(Circulation. 2000;101:415.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Induction of a Myocardial Adrenomedullin Signaling System During Ischemic Heart Failure in Rats
From Merck Sharp & Dohme–Cardiovascular Research Center (E.Ø., C.S., H.A.), and the Institute for Surgical Research, The National Hospital, University of Oslo (E.Ø., L.E.V., A.Y., C.S., H.K.G., H.A.), Oslo, Norway.
Correspondence to Håvard Attramadal, MD, PhD, Institute for Surgical Research, Rikshospitalet/The National Hospital, N-0027 Oslo, Norway. E-mail havarda{at}rh.uio.no
Background—Increased plasma adrenomedullin (ADM) levels have been reported in congestive heart failure (HF). The present study was designed to investigate myocardial regulation of the different components of the ADM signaling system (ADM, ADM receptor, and receptor-activity–modifying protein-2, RAMP-2) during ischemic HF in rats and to identify the cells in the myocardium displaying ADM-like immunoreactivity (ADM-ir). Furthermore, the effects of endothelin (ET) receptor antagonism on expression of the myocardial ADM system during HF were investigated.
Methods and Results—Northern blot analysis revealed increased ADM mRNA expression in the nonischemic left ventricle, with maximal levels 28 days after induction of myocardial infarction (1.5-fold, P<0.05) compared with the sham group. Parallel elevations of myocardial ADM receptor and RAMP-2 mRNA levels were also observed (2.3- and 1.5-fold increase, respectively; P<0.05). In addition, high levels of ADM mRNA were seen in the ischemic region. Immunohistochemical analysis revealed a substantial increase of ADM-ir in microvascular endothelium and perivascular interstitial cells of myocardial tissue contiguous to the ischemic region. In addition, radioligand binding studies demonstrated a 1.6-fold increase of specific ADM binding sites in the failing left ventricle (P<0.05). Intervention with the mixed ETA/ETB receptor antagonist bosentan (100 mg · kg-1 · day-1 PO) for 15 days prevented the increase of RAMP-2 mRNA.
Conclusions—The study demonstrates a concerted induction of several components of the myocardial ADM signaling system during postinfarction failure and that the vessels are the main source of myocardial ADM. Our observations indicate a role for ADM as an autocrine/paracrine factor during ventricular remodeling after myocardial infarction.
Key Words: adrenomedullin • endothelin • myocardium • heart failure
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