The nonpeptide angiotensin II antagonist DuP 753 is a potent stimulus for prostacyclin synthesis.
In an attempt to define the angiotensin II receptor subtype responsible for prostaglandin release, we studied the effects of the nonpeptide, subtype 1 (or B) selective angiotensin II antagonist, DuP 753. Release of prostaglandin E2 produced by angiotensin II from rat C6 glioma, human astrocytoma, or porcine aortic smooth muscle cells in culture was blocked by the addition of the 10(-7) M of DuP 753. In contrast, the release of prostacyclin, as assessed by measurement of the stable metabolite 6-keto PGF1 alpha, was not attenuated by addition of Du P 753. However, DuP 753 either alone or in combination with angiotensin II, produced dose-dependent increases in prostacyclin release with doses as low as 10(-8) M. In the absence of angiotensin II, DuP 753 also increased prostaglandin E2 release at high doses but the magnitude of the potentiation was substantially less than for prostacyclin release (50 to 250% v 400 to 2800% above basal). Thus, we clearly show that angiotensin II stimulates PGE2 release via subtype 1 (or B) angiotensin receptors. Whether the effect of DuP 753 on prostaglandin release is a result of agonistic properties or intrinsic effects unrelated to blockage of angiotensin II receptors remains to be determined. The marked stimulatory effect of DuP 753 release precludes characterization of the receptor subtype that mediates the Ang II-induced release of prostacyclin. Nonetheless, potent stimulation of prostacyclin release by DuP 753, especially in vascular smooth muscle cells, requires reevaluation of the mechanisms that participate in the anti-hypertensive effects of the compound.
Jaiswal
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Department of Brain and Vascular Research, Cleveland Clinic Foundation, Ohio 44195-5070.
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D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000145:classification / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D011464:Epoprostenol; D019808:Losartan; D015232:Dinoprostone