Analysis of an H1 receptor‐mediated, zinc‐potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein
Analysis of an H1 receptor‐mediated, zinc‐potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein
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DOI：
10.1038/sj.bjp.0702184
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发表时间：
1998-11
影响因子：
7.3
通讯作者：
Anne O'Dowd;David J. Miller
中科院分区：
文献类型：
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作者：
Anne O'Dowd;David J. Miller
本文研究了二肽肌肽（β-丙氨酰-L-组氨酸）对离体兔隐静脉（RSV）环的收缩作用，并发现其收缩作用可被H1受体拮抗剂美托咪明所拮抗。与肌肽诱导的挛缩相比，RSV中美吡胺敏感的组胺诱导的挛缩较小（73±0.1%）且持续性较差。肌肽诱导的挛缩，美洛昔明拮抗作用的Schild图值为：pA 2 =7.97±0.12，斜率=1.33±0.06（r=0.793）;组胺诱导的挛缩，pA 2 =8.48±0.07，斜率=0.63±0.05，r=0.957）。5-羟色胺能拮抗剂甲硫替平和酮色林，拮抗肌肽和组胺诱导的RSV挛缩，可能反映在H1受体的巧合抑制。肌肽（含锌）可抑制[3 H]-美托咪胺与分离的豚鼠小脑膜的H1特异性结合（在10、30和80 μM锌浓度下，log IC 50分别为−2.78±0.02、−3.93±0.03和−4.64±0.03;校正锌特异性抑制的数值，其logIC 50为−4.20）。在放射性配体结合试验中，肌肽的作用可以描述为Zn·卡恩浓度的函数，表观logIC 50为-5.61。该值与从RSV功能研究中获得的值一致。组胺诱导的挛缩具有吲哚美辛敏感成分（对照反应的27.2±8.3%），肌肽诱导的挛缩不明显。与组胺一样，肌肽在美托洛尔存在下诱发H2介导的（西咪替丁敏感性）松弛，但效力较低（10 mM肌肽时为10.8±3.1%残余张力，而0.1 mM组胺时为13.4±7.5%）。肌肽，如美托洛尔明，可以“揭示”H2介导的组胺松弛，进一步证明肌肽与H1受体结合。我们的结论是肌肽可以作用于平滑肌H1受体引起血管收缩，它也有可能作用于中枢神经系统中的H1受体。
The contractile action of the dipeptide carnosine (β-alanyl-L-histidine), active as a Zn·carnosine complex (Zn·Carn), was investigated in isolated rings of rabbit saphenous vein (RSV) and was found to be antagonized by the H1 antagonist mepyramine. Mepyramine-sensitive, histamine-induced contractures in RSV, were smaller (73±0.1%) and less well sustained than carnosine-induced contractures. Schild plot values for mepyramine antagonism were, for carnosine-induced contractures; pA2=7.97±0.12, slope=1.33±0.06 (r=0.793) and for histamine-induced contractures; pA2=8.48±0.07, slope=0.63±0.05, r=0.957). Serotonergic antagonists methiothepin and ketanserin, antagonize both carnosine- and histamine-induced contractures in RSV, probably reflecting coincidental inhibition at the H1-receptor. Carnosine, with Zn present, can inhibit the H1-specific binding of [3H]-mepyramine to isolated guinea-pig cerebellar membranes (log IC50s−2.78±0.02, −3.93±0.03 and −4.64±0.03 at 10, 30 and 80 μM Zn respectively; values corrected for the Zn-specific inhibition which has a logIC50 of −4.20). In the radioligand binding assay, the effect of carnosine can be described as a function of Zn·Carn concentration with an apparent logIC50 of −5.61. This value is consistent with that obtained from the functional studies on RSV. Histamine-induced contractures have an indomethacine-sensitive component (27.2±8.3% of control response), not apparent with carnosine-induced contractures. Like histamine, carnosine evoked an H2-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8±3.1% residual tension at 10 mM carnosine compared with 13.4±7.5% at 0.1 mM histamine). Carnosine, like mepyramine, can 'reveal' the H2-mediated relaxation of histamine providing further evidence that carnosine binds at the H1 receptor. We conclude that carnosine can act at the smooth muscle H1-receptor to provoke vasoconstriction and that it also has the potential to act at H1-receptors in CNS.