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.
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。