Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats.
Intermedin is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family peptide, which has vasodilatory and hypotensive actions identical to those of adrenomedullin and CGRP. Cleavage sites located between 2 basic amino acids at Arg93-Arg94 result in the production of prepro-intermedin95-147, namely intermedin1-53. The bioactive action of intermedin1-53 and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin1-53 on acute myocardial injury induced by isoproterenol. Myocardial ischemia injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of intermedin1-53 was observed. Plasma lactate dehydrogenase activity, myocardial and plasma malondialdehyde content were higher in the isoproterenol group than that in controls. Isoproterenol-treated rats showed lower maximal rate of increase and decrease of left-ventricle pressure development (+/-left-ventricle dp/dtmax) and higher left-ventricle end-diastolic pressure (all P<0.01), which suggested severe heart failure and myocardial injury. Semi-quantitative RT-PCR analysis showed that the gene expression of calcitonin receptor-like receptor and receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 in ventricular myocardia were up-regulated by 79% (P<0.01), 48% (P<0.01), 31% (P<0.05) and 130% (P<0.01), respectively, compared with controls. In myocardial sarcolemmal membranes, the maximum binding capacity for [125I]-intermedin1-53 was increased by 118% (P<0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin1-53 (5 nmol/kg/day, 2 days) showed 21% (P<0.05) higher myocardial cAMP content, 18% and 31% higher+left-ventricle dp/dtmax and -left-ventricle dp/dtmax respectively, 288% lower left-ventricle end-diastolic pressure (all P<0.01), and attenuated myocardial lactate dehydrogenase leakage and malondialdehyde formation (all P<0.01). Treatment with high dosage intermedin1-53 (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin1-53. These results suggest that the intermedin receptor system was up-regulated in isoproterenol-induced myocardial ischemic injury and intermedin1-53 might play a pivotal cardioprotective role in such injury.
Jia
Yue-Xia
YX
Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083, China.
Yang
Jing-Hui
JH
Pan
Chun-Shui
CS
Geng
Bin
B
Zhang
Jing
J
Xiao
Yang
Y
Zhao
Jing
J
Gerns
Helen
H
Yang
Jun
J
Chang
Jaw-Kang
JK
Wen
Jin Kun
JK
Tang
Chao-Shu
CS
Qi
Yong-Fen
YF
D053607:Adrenomedullin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D058286:Calcitonin Receptor-Like Protein; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007279:Injections, Subcutaneous; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007457:Iodine Radioisotopes; D007545:Isoproterenol / Q000008:administration & dosage / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D009203:Myocardial Infarction / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism
C499411:Adm2 protein, rat; D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D008315:Malondialdehyde; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D007545:Isoproterenol