METHODS: We compared left ventricle (LV) and myocyte function, [Ca2+]i transient ([Ca2+]iT) and β-AR modulation in control male mice (12/group) and isoproterenol-induced HF (150 mg/kg s.c. for 2 days). Two weeks after isoproterenol injection, HF mice received placebo, or G1 (150 μg/kg/day s.c. mini-pump) for 2 weeks.
RESULTS: Isoproterenol-treated mice exhibited HF with preserved ejection fraction (HFpEF) at 2-weeks and progressed to HF with reduced EF (HFrEF) at 4-weeks, manifested by significantly increased LV time constant of relaxation (τ), decreased EF and mitral flow (dV/dtmax), which were accompanied by reduced myocyte contraction (dL/dtmax), relaxation (dR/dtmax) and [Ca2+]iT. Acute isoproterenol-superfusion caused significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. G1 treatment in HF increased basal and isoproterenol-stimulated increases in EF and LV contractility of EES. Importantly, G1 improved basal and isoproterenol-stimulated dL/dtmax, dR/dtmax and [Ca2+]iT to control levels and restored normal cardiac β-AR subtypes modulation.
CONCLUSIONS: Chronic G1 treatment restores normal myocyte basal and β-AR-stimulated contraction, relaxation, and [Ca2+]iT, thereby reversing LV dysfunction and playing a rescue role in a male mouse model of HF.
方法:我们比较了左心室(LV)和肌细胞功能,在对照雄性小鼠(12/组)和异丙肾上腺素诱导的HF(150mg/kgs.c.持续2天)中的[Ca2+]i瞬时([Ca2+]iT)和β-AR调节。注射异丙肾上腺素两周后,HF小鼠接受安慰剂,或G1(150μg/kg/天皮下微型泵)持续2周。
结果:异丙肾上腺素治疗的小鼠在2周时表现出射血分数(HFpEF)保留的HF,并在4周时发展为EF(HFrEF)降低的HF,表现为弛豫的LV时间常数(τ)显著增加,降低EF和二尖瓣流量(dV/dtmax),伴随着减少的肌细胞收缩(dL/dtmax),弛豫(dR/dtmax)和[Ca2+]iT。急性异丙肾上腺素-超融合引起dL/dtmax显著较小的增加,dR/dtmax和[Ca2+]iT。HF中的G1治疗增加了EES的EF和LV收缩性的基础和异丙肾上腺素刺激的增加。重要的是,G1改善了基础和异丙肾上腺素刺激的dL/dtmax,dR/dtmax和[Ca2+]iT控制水平并恢复正常心脏β-AR亚型调制。
结论:慢性G1治疗可恢复正常的基础肌细胞和β-AR刺激的收缩,放松,和[Ca2+]iT,从而逆转LV功能障碍并在HF的雄性小鼠模型中发挥挽救作用。