Wolfrum Sebastian, Nienstedt Julie, Heidbreder Marc, Schneider Kathrin, Dominiak Peter, Dendorfer Andreas
Institute of experimental and clinical Pharmacology and Toxicology, Medical University of Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Regul Pept. 2005 Apr 15;127(1-3):217-24. doi: 10.1016/j.regpep.2004.12.008.
Excitation of sensory nerves and activation of myocardial protein kinase C (PKC) epsilon contribute to the transduction of remote preconditioning (RPC) to the heart. Since calcitonin gene related peptide (CGRP) is an important mediator of sensory neurons we tried to delineate whether CGRP a) protects the heart from ischemic injury, b) is involved in cardioprotection after RPC, and c) leads to an activation of myocardial PKCepsilon. RPC was achieved by brief mesenteric artery occlusion followed by reperfusion. Myocardial infarct size (IS) was measured by TTC staining after temporary coronary artery occlusion (CAO) in rats. CGRP plasma levels were determined by radioimmunoassay and PKCepsilon was measured by quantitative immunoblotting. CGRP infusion reduced infarct size by 57%, an action that was abolished after co-treatment with the PKC inhibitor chelerythrine. RPC significantly increased CGRP plasma levels, reduced infarct size, and activated myocardial PKCepsilon. Infarct size reduction was abolished and PKCepsilon activation was significantly attenuated by CGRP(8-37), a specific CGRP receptor antagonist. Ganglion blockade with hexamethonium did not influence CGRP release by RPC but abolished CGRP mediated myocardial PKCepsilon activation. In conclusion, CGRP protects the heart from ischemic injury and is involved in RPC, presumably by activating myocardial PKCepsilon.
感觉神经的兴奋以及心肌蛋白激酶C（PKC）ε的激活有助于远程预处理（RPC）对心脏的转导作用。由于降钙素基因相关肽（CGRP）是感觉神经元的重要介质，我们试图阐明CGRP是否：a）保护心脏免受缺血性损伤；b）参与RPC后的心脏保护作用；c）导致心肌PKCε的激活。通过短暂的肠系膜动脉闭塞随后再灌注来实现RPC。在大鼠临时冠状动脉闭塞（CAO）后，通过TTC染色测量心肌梗死面积（IS）。通过放射免疫测定法测定血浆CGRP水平，并通过定量免疫印迹法测量PKCε。输注CGRP可使梗死面积减少57%，与PKC抑制剂白屈菜红碱联合处理后，该作用消失。RPC显著提高血浆CGRP水平，减小梗死面积，并激活心肌PKCε。CGRP（8 - 37）是一种特异性CGRP受体拮抗剂，它可消除梗死面积的减小，并显著减弱PKCε的激活。用六甲铵进行神经节阻断并不影响RPC引起的CGRP释放，但可消除CGRP介导的心肌PKCε激活。总之，CGRP可保护心脏免受缺血性损伤，并参与RPC，可能是通过激活心肌PKCε来实现的。
