Brás-Silva Carmen, Fontes-Sousa Ana Patrícia, Moura Cláudia, Areias José Carlos, Leite-Moreira Adelino F
Department of Physiology, Faculty of Medicine, University of Porto, Portugal.
Exp Biol Med (Maywood). 2006 Jun;231(6):893-8.
Inotropic effects of selective ET(B) receptor stimulation depend on the functional integrity of the endocardial endothelium (EE), which is negative when it is intact and positive when it is damaged. These results have been attributed to the existence of two subtypes of ET(B) receptors in the heart: (i) ET(B1), located on the EE, decreases inotropy; (ii) ET(B2), located on myocardial cells, increases inotropy. In the present study we investigated the functional integrity of the EE in a heart failure (HF) model (doxorubicin-induced cardiomyopathy) by evaluating the contractile response to ET(B1) receptor stimulation. New Zealand White rabbits were treated with doxorubicin (DOX-HF, 1 mg/kg, iv, twice weekly for 8 weeks) or with saline. Contractile effects of increasing doses of a selective agonist of endothelial ET(B) receptors, IRL-1620 (10(-9) to 10(-6) M), were studied in papillary muscles (Krebs-Ringer: 1.8 mM CaCl2, 35 degrees C) from control (n = 10) and DOX-HF rabbits (n = 7). Isotonic and isometric twitches were recorded and analyzed. Reported parameters included active tension (AT) and maximum velocities of tension rise (dT/dt(max)) and decline (dT/dt(min)). On echocardiography, DOX-HF rabbits had increased left ventricular (LV) end-diastolic and end-systolic diameters and reduced ejection fraction (52% +/- 2% vs. 61% +/- 1%). Contrary to control papillary muscles, DOX-HF muscles showed a steady decrease in contractility between 1 and 4 Hz. In the control group, IRL-1620 induced dose-dependent negative inotropic and lusitropic effects that decreased at 10(-6) M: 26% +/- 3%, AT; 17% +/- 3%, dT/dt(max); and 16% +/- 5%, dT/dt(min). In the DOX-HF group, these effects were significantly reduced. At the same concentration, IRL-1620 decreased AT (8% +/- 3%) and dT/dt(max) (8% +/- 3%), without significantly affecting dT/dt(min). This study showed an impaired response to endothelial ET(B) receptor stimulation, providing for the first time strong evidence of the occurrence of EE dysfunction in the failing heart and further highlighting the potential use of ET(B) receptor stimulation as a marker of EE function.
选择性内皮素（ET）（B）受体刺激的变力作用取决于心内膜内皮（EE）的功能完整性，EE完整时其变力作用为负，受损时为正。这些结果归因于心脏中存在两种ET（B）受体亚型：（i）位于EE上的ET（B1）受体，可降低心肌收缩力；（ii）位于心肌细胞上的ET（B2）受体，可增强心肌收缩力。在本研究中，我们通过评估对ET（B1）受体刺激的收缩反应，研究了心力衰竭（HF）模型（阿霉素诱导的心肌病）中EE的功能完整性。将新西兰白兔分为阿霉素治疗组（DOX-HF组，1 mg/kg，静脉注射，每周两次，共8周）和生理盐水对照组。在来自对照组（n = 10）和DOX-HF组（n = 7）的乳头肌（Krebs-Ringer液：1.8 mM CaCl2，35℃）中研究了内皮ET（B）受体选择性激动剂IRL-1620（10(-9)至10(-6) M）剂量增加时的收缩作用。记录并分析了等张和等长收缩。报告的参数包括主动张力（AT）、张力上升的最大速度（dT/dt(max)）和下降速度（dT/dt(min)）。超声心动图显示，DOX-HF组家兔左心室舒张末期和收缩末期直径增加，射血分数降低（分别为52%±2%和61%±1%）。与对照乳头肌相反，DOX-HF组乳头肌在1至4 Hz之间收缩力呈稳定下降。在对照组中，IRL-1620诱导剂量依赖性的负性变力和变时作用，在10(-6) M时作用减弱：AT降低26%±3%；dT/dt(max)降低17%±3%；dT/dt(min)降低16%±5%。在DOX-HF组中，这些作用明显减弱。在相同浓度下，IRL-1620使AT降低（8%±3%），dT/dt(max)降低（8%±3%），但对dT/dt(min)无明显影响。本研究显示对内皮ET（B）受体刺激的反应受损，首次为衰竭心脏中EE功能障碍的发生提供了有力证据，并进一步强调了ET（B）受体刺激作为EE功能标志物的潜在用途。
