title: Upregulation of adrenomedullin and its receptor components during cardiomyocyte hypertrophy induced by chronic inhibition of nitric oxide synthesis in rats.
abstract: Adrenomedullin may provide a compensatory mechanism to attenuate left ventricular hypertrophy (LVH). Nitric oxide synthase inhibition, induced by chronic administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats, induces cardiac hypertrophy in some, but not all cases; there are few reports of direct assessment of cardiomyocyte parameters. The objective was to characterize hypertrophic parameters in left (LV) and right ventricular (RV) cardiomyocytes after administration of L-NAME to rats for 8 wk and to determine whether adrenomedullin and its receptor components were upregulated. After treatment with L-NAME (20 and 50 mg x kg(-1) x day(-1)), compared with nontreated animals, 1) systolic blood pressure increased (by 34.2 and 104.9 mmHg), 2) heart weight-to-body wt ratio increased 24.1% at the higher dose (P < 0.05), 3) cardiomyocyte protein mass increased (P = NS), 4) cardiomyocyte protein synthesis ([14C]phenylalanine incorporation) increased (P < 0.05), 5) expression of skeletal alpha-actin, atrial natriuretic peptide, brain natriuretic peptide, and ET-1 mRNAs was enhanced (P < 0.05) in LV but not RV cardiomyocytes at 20 and 50 mg x kg(-1) x day(-1), respectively, and 6) expression of adrenomedullin, receptor activity-modifying protein 3 (RAMP3), and RAMP2 (but not calcitonin receptor-like receptor and RAMP1) mRNAs was increased by L-NAME (20 mg x kg(-1) x day(-1)) in LV. In conclusion, L-NAME enhanced protein synthesis in both LV and RV cardiomyocytes but elicited a hypertrophic phenotype accompanied by altered expression of the counterregulatory peptide adrenomedullin and receptor components (RAMP2, RAMP3) in LV only, indicating that the former is due to impaired nitric oxide synthesis, whereas the phenotypic changes are due to pressure overload.
authors.affiliation: Division of Medicine and Therapeutics, School of Medicine, The Queen's Univ. of Belfast, Whitla Medical Bldg., 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom. d.bell@qub.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Bell
authors.forename: You-You
authors.initials: YY
authors.lastname: Zhao
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kelso
authors.forename: Eugene M
authors.initials: EM
authors.lastname: McHenry
authors.forename: Louise M
authors.initials: LM
authors.lastname: Rush
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Lamont
authors.forename: D Paul
authors.initials: DP
authors.lastname: Nicholls
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McDermott
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006352:Heart Ventricles; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009929:Organ Size; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010455:Peptides; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester