Calcitonin gene related peptide mediates cardioprotection by remote preconditioning.
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.
Wolfrum
Sebastian
S
Institute of experimental and clinical Pharmacology and Toxicology, Medical University of Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. wolfrum@medinf-mu.luebeck.de
Nienstedt
Julie
J
Heidbreder
Marc
M
Schneider
Kathrin
K
Dominiak
Peter
P
Dendorfer
Andreas
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia; D009475:Neurons, Afferent / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D002316:Cardiotonic Agents; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D015740:Calcitonin Gene-Related Peptide