Effects of the novel dopamine beta-hydroxylase inhibitor SK&F 102698 on catecholamines and blood pressure in spontaneously hypertensive rats.
The novel dopamine beta-hydroxylase (D beta H) inhibitor SK&F 102698 was characterized in vitro with soluble enzyme from bovine adrenal medulla and in vivo by measuring the dopamine/norepinephrine (DA/NE) ratio in the mesenteric artery, heart and brains of spontaneously hypertensive rats (SHR). SK&F 102698 was a potent D beta H inhibitor with an IC50 of 1.2 microM on crude enzyme and had a Ki value of 40 nM on purified enzyme. SK&F 102698 produced a dose-dependent fall in NE and a dose-dependent increase in DA in the vasculature of SHR after p.o. administration. Elevation of the vascular DA/NE ratio was observed within 0.5 hr after administration. Peak effects were observed at 12 hr and values were still significantly increased at 18 hr. The rise in the DA/NE ratio of the blood vessels correlated with the fall in blood pressure following the first 4 hr after SK&F 102698. SK&F 102698 inhibited SHR heart D beta H and elevated the myocardial DA/NE ratio approximately 2.4-fold. SK&F 102698 also caused a dose-dependent increase in the whole brain DA/NE ratio of SHR. Catecholamine levels were also studied in six discrete brain regions and SK&F 102698 produced the greatest increase in the DA/NE ratio in the cerebellum, brain stem and midbrain regions, whereas the striatum was the region least affected. No overt sedation was observed in the rats. Further study with SK&F 102698 is warranted to better explore the role of DA and D beta H in pathophysiology, and to determine whether this drug or a congener D beta H inhibitor will be a useful therapeutic agent in humans.
Berkowitz
B A
BA
Smith Kline and French Laboratories, Philadelphia, Pennsylvania.
Arleth
A J
AJ
Sung
C P
CP
Kruse
L I
LI
DeWolf
W E
WE
Ohlstein
E H
EH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001808:Blood Vessels / Q000032:analysis; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000032:analysis*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D005669:Fusaric Acid / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors
C052414:1-(3,5-difluorobenzyl)imidazole-2-thiol; D000959:Antihypertensive Agents; D002395:Catecholamines; D007093:Imidazoles; D004299:Dopamine beta-Hydroxylase; D005669:Fusaric Acid