心内膜内皮在由内皮素-1诱导的心肌舒张性增加中的必要作用。

Obligatory role of the endocardial endothelium in the increase of myocardial distensibility induced by endothelin-1.

作者信息

Brás-Silva Carmen, Leite-Moreira Adelino F

机构信息

Department of Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

出版信息

Exp Biol Med (Maywood). 2006 Jun;231(6):876-81.

PMID:16741016

Abstract

This study investigated how the endocardial endothelium (EE) and particularly endothelial type B (ET(B)) receptors influence the effects of endothelin-1 (ET-1) on diastolic distensibility. ET-1 (0.1, 1, and 10 nM) was tested in rabbit papillary muscles (Krebs-Ringer; 1.8 mM CaCl2, 35 degrees C) (i) with intact EE (n = 10), (ii) with damaged EE (0.5% Triton X-100, n = 11), and (iii) in the presence of RES-701-1 (selective endothelial ET(B1) receptor antagonist, 1 microM, n = 6). Additionally, increasing doses (0.1 nM to 1 microM) of Sarafotoxin S6c (SRTXc, a selective ET(B) receptor agonist) and IRL-1620 (a selective endothelial ET(B1) agonist) were studied (i) in muscles with intact EE (n = 7 and n = 6, respectively) and (ii) after damaging the EE (n = 8 and n = 7, respectively). In papillary muscles with intact EE, ET-1 induced dose-dependent positive inotropic and lusitropic effects. At 10 nM, active tension (AT) increased 78% +/- 17%, maximum velocity of tension rise (dT/dt(max)) increased 82% +/- 10%, and maximum velocity of tension decline (dT/dt(min)) increased 77% +/- 17%. These effects were maintained when ET-1 was given after damaging the EE (AT increased 70% +/- 12%, dT/dt(max) increased 93% +/- 14%, and dT/dt(min) increased 56% +/- 14%), but were significantly reduced in the presence of RES-701-1 (AT increased 30% +/- 6%, dT/dt(max) increased 37% +/- 7%, and dT/ dt(min) increased 29% +/- 9%). ET-1 reduced resting tension (RT) and increased diastolic distensibility by 3% +/- 1%, 5% +/- 1%, and 9% +/- 2% (at 0.1, 1, and 10 nM, respectively) in muscles with intact EE. This effect was abolished after damaging the EE or in the presence of RES-701-1. In muscles with intact EE, SRTXc had no significant effects, whereas, when given after damaging the EE, SRTXc (1 microM) increased inotropy and lusitropy (AT increased 116% +/- 24%, dT/dt(max) 110% +/- 28%, and dT/dt(min) 88% +/- 19%) without affecting RT. IRL-1620 dose-dependently decreased AT, dT/dt(max), and dT/dt(min) in muscles with intact EE-effects that were abolished after EE damage. No significant effects were elicited by IRL-1620 in RT. ET-1-induced increase in myocardial distensibility, previously shown to be mediated by ET(A) receptor stimulation, requires an intact EE and active endothelial ET(B1) receptors.

摘要

本研究调查了心内膜内皮（EE），特别是内皮B型（ET(B)）受体如何影响内皮素-1（ET-1）对舒张期扩张性的作用。在兔乳头肌（Krebs-Ringer液；1.8 mM氯化钙，35℃）中测试ET-1（0.1、1和10 nM）：（i）EE完整（n = 10）；（ii）EE受损（0.5% Triton X-100，n = 11）；（iii）存在RES-701-1（选择性内皮ET(B1)受体拮抗剂，1 microM，n = 6）。此外，研究了递增剂量（0.1 nM至1 microM）的铃蟾毒素S6c（SRTXc，一种选择性ET(B)受体激动剂）和IRL-1620（一种选择性内皮ET(B1)激动剂）：（i）在EE完整的肌肉中（分别为n = 7和n = 6）；（ii）EE受损后（分别为n = 8和n = 7）。在EE完整的乳头肌中，ET-1诱导剂量依赖性的正性肌力和舒张期松弛作用。在10 nM时，主动张力（AT）增加78%±17%，张力上升最大速度（dT/dt(max)）增加82%±10%，张力下降最大速度（dT/dt(min)）增加77%±17%。当EE受损后给予ET-1时，这些作用得以维持（AT增加70%±12%，dT/dt(max)增加93%±14%，dT/dt(min)增加56%±14%），但在存在RES-701-1时显著减弱（AT增加30%±6%，dT/dt(max)增加37%±7%，dT/dt(min)增加29%±9%）。在EE完整的肌肉中，ET-1使静息张力（RT）降低，舒张期扩张性分别增加3%±1%、5%±1%和9%±2%（分别在0.1、1和10 nM时）。EE受损后或存在RES-701-1时，此作用消失。在EE完整的肌肉中，SRTXc无显著作用，而EE受损后给予SRTXc（1 microM）可增加肌力和舒张期松弛（AT增加116%±24%，dT/dt(max)增加110%±28%，dT/dt(min)增加88%±19%），且不影响RT。在EE完整的肌肉中，IRL-1620剂量依赖性地降低AT、dT/dt(max)和dT/dt(min)——EE受损后这些作用消失。IRL-1620对RT无显著影响。ET-1诱导的心肌扩张性增加，先前已证明是由ET(A)受体刺激介导的，需要完整的EE和活跃的内皮ET(B1)受体。