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-intennedin(95-147), namely intermedin(1-53). The bioactive action of intermedin(1-53) and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin(1-53) 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 intemedin(1-53) 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/dt(max)) 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 [I-125]-intermedin(1-53) was increased by 118% (P < 0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin(1-53) (5 nmol/kg/day, 2 days) showed 21 % (P < 0.05) higher myocardial cAMP content, 18% and 31 % higher + left-ventricle dp/dt(max) and -left-ventricle dp/dt(max) 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 intermedin(1-53) (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin(1-53). These results suggest that the intermedin receptor system was up-regulated in isoproterenol induced myocardial ischemic injury and intermedin(1-53) might play a pivotal cardioprotective role in such injury. (c) 2006 Elsevier B.V. All rights reserved.