Aminoguanidine inhibits mitogen-activated protein kinase and improves cardiac performance and cardiovascular remodeling in failing hearts of salt-sensitive hypertensive rats.

Abstract

Congestive heart failure (CHF) is associated with inducible nitric oxide synthase (iNOS) expression in the failing human heart, and recently we have also demonstrated that iNOS expression was upregulated in Dahl salt-sensitive hypertensive (DS) rats with cardiac dysfunction and vascular remodeling. Thus, we evaluated whether aminoguanidine (AG), a selective iNOS inhibitor, protects against cardiac dysfunction and vascular remodeling in DS rats receiving a high-salt diet. AG (DSHF-AG, 150 mg/kg per day) or vehicle (DSHF-V) were given from left ventricular hypertrophy stage (11 weeks) to CHF stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship (contractility: E(es)) was measured by conductance catheter. Decreased E(es) in DSHF-V was significantly ameliorated by AG treatment. The iNOS mRNA and protein expression and phospho-p42/p44 extracellular signal-regulated kinase (ERK) activities in the left ventricle were significantly upregulated in DSHF-V compared with control rats, and significantly suppressed in DSHF-AG compared with DSHF-V. DSHF-V showed a significant increase of perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by AG treatment. We demonstrated that the selective iNOS inhibitor, AG, may be at least a potential therapeutic strategy for treating CHF and cardiovascular remodeling.