In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors.
L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.
Kivlighn
S D
SD
Department of Cardiovascular Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
Zingaro
G J
GJ
Gabel
R A
RA
Broten
T P
TP
Chang
R S
RS
Ondeyka
D L
DL
Mantlo
N B
NB
Gibson
R E
RE
Greenlee
W J
WJ
Siegl
P K
PK
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; C098860:L 163017; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II