AT1 receptors mediate the release of prostaglandins in porcine smooth muscle cells and rat astrocytes.
Angiotensin II (AII) can release arachidonic acid metabolites such as prostacyclin (PGI2) and PGE2 from cells in cultures. It has recently been reported that the AT1 selective nonpeptide AII receptor antagonist losartan had similar effects. The present study was undertaken to further evaluate the effects of AII and losartan on cells which synthesize prostaglandins, including vascular smooth muscle, endothelial, and glial cells. Inhibition of specific [125I]AII binding was demonstrated in porcine smooth muscle cell (PSMC) suspensions with unlabeled AII and losartan. The IC50 values were 1.3 x 10(-9) mol/L and 7.7 x 10(-9) mol/L, respectively. PD123177 (an AT2 selective antagonist) had no effect on binding. AII produced a concentration-related increase in calcium mobilization (fura-2 fluorescence) which was blocked by losartan (IC50 = 8.4 x 10(-8) mol/L) but not by PD123177 (10(-6) mol/L). AII (10(-7) to 10(-5) mol/L) stimulated the basal release of PGI2 by 100%. This response was blocked by losartan (10(-6) to 10(-5) mol/L) but not by PD123177 (10(-6) to 10(-5) mol/L) and neither agent stimulated basal release in PSMC. Similar effects of AII and antagonists were observed upon receptor binding and PGE2 release in primary rat astrocyte (RA) cultures. AII did not release PGI2 from porcine endothelial cells, bovine pulmonary arterial endothelial cells, or rat C6 glioma cells. Losartan had no significant effect at 10(-5) mol/L. By contrast, bradykinin or the calcium ionophore A23187 dramatically increased PGI2 release in each of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Leung
K H
KH
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
Chang
R S
RS
Lotti
V J
VJ
Roscoe
W A
WA
Smith
R D
RD
Timmermans
P B
PB
Chiu
A T
AT
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D001713:Biphenyl Compounds / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D011464:Epoprostenol / Q000378:metabolism; D005910:Glioma; D007093:Imidazoles / Q000494:pharmacology; D007457:Iodine Radioisotopes; D019808:Losartan; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D011453:Prostaglandins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011863:Radioimmunoassay; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000032:analysis / Q000502:physiology*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D013931:Thromboxanes / Q000378:metabolism; D014407:Tumor Cells, Cultured
D057911:Angiotensin Receptor Antagonists; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011453:Prostaglandins; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D013931:Thromboxanes; D000804:Angiotensin II; C066253:PD 123177; D000001:Calcimycin; D015237:Dinoprost; D011464:Epoprostenol; D019808:Losartan