title: Effects of TCV-116 on expression of NOS and adrenomedullin in failing heart of Dahl salt-sensitive rats.
abstract: We examined the effects of TCV-116, an angiotensin II type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS), inducible NOS (iNOS), and adrenomedullin (ADM) expression in the left ventricle (LV) and evaluated these relation to myocardial remodeling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet. TCV-116 (DSHF-T, 5 mg/kg/day, subdepressor dose) or vehicle (DSHF-V) were given from left ventricular hypertrophy to heart failure stage for 7 weeks. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSHF-V was significantly ameliorated in DSHF-T. The eNOS mRNA and protein in the LV was significantly suppressed in DSHF-V compared with control rats (DR-C), and significantly increased in DSHF-T compared with DSHF-V. The iNOS mRNA and protein, ADM mRNA and immunoreactive ADM contents, and type I collagen mRNA in the LV were significantly increased in DSHF-V compared with DR-C, and significantly decreased in DSHF-T compared with DSHF-V. DSHF-V showed a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. In conclusion, myocardial remodeling and heart failure in DS rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of TCV-116, which may be due to a increased in eNOS and a decreased in iNOS mRNA and protein expression in the LV. Moreover, the ADM mRNA and immunoreactive ADM contents are upregulated in failing heart of DS rats fed a high-salt diet, and increased ADM expression may have a role in the defense mechanism against further cardiac dysfunction and impaired myocardial remodeling.
authors.affiliation: Department of Medicine, Division of Hypertension and Cardiorenal Disease, Dokkyo University School of Medicine, Tochigi 321-0293, Mibu, Japan. a-fukuda@dokkyomed.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Kobayashi
authors.forename: T
authors.initials: T
authors.lastname: Nishikimi
authors.forename: S
authors.initials: S
authors.lastname: Horinaka
authors.forename: T
authors.initials: T
authors.lastname: Ishimitsu
authors.forename: H
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D053607:Adrenomedullin; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis*; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000032:analysis*; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D053607:Adrenomedullin; D009569:Nitric Oxide; C077793:candesartan cilexetil