Abstract 3542: Enhanced C-Type Natriuretic Peptide Positive Modulation on Cardiac Performance in Heart Failure: Effects on Left Ventricle and Myocyte Contraction, [Ca2+]i Transient and Ca2+ Current
Background. C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family has vasodilatory and antimitogenic actions, but its direct cardiac effect remains controversial. In heart failure (HF) patients, circulating and myocardial CNP levels are increased, which may alter left ventricle (LV) functional response to CNP. However, the alterations and cellular mechanism of CNP-induced cardiac response in HF remain unclearly defined. We assessed the hypothesis that, in HF, CNP may produce enhanced positive modulation on myocyte [Ca2+]i transient ([Ca2+]iT) and L-type Ca2+ current (ICa,L) and improve LV and myocyte functional performance.
Methods. We assessed LV systolic and diastolic function and compared myocyte contractile, [Ca2+]iT, and ICa,L responses to CNP in 10 normal (N) and 10 age-matched adult rats with isoproterenol (ISO)-induced HF (3 months after 250 mg/kg, sq, for 2 days). Hemodynamic data were measured using MIKRO-TIP pressure (P)/volume (V) catheters.
Results. In normal rats, CNP (2 μg/kg plus 0.4 μg/kg/min, iv, 10 min) caused leftward shifts and increased slopes of P-V relations (EES) (12%, 1.11 vs 0.99 mmHg/μl) with decreased LV time constant relaxation (ô, 21%, 9.8 vs 12.4 ms). In HF rats, CNP produced a significantly greater increase in EES (38%, 0.70 vs 0.51 mmHg/μl) and a decrease in τ (30%, 14.0 vs 19.9 ms), indicating enhanced increase in LV contractility and the rate of LV relaxation. Consistently, in isolated myocytes, superfusion of CNP (10−7 M) caused improved cell contraction and relaxation in both normal and HF myocytes. In HF myocytes, CNP resulted in significantly greater increases in the peak velocity of shortening (dL/dtmax, 17%, 165.5 vs 141.1; 37%, 112.9 vs 82.4 μm/sec) and relengthening (dR/dtmax) (18%, 138.9 vs 117.9; 75%, 93.4 vs 53.5 μm/sec) accompanied by significantly larger increases in [Ca2+]iT (6.4%, 0.33 vs 0.31; 28%, 0.18 vs 0.14) and ICa,L (11%, 9.1 vs 8.2; 23%, 5.8 vs 4.7 pA/pF).
Conclusions: CNP produces positive modulation on cardiac performance in both normal and HF rats. In HF, CNP caused greater improvement of LV, myocyte contraction, and relaxation with further augmentation of increased [Ca2+]iT and ICa,L. These findings support the usefulness of CNP as a potential therapeutic agent in HF.