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Inhibition of the release of endothelium‐derived relaxing factor in vitro and in vivo by dipeptides containing N G ‐nitro‐ l ‐arginine
Author(s) -
Thiemermann Christoph,
Mustafa Marina,
Mester P. Achim,
Mitchell Jane A.,
Hecker Markus,
Vane John R.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12380.x
Subject(s) - bradykinin , endothelium derived relaxing factor , chemistry , endothelium , in vivo , acetylcholine , arginine , prostacyclin , in vitro , nitroarginine , vasodilation , endocrinology , medicine , biochemistry , pharmacology , amino acid , biology , receptor , microbiology and biotechnology
1 We have shown that dipeptides containing N G ‐nitro‐ l ‐arginine (NO 2 Arg) inhibit the biosynthesis of endothelium‐derived relaxing factor (EDRF) in vitro and in vivo.2 In anaesthetized rats, intravenous administration at 1–30 mg kg −1 of the methyl ester of NO 2 Arg, NO 2 ‐Arg‐ l ‐phenylalanine (NO 2 Arg‐Phe), l ‐alanyl‐NO 2 Arg (Ala‐NO 2 Arg) or NO 2 Arg‐ l ‐arginine (NO 2 Arg‐Arg) produced dose‐related increases in mean arterial blood pressure (MABP) which were unaffected by d ‐arginine ( d ‐Arg; 20 mg kg −1 min −1 for 15 min), but prevented by co‐infusions of l ‐arginine ( l ‐Arg; 20 mg kg −1 min −1 for 15 min) or by their parent dipeptides. 3 NO 2 Arg methyl ester, NO 2 Arg‐Phe methyl ester or Ala‐NO 2 Arg methyl ester (10 mg kg −1 , i.v.) also inhibited the reduction in MABP caused by the endothelium‐dependent vasodilator, acetylcholine (30 μg kg −1 min −1 for 3 min), but not those induced by glyceryl trinitrate (20 μg kg −1 min −1 for 3 min) or iloprost (6 μg kg −1 min −1 for 3 min) which act directly on the vascular smooth muscle. 4 Moreover, NO 2 Arg methyl ester, NO 2 Arg‐Phe methyl ester or NO 2 Arg‐Arg methyl ester (100 μ m ) inhibited the acetylcholine‐induced relaxation of rabbit aortic strips, and NO 2 Arg‐Phe methyl ester (30 μ m ) blocked the stimulated (bradykinin, 30 pmol) release of EDRF from bovine aortic endothelial cells grown on microcarrier beads. 5 In endothelial cells grown in l ‐Arg‐deficient medium, l ‐Arg‐containing dipeptides such as l ‐Arg‐ l ‐Phe, l ‐Ala‐ l ‐Arg or l ‐Arg‐ l ‐Arg increased both the basal and stimulated release of EDRF. Moreover, the l ‐Arg containing dipeptides, but not their NO 2 Arg analogues, were rapidly cleaved by these cells. 6 Thus, dipeptides containing NO 2 Arg can directly interfere with the biosynthesis of EDRF in vitro and in vivo. Moreover, the potentiation of EDRF release from endothelial cells deprived of l ‐Arg by dipeptides containing l ‐Arg suggests that such peptides may serve as an additional or alternative substrate for the biosynthesis of EDRF.