Abstract 1876: Functional Effect of Chronic Urotensin II Receptor Antagonist on L-Type Ca2+ Current in Mouse Model of Progressive Heart Failure
Voltage-gated Ca2+ channels play fundamental roles in the regulation of cardiac function by various neurotransmitters. Recently, we have shown that urotensin II (UII), a potent vasoconstrictor, inhibits L-type Ca2+ current (ICa,L) and produces negative inotropic action. In heart failure (HF), the UII-mediated pathway is upregulated, suggesting a therapeutic value of UII receptor antagonist (UII-ANT) for HF. However, the role and mechanism of chronic UII-ANT in HF is unclear. We tested the hypothesis that chronic UII-ANT may improve cardiac ICa,L, preventing β-adrenergic deregulation on ICa,L and limit HF progression. We examined plasma levels of norepinephrine (NE), left ventricular (LV) function, and myocyte ICa,L responses to isoproterenol (ISO) in 3 age-matched groups of mice:
HF (n = 7), 2 months after ISO (150 mg/kg sq for 2 days);
HF/UII-ANT (n = 11), 1 month after receiving ISO, then urantide, a potent UII-ANT (10−5 M/kg/day, sq via implanted osmotic mini pump), given for 1 month; and
Controls (n = 7). ICa,L was measured using whole-cell voltage clamp technique.
Compared with controls, ISO-treated mice progressed to HF with 4.7-fold increase in plasma NE (18975 vs 4066 pg/ml) and LV dilatation associated with increased myocyte length (ML, 155 vs120 μm) and heart-to-body weight ratio (H/BW, 7.6 vs 5.5 g/kg). Stroke volume (SV, 30.3 vs 61.4 μl) and ejection fraction (EF, 39% vs 60%) were decreased. Compared with normal myocytes, in HF myocytes, ICa,L was reduced (50%, 3.7 ± 0.2 vs 7.4 ± 0.2 pA/pF), and ICa,L response to β-AR stimulation (ISO, 10−8 M) was attenuated (11% vs 35%) (p < 0.01). In HF/UII-ANT mice, plasma NE (5148 pg/ml), SV (57.9 μl), and EF (57%) returned close to control levels with retained normal ML (124 μm) and H/BW (5.9 g/kg). Moreover, compared with controls, in HF/UII-ANT mice, ISO caused similar increases in the peak ICa,L (32% vs 35%). Chronic UII-ANT treatment normalizes LV L-type Ca2+ channel basal function and β-adrenergic regulation, leading to regression of LV and myocyte dysfunction and remodeling in mice with ISO-induced HF.
This research has received full or partial funding support from the American Heart Association, AHA National Center.