Abstract 4365: A Recombinant A-Type Natriuretic Peptide Improves Cardiac Function Probably through Suppression of Intracellular ROS in Heart Failure
Background: We previously reported that reactive oxygen species (ROS) causes Ca2+ leak through the ryanodine receptor (RyR), leading to contractile dysfunction, and eventually heart failure (HF). Here, we clarified an antioxidant action of carperitide, an exogenous A-type natriuretic peptide (ANP) in patients with heart failure and in isolated canine failing cardiomyocytes as well.
Methods and Results: In control subjects (N: n=10) and patients with HF (n=20), blood sampling was simultaneously performed from coronary sinus (CS) and artery (A) to measure 8-hydroxy-2-deoxyguanosine (8-OHdG: ng/ml), a marker of oxidative DNA damage. The serum 8-OHdG level was higher in (CS) than in (A) only in HF (HF: 0.57 ±0.33 in CS; 0.31 ± 0.16 in A; N: 0.17±0.07 in CS; 0.16 ± 0.06 in A), indicating that ROS is produced in failing cardiac tissue. The difference in the serum 8-OHdG between (CS) and (A) was increased as NYHA class elevates (r=0.65, p<0.01). The urine 8-OHdG/creatinine level (ng/mg) also correlated with the NYHA class (r= 0.62, p<0.001), LVEF (r=0.43, p <0.001) and PCWP (r=0.54, p<0.001). As protocol 1, we examined whether ANP (0.25 micrograms/kg/min, i.v.) decreases urine 8-OHdG/creatinine during the treatment of HF (n=8, for 3 days), as compared with that of nitroglycerin (NTG; n=8, for 3 days). Either treatment with ANP or NTG similarly improved hemodynamic parameters, such as cardiac index, PCWP, systemic vascular resistance, and pulmonary arterial resistance. In ANP-treated group, however, urine 8-OHdG/creatinine significantly decreased as compared with in NTG-treated group (ANP: 9.8±3.5; NTG:14.5±4.2, p<0.05). As Protocol 2, we produced canine tachycardia-induced HF model by 4-week’s rapid RV pacing (250 bpm) (EF 27±5%, n=6). Then, using the failing cardiomyocytes, we investigated the direct effect of ANP on intracellular ROS (by 2,7,-dichlorofluorescin diacetate fluorescence). In the failing cardiomyocytes, intracellular ROS markedly increased, as compared with normal cardiomyocyte. Interestingly, ANP (1×10 – 8 mol/L) significantly suppressed ROS production seen in failing cardiomyocyte.
Conclusion: Exogenous ANP has a potent antioxidant action that may contribute to an improvement of hemodynamics in patients with HF.