Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys.
The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.
Gibson
R E
RE
Department of Radiopharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Thorpe
H H
HH
Cartwright
M E
ME
Frank
J D
JD
Schorn
T W
TW
Bunting
P B
PB
Siegl
P K
PK
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015773:Enalaprilat / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D019808:Losartan; D008253:Macaca mulatta; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D012083:Renin / Q000097:blood*; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; D000450:Aldosterone; C009210:sarleucin; D012083:Renin; D015773:Enalaprilat; D019808:Losartan