Article date: September 1991
By: Christoph Thiemermann, Marina Mustafa, P. Achim Mester, Jane A. Mitchell, Markus Hecker, John R. Vane, in Volume 104, Issue 1, pages 31-38
We have shown that dipeptides containing NG‐nitro‐l‐arginine (NO2Arg) inhibit the biosynthesis of endothelium‐derived relaxing factor (EDRF) in vitro and in vivo.
In anaesthetized rats, intravenous administration at 1–30 mg kg−1 of the methyl ester of NO2Arg, NO2‐Arg‐l‐phenylalanine (NO2Arg‐Phe), l‐alanyl‐NO2Arg (Ala‐NO2Arg) or NO2Arg‐l‐arginine (NO2Arg‐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.
NO2Arg methyl ester, NO2Arg‐Phe methyl ester or Ala‐NO2Arg 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.
Moreover, NO2Arg methyl ester, NO2Arg‐Phe methyl ester or NO2Arg‐Arg methyl ester (100 μm) inhibited the acetylcholine‐induced relaxation of rabbit aortic strips, and NO2Arg‐Phe methyl ester (30 μm) blocked the stimulated (bradykinin, 30 pmol) release of EDRF from bovine aortic endothelial cells grown on microcarrier beads.
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 NO2Arg analogues, were rapidly cleaved by these cells.
Thus, dipeptides containing NO2Arg 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.
We have shown that dipeptides containing NG‐nitro‐l‐arginine (NO2Arg) inhibit the biosynthesis of endothelium‐derived relaxing factor (EDRF) in vitro and in vivo.
In anaesthetized rats, intravenous administration at 1–30 mg kg−1 of the methyl ester of NO2Arg, NO2‐Arg‐l‐phenylalanine (NO2Arg‐Phe), l‐alanyl‐NO2Arg (Ala‐NO2Arg) or NO2Arg‐l‐arginine (NO2Arg‐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.
NO2Arg methyl ester, NO2Arg‐Phe methyl ester or Ala‐NO2Arg 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.
Moreover, NO2Arg methyl ester, NO2Arg‐Phe methyl ester or NO2Arg‐Arg methyl ester (100 μm) inhibited the acetylcholine‐induced relaxation of rabbit aortic strips, and NO2Arg‐Phe methyl ester (30 μm) blocked the stimulated (bradykinin, 30 pmol) release of EDRF from bovine aortic endothelial cells grown on microcarrier beads.
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 NO2Arg analogues, were rapidly cleaved by these cells.
Thus, dipeptides containing NO2Arg 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.
DOI: 10.1111/j.1476-5381.1991.tb12380.x
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