Abstract 5955: Role of Bradykinin and Chymase in Cardiorenal Function Under Long-Term ACE Inhibition in Heart Failure
Renal insufficiency is relatively common in patients with heart failure (HF) and patients with chronic kidney disease are known to have a significant increase in cardiovascular morbidity and mortality. Angiotensin (Ang) II plays an important role in water and sodium (Na) balance and renal injury. Although ACE inhibitors (ACEIs) suppress the formation of Ang II and are useful in the treatment of HF, the agents also prevent the breakdown of bradykinin (BK), which exerts its vasodilative action through BK type 2 (B2) receptors. On the other hand, over 50% of renal Ang II formation in HF is mediated by ACE independent chymase pathway. The roles of BK and chymase in the cardiorenal function under chronic treatment of ACEI has not been fully elucidated as yet. We therefore evaluated the cardiorenal effects of a specific B2 receptor antagonist, FR173657 (FR, 0.3mg/kg/day) or a specific chymase inhibitor, (ChyI, 100mg/kg/day) with an ACEI, enalapril (1mg/kg/day) compared to those of enalapril alone in dogs with tachycardia induced HF (22days). Cardiac contractile function markedly deteriorated and body fluid retention and impaired renal function accompanied with upregulation of renal ACE and chymase mRNA levels after the induction of severe HF. However, enalapril significantly improved the ejection fraction (vehicle 19% vs. enalapril 36%, p<0.01) and increased urine excretion (vehicle 0.36 vs. enalapril 0.55 ml/min, p<0.05) associated with increases in the glomerular filtration rate (GFR) and renal plasma flow (RPF) (vehicle 24 vs. enalapril 60 ml/min, and 74 vs. 169 ml/min, respectively p<0.05) in HF. There were no differences observed in blood pressure and LV ejection fraction among three treatment groups. FR did not statistically affect urinary Na excretion, GFR and RPF compared to the ACE inhibition alone, however, the chymase inhibition has more significantly increased water and Na excretion rate (0.70 vs. 0.55 ml/min and 56 vs. 26 μEq/min, respectively p<0.05) and GFR (70 vs. 59 ml/min, p<0.05) compared to the ACE inhibition alone. In conclusion, endogenous BK does not likely contributes to the renoprotective effects of ACEI, however, combining ACE and chymase inhibition has greater therapeutic potential in the amelioration of renal function in HF.