Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally active antihypertensive agent.
2-n-Butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazole-5-yl)biphenyl-4-y l) methyl]imidazole, potassium salt (DuP 753) is a potent, p.o. active antihypertensive agent exerting its action by specific blockade of angiotensin II receptors. It inhibited the specific binding of labeled angiotensin II to its receptor sites in rat adrenal cortical membranes and in cultured rat smooth muscle cells with IC50 values of 19 and 20 X 10(-9) M, respectively. Functional antagonism was demonstrated by its blockage of angiotensin II (3 X 10(-8) M)-induced 45Ca++ efflux in rat aortic smooth muscle cells with an IC50 of 2 X 10(-8) M. In rabbit aorta, DuP 753 antagonized the contractile response to angiotensin II competitively with a pA2 value of 8.48 but had no effect on the responses induced by norepinephrine or KCl. In both in vitro and in vivo assays, no partial agonistic effect was detected even with concentrations of up to 10(-5) M. In addition, this agent (10(-5) or 10(-4) M) exhibited no direct effect on converting enzyme (rabbit lung) or renin (rat plasma). These data demonstrate that DuP 753, is a potent and highly specific angiotensin II receptor antagonist. This agent may be a useful experimental or therapeutic tool for interference with the renin-angiotensin system in health and diseases.
Chiu
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Medical Products Department, E. I. du Pont de Nemours & Company, Wilmington, Delaware.
McCall
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Price
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Wong
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Carini
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Duncia
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Wexler
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Yoo
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Johnson
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Timmermans
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D000284:Administration, Oral; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001393:Azoles; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan; D002118:Calcium