Abstract 11921: Altered Cardiomyocyte Functional Response to Vasopressin in Heart Failure
Background. In heart failure (HF), circulating levels of arginine vasopressin (AVP) are elevated and there is direct relationship between a rise in AVP levels and increased morbidity and mortality. Recent observations further demonstrated the increased AVP 1A receptor (V1AR) expression in failing human hearts and suggested that these alterations may alter cardiac contractile behavior in HF. However, the direct cardiac effects of V1AR in normal and HF remain undetermined. The cellular basis for AVP-associated adverse clinical consequences in HF is unclear. We assessed the hypothesis that in HF, AVP may produce negative modulation on [Ca2+]i regulation and cause direct depression in cardiomyocyte contractile performance.
Methods. We assessed LV myocyte functional and calcium transient ([Ca2+]iT) responses to AVP (10-7 M) in 8 control and 12 SD rats with isoproterenol (ISO) induced HF (2 months after 170 mg/kg sq for 2 days) in the absence and presence of selective V1AR blockade ([Pmp1, Tyr (OMe) 2, Arg8] AVP, 10-6 M), or pretreatment of myocytes with Gi inhibitor (PTX, 2 μg/ml, 6 hrs).
Results. Compared with controls, ISO-treated rats had established HF after ISO at 2 months with significant LV dilatation and decreased ejection fraction (EF, 31% vs 61%). In normal myocytes, versus baselines, AVP superfusion caused no significant changes in myocyte contraction (dL/dtmax)(130.6 vs 136.8 μm/s), relaxation (dR/dtmax) (99.5 vs 103.5 μm/s) and [Ca2+]iT(0.24 vs 0.24). In contrast, in HF, myocyte function was impaired and further depressed by AVP. Versus HF baselines, AVP resulted significantly decreases in dL/dtmax (24%, 57.2 vs 75.4 μm/s) and dR/dtmax (20%, 39.3 vs 49.0 μm/s) accompanied by reduced [Ca2+]iT(17%, 0.14 vs 0.17). In HF myocytes, these AVP mediated effects were abolished by prior exposure of myocytes to V1AR blockade or PTX.
Conclusions. HF alters AVP cardiac effects. In HF, AVP exacerbates the dysfunctional [Ca2+]i homeostasis, producing decreased the peak systolic [Ca2+]iT. AVP causes direct inhibitions of LV myocyte contraction and relaxation, These effects are coupled with the activation of V1AR and are likely to be mediated through the PTX-sensitive G protein pathway and may thus play an important role in promoting functional impairment in HF.
Author Disclosures: T. Li: None. X. Zhang: None. H. Cheng: None. W. Li: None. C. Cheng: None.
- © 2015 by American Heart Association, Inc.