Abstract 1490: The Nitric Oxide (NO) Donor Molsidomine Rescues Heart Function in Experimental Cardiorenal Failure
Chronic kidney disease (CKD) is associated with a high risk for left ventricular systolic dysfunction (LVSD) and heart failure. Studies of CKD in rats by subtotal nephrectomy (SNX) however do not show apparent LVSD. We developed a rat model of cardiorenal failure by combining SNX with temporary low grade NO synthase (NOS) inhibition (ASN 2007). In this model, LVSD, heart failure and high mortality occurred. LVSD and decreased NO production were persistent after stopping NOS inhibition. We hypothesized that LVSD and heart failure were due to the low NO availability, and hence studied whether NO supplementation could reverse LVSD. Rats underwent SNX and treatment with the NOS inhibitor N-nitro-L-arginine (LNNA; 20 mg/l water) from 3 wks before to 8 wks after SNX. At wk 11, rats were stratified for cardiac and renal function. A subgroup (MOLS) was treated with the long-acting, tolerance-free NO donor molsidomine (120 mg/l) for 4 wks. Cardiac and renal function were measured regularly and terminal histology was assessed. In SNX, hearts were dilated and hypertrophic. SNX+LNNA caused LVSD (ejection fraction at wk 8: 39±2% vs. 63±3% in SNX; P<0.01), heart failure with dyspnoea and high mortality (wk 8: 31% vs 0% in SNX). After wk 11, further mortality occurred in SNX+LNNA (22%) and cardiac dysfunction persisted until the end of the study (wk 15, table⇓). Molsidomine restored cardiac function, increased creatinine clearance and prevented mortality. Systolic blood pressure and systemic vascular resistance did not change. Structural variables like glomerulosclerosis, cardiomyocyte area, and cardiac interstitial and perivascular fibrosis were also not affected. In a rat model of severe cardiorenal failure the NO donor molsidomine significantly improves systolic function and ameliorates renal dysfunction. This is probably due to the decreased end-diastolic pressure which reduces wall stress, without an effect on afterload.