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Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure

Item Type:Article
Title:Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure
Creators Name:Westermann, D. and Riad, A. and Richter, U. and Jaeger, S. and Savvatis, K. and Schuchardt, M. and Bergmann, N. and Toelle, M. and Nagorsen, D. and Gotthardt, M. and Schultheiss, H.P. and Tschoepe, C.
Abstract:BACKGROUND: Diastolic heart failure is a rising problem with a high incidence and similar mortality and morbidity compared to patients with systolic heart failure. Nevertheless, the underlying pathophysiology is still debated. AIM: We investigated the effect of pharmacological enhancement of endothelial nitric oxide synthase (eNOS) on experimental diastolic heart failure (DHF). METHODS: DHF was induced in 60 DAHL salt-sensitive rats by salt diet in 8-week-old animals. 30 were treated with the eNOS enhancer AVE3085 (DHFeNOS) and 30 with placebo (DHF). Rats with normal salt intake served as controls. RESULTS AND CONCLUSION: Diastolic dysfunction with increased diastolic stiffness constant and increased left ventricular (LV) pressure was analyzed by invasive pressure-volume loop measurements in the DHF group compared to controls. Cardiac hypertrophy as indicated by LV mass measurements by echocardiography, and increased cardiac collagen content as measured by immunohistochemistry were associated with an increased activation state of calcineurin, AKT, ERK(1/2), but not JNK and p38 kinases. Titin isoforms were not altered in this model of DHF. Treatment with AVE3085 significantly increased eNOS mRNA and protein levels in the cardiac tissue and decreases NAD(P)H oxidase subunits p22phox and gp91phox. Diastolic dysfunction was attenuated and cardiac hypertrophy and fibrosis were improved in comparison with untreated DHF animals. This was associated with a normalized activation state of calcineurin, AKT and ERK(1/2). Therefore, we suggest that targeting the NO system might yield a future therapeutic aim for the treatment of DHF.
Keywords:Diastolic Dysfunction, Nitric Oxide, Heart Failure, Pressure-Volume Loops, Animals, Rats
Source:Basic Research in Cardiology
Page Range:499-509
Date:September 2009
Official Publication:https://doi.org/10.1007/s00395-009-0014-6
PubMed:View item in PubMed

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