Abstract 2941: Chymase Inhibitor Improves Renal Dysfunction Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure
Heart failure (HF) is characterized as body fluid retention and impaired renal function is one of the predictors of mortality in HF. Angiotensin-II plays an important role in water and sodium balance and renal injury. Over 50% of renal angiotensin-II formation in HF is mediated by ACE independent chymase pathway. Moreover, chymase directly promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor(TGF)-beta in vitro. However, the additional therapeutic effects of chymase inhibition on the renal function in HF under chronic ACE inhibition have not been well documented yet. We evaluated the long-term effects of concomitant therapy of an ACE inhibitor (ACEI, Enalapril; 0.3mg/kg; n = 7) with a specific chymase inhibitor (ChyI, TEI; 100mg/kg/day; n = 7) on cardiorenal function and gene expressions which were characterized as molecular markers for fibrosis closely linked with renal angiotensin-II levels in dogs with tachycardia induced HF. Vehicle dogs were given placebo (n = 7). Our results are shown in the Table⇓. The concomitant inhibition has more significantly reduced renal mRNA levels closely linked with collagen metabolism and increased urine volume accompanied with renal plasma flow (RPF), glomerular filtration rate (GFR) and Na excretion rate compared to the ACE inhibition alone. Combining the two modes of enzyme inhibition has greater therapeutic potential in the prevention of renal fibrosis and improves water and sodium balance associated with the amelioration of renal hemodynamics with no hypotensive effect in HF.