High Levels of Circulating Epinehrine Trigger Apical Cardiodepression in a beta(2)-Adrenergic Receptor/G(i)-Dependent Manner A New Model of Takotsubo Cardiomyopathy

Article

关键词: G-PROTEIN;    VENTRICULAR MYOCYTES;    CELL-SURVIVAL;    IN-VIVO;    RECEPTOR;    HEART;    CONTRACTION;    PHOSPHORYLATION;    OVEREXPRESSION;    CARDIOMYOCYTES;   

DOI  :  10.1161/CIRCULATIONAHA.112.111591

来源: SCIE

【 摘 要 】

Background-Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyophathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic beta(2)-adrenergic receptor (beta(2)AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways. Methods and Results-We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G(i) inactivation by pertussis toxin pretreatment. beta(2)AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vivo studies demonstrated high-dose epinephrine can induce direct cardiomyocytes cardiodepression and cardioprotection in a beta 2AR-Gi-dependent manner. Preventing epinephereine-G(i) effects increased mortality in the Takotsubo model, whereas beta-blockers that activate beta(2)AR-G(i) exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acure cardiac dysfunction without increased mortality. Conclusions-We suggest that biased agonism of epinephrine for beta(2)-AR-G(s) at low concentrations and for G(i) at high concentrations underpins the acute apical cardiopression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in beta(2)ARs explaining the differential regional responses. We suggest this epinephrine-specific beta(2)AR-G(i) signaling may have evolved as a cardioprotective stategy to limit catecholamine-induced myocardial toxicity during acute stress (Circulation. 2012; 126:697-706.)

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