Mink Steven N, Cheng Zhao-Qin, Bose Ratna, Jacobs Hans, Kasian Krika, Roberts Diane E, Santos-Martinez Luis E, Light R Bruce
Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3140-9. doi: 10.1152/ajpheart.00502.2007. Epub 2007 Aug 31.
We previously showed that lysozyme (Lzm-S), derived from leukocytes, caused myocardial depression in canine sepsis by binding to the endocardial endothelium to release nitric oxide (NO). NO then diffuses to adjacent myocytes to activate the cGMP pathway. In a canine right ventricular trabecular (RVT) preparation, Lzm-S also decreased the inotropic response to field stimulation (FSR) during which the sympathetic and parasympathetic nerves were simulated to measure the adrenergic response. In the present study, we determined whether the pathway by which Lzm-S decreased FSR was different from the pathway by which Lzm-S reduced steady-state (SS) contraction. Furthermore, we determined whether the decrease in FSR was due to a decrease in sympathetic stimulation or enhanced parasympathetic signaling. In the RVT preparation, we found that the inhibitory effect of Lzm-S on FSR was prevented by NO synthase (NOS) inhibitors. A cGMP inhibitor also blocked the depressant activity of Lzm-S. However, in contrast to the Lzm-S-induced decline in SS contraction, chemical removal of the endocardial endothelium by Triton X-100 to eliminate endothelial NO release did not prevent the decrease in FSR. An inhibitory G protein was involved in the effect of Lzm-S, since FSR could be restored by treatment with pertussis toxin. Atropine prevented the Lzm-S-induced decline in FSR, whereas beta(1)- and beta(2)-adrenoceptor function was not impaired by Lzm-S. These results indicate that the Lzm-S-induced decrease in FSR results from a nonendothelial release of NO. NO then acts through inhibitory G protein to enhance parasympathetic signaling.
我们之前发现，源自白细胞的溶菌酶（Lzm-S）通过与心内膜内皮细胞结合释放一氧化氮（NO），从而导致犬类脓毒症时的心肌抑制。NO随后扩散至相邻的心肌细胞以激活环磷酸鸟苷（cGMP）途径。在犬类右心室小梁（RVT）标本中，Lzm-S也降低了对场刺激（FSR）的变力反应，在此期间模拟交感神经和副交感神经以测量肾上腺素能反应。在本研究中，我们确定Lzm-S降低FSR的途径是否不同于其降低稳态（SS）收缩的途径。此外，我们确定FSR的降低是由于交感神经刺激减少还是副交感神经信号增强所致。在RVT标本中，我们发现一氧化氮合酶（NOS）抑制剂可阻止Lzm-S对FSR的抑制作用。一种cGMP抑制剂也可阻断Lzm-S的抑制活性。然而，与Lzm-S引起的SS收缩下降相反，用 Triton X-100化学去除心内膜内皮以消除内皮NO释放并不能阻止FSR的下降。一种抑制性G蛋白参与了Lzm-S的作用，因为用百日咳毒素处理可恢复FSR。阿托品可阻止Lzm-S引起的FSR下降，而Lzm-S并未损害β1和β2肾上腺素能受体功能。这些结果表明，Lzm-S引起的FSR下降是由NO的非内皮释放所致。NO随后通过抑制性G蛋白起作用以增强副交感神经信号。
