Abstract 20240: CD-NP, a Novel Dual Guanylyl Cyclase Receptor Activator, Decreases Fibrosis and Improves Diastolic Dysfunction Produced by Mild Renal Insufficiency
Reduced renal function increases cardiovascular (CV) morbidity and mortality. We have reported that mild reduction in renal function produced by unilateral nephrectomy (UNX) increases myocardial collagen content resulting in myocardial diastolic impairment in the absence of hypertension. Natriuretic peptides (NPs) possess cardiorenal protective properties via activation of particulate guanylyl cyclase (GC) receptors. We hypothesized that in this model of mild renal dysfunction, that a novel Mayo designed chimeric NP, CD-NP, would prevent cardiac remodeling, diastolic impairment, suppress aldosterone (Aldo) and preserve renal function. CD-NP represents the first dual GC receptor agonist which has anti-fibrotic via GC-B, aldosterone suppressing and renopreserving properties via GC-A without excessive hypotension.
Methods: Cardiorenal function and structure were assessed in Wistar rats (UNX;n=9) and (CD-NP UNX;n=9) 4 weeks (wk) after UNX. At wk 4 GFR, Na, water excretion, and Aldo were assessed. LV mass, EF, circumferential systolic strain (Cs) and, early (Csr-E) and late (Csr-A) diastolic strain rates and ratio were assessed by echo speckle tracking. CD-NP was administered through osmotic minipumps (170 ng/kg/min for 2 wk) following UNX.
Results: At wk 4, fibrosis (Picrosirius Red) in the LV of UNX CD-NP compared to UNX was decreased (UNX: 4.2±0.5, UNX CDNP: 3±0.4%, p<0.05). Aldosterone was suppressed in the CD-NP UNX group compared to the UNX group (UNX: 30.4±6, UNX CD-NP:12.6±1.8 ng/dL, p<0.05). Proteinuria was reduced in the CD-NP UNX group (p<0.001). Echocardiography demonstrated EF was higher in the CD-NP UNX group (UNX:77±2.3, CD-NP UNX: 81±3 %, p<0.05); Csr-E and Csr-E/A ratio were higher in the CD-NP UNX group (p<0.05) consistent with improved diastolic function. Blood pressure, Na and water excretions were not different between groups.
Conclusions: CD-NP decreased LV fibrosis in experimental mild renal insufficiency, suppressed aldosterone, decreased proteinuria and improved overall diastolic function without changes in blood pressure. These studies suggest a potential therapeutic role for CD-NP in the prevention of the cardiac fibrosis and diastolic dysfunction associated with experimental early chronic kidney disease.
- © 2010 by American Heart Association, Inc.