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Abstract：
BACKGROUND: Infusion of exogenous catecholamines (i.e., norepinephrine [NE] and dobutamine) is a recommended treatment for septic shock with myocardial dysfunction. However, sustained catecholamine infusion is linked to cardiac toxicity and impaired responsiveness. Several pre-clinical and clinical studies have investigated the use of alternative vasopressors in the treatment of septic shock, with limited benefits and generally no effect on mortality. Apelin-13 (APL-13) is an endogenous positive inotrope and vasoactive peptide and has been demonstrated cardioprotective with vasomodulator and sparing life effects in animal models of septic shock. A primary objective of this study was to evaluate the NE-sparing effect of APL-13 infusion in an experimental sepsis-induced hypotension.
METHODS: For this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).
RESULTS: A reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).
CONCLUSIONS: APL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.
METHODS: For this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).
RESULTS: A reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).
CONCLUSIONS: APL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.
摘要：
背景：输注外源性儿茶酚胺（即，去甲肾上腺素[NE]和多巴酚丁胺）是感染性休克伴心肌功能障碍的推荐治疗方法。然而,持续的儿茶酚胺输注与心脏毒性和反应性受损有关.一些临床前和临床研究已经调查了替代血管加压药在感染性休克治疗中的使用，益处有限，通常对死亡率没有影响。Apelin-13（APL-13）是一种内源性正性肌力和血管活性肽，已被证明具有血管调节剂的心脏保护作用，并在败血性休克的动物模型中保留了生命作用。这项研究的主要目的是评估APL-13输注在实验性脓毒症诱导的低血压中的NE保护作用。
方法：对于这个目标，在雄性大鼠中通过盲肠结扎和穿孔（CLP）诱导脓毒症，并通过颈动脉导管连续监测动脉血压（BP）。Monitoring,对有意识的动物进行液体复苏和实验治疗。根据试验分析，在CLP后3小时开始生理盐水液体复苏(2.5mL/Kg/h),并维持至终点.因此，滴定剂量的NE，有或没有固定剂量的APL-13或apelin受体拮抗剂F13A联合输注，当收缩压（SBP）从基线下降20%时，开始，恢复SBP值≥115±1.5mmHg（基线平均值±SEM）。
结果：在预定的4.5±0.5h的治疗时间（17.37±1.74µg/Kg/h[APL-13]vs.25.64±2.61µg/Kg/h[对照NE]与28.60±4.79µg/Kg/min[F13A]，P=0.0491)。随着时间的推移，APL-13共输注观察到NE输注速率降低了60%，（p=0.008与单独的NE），而F13A联合输注使NE输注速率随时间增加218%(p=0.003vs.NE+APL-13)。心脏功能的相关改善可能是通过（i）左心室舒张末期容积增加（0.18±0.02mL[对照NE]与0.30±0.03毫升[APL-13]，P=0.0051),每搏量(0.11±0.01mL[对照NE]与0.21±0.01毫升[APL-13]，P<0.001）和心输出量（67.57±8.63mL/min[对照NE]与112.20±8.53mL/min[APL-13]，P=0.0036),和（ii）有效动脉弹性降低（920.6±81.4mmHg/mL/min[对照NE]与497.633.44mmHg/mL/min。[APL-13],P=0.0002)。与仅接受NE的动物相比，APL-13的施用也与乳酸水平的降低有关（7.08±0.40[对照NE]与4.78±0.60【APL-13】，P<0.01)。
结论：APL-13在治疗脓毒症休克方面显示出保留NE的益处，潜在减少长期外源性儿茶酚胺给药的有害影响。
方法：对于这个目标，在雄性大鼠中通过盲肠结扎和穿孔（CLP）诱导脓毒症，并通过颈动脉导管连续监测动脉血压（BP）。Monitoring,对有意识的动物进行液体复苏和实验治疗。根据试验分析，在CLP后3小时开始生理盐水液体复苏(2.5mL/Kg/h),并维持至终点.因此，滴定剂量的NE，有或没有固定剂量的APL-13或apelin受体拮抗剂F13A联合输注，当收缩压（SBP）从基线下降20%时，开始，恢复SBP值≥115±1.5mmHg（基线平均值±SEM）。
结果：在预定的4.5±0.5h的治疗时间（17.37±1.74µg/Kg/h[APL-13]vs.25.64±2.61µg/Kg/h[对照NE]与28.60±4.79µg/Kg/min[F13A]，P=0.0491)。随着时间的推移，APL-13共输注观察到NE输注速率降低了60%，（p=0.008与单独的NE），而F13A联合输注使NE输注速率随时间增加218%(p=0.003vs.NE+APL-13)。心脏功能的相关改善可能是通过（i）左心室舒张末期容积增加（0.18±0.02mL[对照NE]与0.30±0.03毫升[APL-13]，P=0.0051),每搏量(0.11±0.01mL[对照NE]与0.21±0.01毫升[APL-13]，P<0.001）和心输出量（67.57±8.63mL/min[对照NE]与112.20±8.53mL/min[APL-13]，P=0.0036),和（ii）有效动脉弹性降低（920.6±81.4mmHg/mL/min[对照NE]与497.633.44mmHg/mL/min。[APL-13],P=0.0002)。与仅接受NE的动物相比，APL-13的施用也与乳酸水平的降低有关（7.08±0.40[对照NE]与4.78±0.60【APL-13】，P<0.01)。
结论：APL-13在治疗脓毒症休克方面显示出保留NE的益处，潜在减少长期外源性儿茶酚胺给药的有害影响。
