血管紧张素转换酶调节的非胆碱能交感肾上腺儿茶酚胺释放介导了与凝血β-因子XIIa相关的人类“新升压蛋白”的心血管作用。

Angiotensin converting enzyme-regulated, noncholinergic sympathoadrenal catecholamine release mediates the cardiovascular actions of human 'new pressor protein' related to coagulation beta-factor XIIa.

作者信息

Papageorgiou Peter C, Simos Demetrios, Boomsma Frans, Rojkjaer Rasmus, Osmond Daniel H

机构信息

Department of Physiology, University of Toronto, Toronto, Canada.

出版信息

Can J Cardiol. 2009 Apr;25(4):e100-8. doi: 10.1016/s0828-282x(09)70067-4.

DOI:10.1016/s0828-282x(09)70067-4

PMID:19340353

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2706768/

Abstract

BACKGROUND

Human 'new pressor protein' (NPP), related to coagulation beta-factor XIIa (beta-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/beta-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/beta-FXIIa contributed to their hypertension.

OBJECTIVE

To investigate the mechanism of action of NPP/beta-FXIIa.

METHODS

Hemodynamic and sympathoadrenal responses to NPP (20 microL plasma equivalent/rat) or coagulation beta-FXIIa (300 ng/kg intravenously) were measured in rats treated with pentolinium (ganglion blockade [+GB]) and/or captopril (+CAP; angiotensin converting enzyme [ACE] inhibition).

RESULTS

In controls not receiving GB or CAP (-GB-CAP), NPP/beta-FXIIa raised plasma epinephrine (E) sixfold, SBP/DBP by 14/8 mmHg and HR by 15 beats/min. With blockade of the cholinergic pathway to the sympathoadrenal system (+GB), basal E, norepinephrine (NE), SBP, DBP and HR all dropped. However NPP/beta-FXIIa remained capable of raising E 20-fold, NE fourfold, SBP/DBP by 27/11 mmHg and HR by 20 beats/min, suggesting that it acted through a 'noncholinergic' mechanism. With +CAP alone, NPP/beta-FXIIa raised plasma E 18-fold, NE threefold, SBP/ DBP by 29/8 mmHg and HR by 73 beats/min, implicating an ACE-regulated 'peptidergic' mechanism. Combining +GB with +CAP potentiated NPP/beta-FXIIa actions further by raising E 50-fold, NE sevenfold, SBP/DBP by 55/20 mmHg and HR by 87 beats/min, strengthening the efficacy of this alternate pathway.

CONCLUSIONS

The cardiovascular effects of NPP/beta-FXIIa are considerably mediated by a noncholinergic (peptidergic) ACE-regulated mechanism for sympathoadrenal catecholamine release that is enhanced by +GB and/or +CAP. Under inflammatory procoagulant conditions, endogenously produced NPP/beta-FXIIa may interfere with the antihypertensive effects of ACE inhibition therapy.

摘要

背景

人类“新型升压蛋白”（NPP）与凝血β-因子XIIa（β-FXIIa）相关，在生物测定大鼠中能有效释放交感肾上腺儿茶酚胺，同时收缩压和舒张压（SBP/DBP）及心率（HR）升高。先前报道，接受血液透析的高血压无肾儿科患者血浆NPP/β-FXIIa水平升高与液体状态和血压变化相关，提示NPP/β-FXIIa与他们的高血压有关。

目的

研究NPP/β-FXIIa的作用机制。

方法

在接受潘托铵（神经节阻断[+GB]）和/或卡托普利（+CAP；血管紧张素转换酶[ACE]抑制）治疗的大鼠中，测量对NPP（20微升血浆当量/大鼠）或凝血β-FXIIa（300纳克/千克静脉注射）的血流动力学和交感肾上腺反应。

结果

在未接受GB或CAP治疗的对照组（-GB-CAP）中，NPP/β-FXIIa使血浆肾上腺素（E）升高6倍，SBP/DBP升高14/8毫米汞柱，HR升高15次/分钟。通过阻断通往交感肾上腺系统的胆碱能途径（+GB），基础E、去甲肾上腺素（NE）、SBP、DBP和HR均下降。然而，NPP/β-FXIIa仍能使E升高20倍，NE升高4倍，SBP/DBP升高27/11毫米汞柱，HR升高20次/分钟，提示其通过“非胆碱能”机制起作用。单独使用+CAP时，NPP/β-FXIIa使血浆E升高18倍，NE升高3倍，SBP/DBP升高29/8毫米汞柱，HR升高73次/分钟，提示存在ACE调节的“肽能”机制。将+GB与+CAP联合使用可进一步增强NPP/β-FXIIa的作用，使E升高50倍，NE升高7倍，SBP/DBP升高55/20毫米汞柱，HR升高87次/分钟，增强了这条替代途径的效力。