Abstract 12575: Cellular Basis of C-Type Natriuretic Peptide Produced Augmentation on Left Ventricular Systolic and Diastolic Functional Performance in Heart Failure
Background: In addition to its well-known vasodilating and natriuretic actions, C-type natriuretic peptide (CNP), has been viewed as an endogenous inhibitor of the renin-angiotensin system, but its direct cardiac effects remain controversial. In heart failure (HF), circulating and myocardial CNP levels are increased, which may alter LV functional response to CNP. However, the alterations and cellular mechanisms of CNP-induced cardiac response in HF remain unclearly defined. We assessed the hypothesis that in HF, CNP might 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 a clinically relevant dose of CNP (2 μg/kg bolus plus 0.4 μg/kg/min, iv, 10 min) in 12 normal (N) and 12 age-matched adult rats with isoproterenol (ISO)-induced HF (2 months after 170 mg/kg, sq, for 2 days).
Results: In normal rats, CNP caused leftward shifts and increased slopes of PES-VES relations (EES) (14%, 1.17 vs 1.04 mmHg/μl) with decreased LV time constant relaxation (τ, 19%, 9.0 vs 11.1ms). In HF rats, versus normal, CNP produced a significantly greater increase in EES (37%, 0.81 vs 0.59 mmHg/μl) and a decrease in τ (31%, 11.0 vs 15.9 ms), indicating enhanced increases in LV contractility and the rate of LV relaxation. Consistently, in isolated myocytes, superfusion of CNP (5x10-7 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, 18%, 167.4 vs 141.9; 39%, 103.9 vs 74.9 μm/sec) and relengthening (dR/dtmax, 19%, 134.7 vs 113.2; 71%, 92.1 vs 53.8 μm/sec) accompanied by significantly larger increases in [Ca2+]iT (9.5%, 0.23 vs 0.21; 29%, 0.22 vs 0.17) and ICa,L (12%, 9.1 vs 8.1; 28%, 5.9 vs 4.6 pA/pF).
Conclusions: CNP produces positive modulation on cardiac performance in both normal and HF rats. In HF, CNP caused greater improvement of LV and myocyte contraction, and relaxation with further augmentation of increased [Ca2+]iT andICa,L. These findings support the usefulness of CNP as a new therapeutic option for HF.
Author Disclosures: Z. Zhang: None. X. Zhang: None. T. Li: None. H. Cheng: None. P. Zhou: None. C. Cheng: None.
- © 2016 by American Heart Association, Inc.