New category of vasopressin receptor in the central nervous system. Evidence that this receptor mediates the release of a humoral factor VIII-mobilizing principle.
New category of vasopressin receptor in the central nervous system. Evidence that this receptor mediates the release of a humoral factor VIII-mobilizing principle.
复制标题
中枢神经系统中加压素受体的新类别。
DOI：
10.1111/j.1399-3011.1981.tb01963.x
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发表时间：
1981
期刊：
影响因子：
--
通讯作者：
Schwartz,IL
中科院分区：
文献类型：
--
作者：
Cort,JH;Fischman,AJ;Dodds,WJ;Rand,JH;Schwartz,IL
精氨酸加压素分子（AVP）中9-D-Ala-NH 2取代9-Gly-NH 2可抑制升压和抗利尿活性，但保留完整并增强类似物增加血浆凝血因子VIII（FVIII）水平的能力。当类似物的N-末端脱氨基时以及当1-6二硫桥转化为硫醚桥时，也存在AVP活性生物谱的这种变化。FVIII动员反应中涉及的血管加压素受体（VR）似乎代表了第三类VR，其在激素受体触发的构象要求方面与平滑肌VR和抗利尿剂VR不同。通过比较静脉注射和各种动脉内注射后混合静脉血中的血浆FVIII水平，提出了第三类（血液学）受体部位（HF-R）位于中枢神经系统（CNS）的证据。在麻醉犬中进行供体-受体实验。通过股静脉注射给予供体动物AVP的9-D-Ala-NH 2类似物（dDAlaAVP），20 min后从颈内静脉采血;然后将从后一供体血液样品获得的20 ml血浆注射液注射到受体动物的股静脉中。该注射引起迄今观察到的最大dDAlaAVP诱导的血浆FVIII水平增加（在迄今为止使用的所有实验条件下），强烈表明（a）大脑释放了一种迄今未被认识到的动员FVIII（合成刺激和/或释放）因子，（B）dDAlaAVP作用的血液因子受体（HF-R）可能超出血脑屏障，以及（c）作用于HF-R的AVP样分子在其血液功能中是体液第一信使，就像它们作用于平滑肌和远端肾单位一样-但在HF-R，与加压和抗利尿受体不同，这些分子的功能是影响体液第二信使的释放，其又引起FVIII和纤溶酶原激活物（PA）的释放和/或合成增加。9-D-Ala-NH 2AVP类似物在治疗FVIII缺乏相关出血综合征方面应优于1-脱氨基-[8-D-Arg]-VP（dDAVP），因为它消除了水潴留的不良副作用。
Substitution of 9‐D‐Ala‐NH2for 9‐Gly‐NH2in the arginine‐vasopressin molecule (AVP) results in suppression of both pressor and antidiuretic activities, but leaves intact and augmented the ability of the analog to increase plasma levels of Factor VIII (FVIII). This change in the biological spectrum of AVP activities is also present when the N‐terminus of the analog is desaminated and when the 1–6 disulfide bridge is converted to a thioether bridge. The vasopressin receptor (VR) involved in the FVIII mobilization response appears to represent a third category of VR which is distinct from the smooth muscle VR and the antidiuretic VR in terms of conformational requirements for hormone‐receptor triggering. By comparing plasma FVIII levels in mixed venous blood after intravenous and various intra‐arterial injections, evidence was adduced that this third (hematological) category of receptor site (HF‐R) is in the central nervous system (CNS). Donor‐receiver experiments were carried out in anesthetized dogs. The donor animal was given the 9‐D‐Ala‐NH2analog of AVP (dDAlaAVP) by injection into the femoral vein and blood was withdrawn from the internal jugular vein 20 min later; then an injection of 20 ml plasma obtained from this latter sample of donor blood was injected into the femoral vein of a receiver animal. This injection elicited the largest dDAlaAVP‐induced increase in plasma FVIII level yet observed (under all experimental conditions employed to date), strongly suggesting (a) that the brain releases a hitherto unrecognized mobilizing (synthesis‐stimulating and/or releasing) factor for FVIII, (b) that the hematological factor receptor (HF‐R) at which dDAlaAVP acts may be beyond the blood brain barrier and (c) that AVP‐like molecules which act at HF‐R are humoral first messengers in their hematologic function as they are in their actions on smooth muscle and the distal nephron – but at the HF‐R, unlike at the pressor and antidiuretic receptors, these molecules function to effect the release of humoral second messengers which in turn bring about the release and/or increased synthesis of FVIII and plasminogen activator (PA). The 9‐D‐ Ala‐NH2AVP analog should offer advantage over 1‐desamino‐[8‐D‐Arg]‐VP (dDAVP) in the management of bleeding syndromes related to FVIII deficiency because the undesired side effect of water retention is eliminated.