Abstract 12206: Altered Cardiomyocyte Inotropic Response to Chymase/Ang-(1-12) Pathway Activation in Heart Failure
Background: Angiotensin-(1-12) [Ang-(1-12)], a new member of the renin-angiotensin system (RAS) has been identified as a chymase-dependent source for Angiotensin II (Ang II) inotropic activity. Recent observations suggest that activation of this non-canonical chymase/Ang-(1-12) pathway may modulate cardiac function bypassing the inhibitory effects of RAS blockade with ACEI and ARBs in heart failure (HF). However, the direct cardiac effects of Ang-(1-12) and Ang II are unclear. Moreover, whether and how HF alters Ang-(1-12) and Ang II cardiac responses are undefined. We assessed the hypothesis that HF is associated with a reduced action of Ang-(1-12) on myocyte contractility and [Ca2+]i regulation.
Methods: We compared LV myocyte contractile and calcium transient ([Ca2+]iT) responses to angiotensin peptides in 12 SD rats with isoproterenol induced HF (2 months after isoproterenol 170 mg/kg sq for 2 days) and 16 age-matched controls.
Results: In normal myocytes, versus baseline, Ang II (10-6 M) superfusion significantly increased myocyte contraction (dL/dtmax) (40%, 184.6 vs 132.1 μm/s), relaxation (dR/dtmax) (34%, 141.3 vs 107.0 μm/s) and [Ca2+]iT (29%, 0.31 vs 0.24). Superfusion of Ang-(1-12) (4x10-6 M) caused similar increases in dL/dtmax (34%) dR/dtmax (25%) and [Ca2+]iT (25%). Compared with the changes in normal myocytes, in HF myocytes, Ang II and Ang-(1-12) caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dtmax, dR/dtmax and [Ca2+]iT. The Ang-(1-12)-mediated effects were abolished by prior exposure of myocytes to chymostatin in both normal and HF. The Ang II-induced inotropic effects were completely prevented in the presence of an inhibitory cAMP analog, Rp-cAMPS (10–4 M 2 h) in both normal and HF myocytes, but were further augmented only in HF after the incubation of myocytes with the Gi inhibitor, pertussis toxin (PTX, 2 μg/ml, 36°C, 5h).
Conclusions: Ang-(1-12) stimulates LV myocyte contractile function and [Ca2+]iT in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes is mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.
Author Disclosures: T. Li: None. X. Zhang: None. S. Ahmad: None. J. Varagic: None. H. Cheng: None. Z. Zhang: None. L. Groban: None. C.M. Ferrario: None. C. Cheng: None.
- © 2016 by American Heart Association, Inc.