1. Academic Validation
  2. Effects of TCV-116 on expression of NOS and adrenomedullin in failing heart of Dahl salt-sensitive rats

Effects of TCV-116 on expression of NOS and adrenomedullin in failing heart of Dahl salt-sensitive rats

  • Atherosclerosis. 2001 Jun;156(2):255-65. doi: 10.1016/s0021-9150(00)00624-9.
N Kobayashi 1 T Nishikimi S Horinaka T Ishimitsu H Matsuoka
Affiliations

Affiliation

  • 1 Department of Medicine, Division of Hypertension and Cardiorenal Disease, Dokkyo University School of Medicine, Tochigi 321-0293, Mibu, Japan. a-fukuda@dokkyomed.ac.jp
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.

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