which is a major metabolite, has been assigned a unique quaternary ammonium N-glucuronide structure, since it gave tripelennamine and D-glucuronic acid on incubation with beta-glucuronidase. The N-oxide, which has also been prepared synthetically, remained unchanged on similar treatment. The other two conjugates were O-glucuronides of hydroxylated derivatives, the glucuronide of hydroxytripelennamine being the principal metabolite. No desmethyltripelennamine was found in the urine, however. Hydroxylation in both cases had occurred in the pyridine ring.