Abi-Gerges N, Tavernier B, Mebazaa A, Faivre V, Paqueron X, Payen D, Fischmeister R, Méry P F
INSERM U-446, Laboratoire de Cardiologie Cellulaire et Moléculaire, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, Cedex, France.
Am J Respir Crit Care Med. 1999 Oct;160(4):1196-204. doi: 10.1164/ajrccm.160.4.9808149.
We report that in vivo injection of endotoxin (EDTX, 6 mg. kg(-)(1)) induces cardiovascular alterations in rats that closely mimic the clinical situation, as assessed by in vivo hemodynamic measurements in anesthetized and conscious, chronically instrumented animals. The patch-clamp technique was used to characterize the L-type calcium current (I(Ca)) and its autonomic regulation in isolated cardiac myocytes. The density of I(Ca) progressively decreased at 12 and 36 h after EDTX injection. However, the dihydropyridine (+/-)Bay K 8644 (100 nM) enhanced I(Ca) to levels similar to those in control and EDTX-treated myocytes. In addition, the net stimulatory effect of a beta-adrenergic agonist (isoproterenol) on I(Ca) was increased 12 h after EDTX injection. This change in the beta-adrenergic effect declined 24 h later. The potentiation in the beta-adrenergic stimulation of I(Ca) was mimicked by L858051 (10 microM), a direct activator of adenylyl cyclase, but not by IBMX (200 microM), a phosphodiesterase inhibitor. Besides, the antiadrenergic effect of acetylcholine on I(Ca) was unchanged 12 h after EDTX injection, but increased 36 h after EDTX injection. These results support the hypothesis that time-dependent changes in the adenylyl cyclase pathway in cardiac myocytes may contribute, via the autonomic regulation of I(Ca), to the severity of myocardial dysfunction during sepsis.
我们报告，通过对麻醉和清醒的、长期植入仪器的动物进行体内血流动力学测量评估发现，体内注射内毒素（EDTX，6 mg·kg⁻¹）可诱导大鼠出现与临床情况极为相似的心血管改变。采用膜片钳技术对分离的心肌细胞中的L型钙电流（I(Ca)）及其自主调节进行表征。EDTX注射后12小时和36小时，I(Ca)密度逐渐降低。然而，二氢吡啶（±）Bay K 8644（100 nM）可将I(Ca)增强至与对照和EDTX处理的心肌细胞相似的水平。此外，β-肾上腺素能激动剂（异丙肾上腺素）对I(Ca)的净刺激作用在EDTX注射后12小时增强。这种β-肾上腺素能效应的变化在24小时后下降。腺苷酸环化酶的直接激活剂L858051（10 μM）可模拟β-肾上腺素能对I(Ca)刺激的增强作用，而磷酸二酯酶抑制剂IBMX（200 μM）则不能。此外，乙酰胆碱对I(Ca)的抗肾上腺素能作用在EDTX注射后12小时未改变，但在EDTX注射后36小时增强。这些结果支持以下假设：心肌细胞中腺苷酸环化酶途径的时间依赖性变化可能通过I(Ca)的自主调节，导致脓毒症期间心肌功能障碍的严重程度增加。
