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Published on: February 15, 2022
Apelin-13 administration allows for norepinephrine sparing in a rat model of cecal ligation and puncture-induced
William Salvail1,2, Dany Salvail2, Frédéric Chagnon1
1Centre de Recherche Clinique du CHU Sherbrooke (CRCHUS), CHUS, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
Insights
Apelin-13 (APL-13) reduces the need for norepinephrine (NE) in treating septic shock, improving cardiac function and lowering lactate levels. This peptide offers a potential alternative to prolonged catecholamine use.
Area of Science:
- Cardiovascular Research
- Critical Care Medicine
- Pharmacology
Background:
- Septic shock often requires catecholamine vasopressors like norepinephrine (NE).
- Sustained NE use can lead to cardiac toxicity and reduced effectiveness.
- Apelin-13 (APL-13) is an endogenous peptide with potential cardioprotective and vasomodulatory effects.
Purpose of the Study:
- To investigate the norepinephrine-sparing effect of Apelin-13 (APL-13) in experimental sepsis-induced hypotension.
- To evaluate the impact of APL-13 on cardiac function and biochemical markers during septic shock.
Main Methods:
- Sepsis was induced in male rats via cecal ligation and puncture (CLP).
- Arterial blood pressure was continuously monitored, with fluid resuscitation initiated 3 hours post-CLP.
- Treated animals received titrated norepinephrine (NE) with or without fixed doses of APL-13 to maintain systolic blood pressure (SBP) ≥ 115 mmHg.
Main Results:
- APL-13 co-infusion significantly reduced the required NE dose by 60% compared to NE alone (P=.008).
- APL-13 improved cardiac function, evidenced by increased left ventricular end-diastolic volume, stroke volume, and cardiac output.
- APL-13 administration led to a decrease in lactate levels (P<.01) and reduced effective arterial elastance.
Conclusions:
- Apelin-13 (APL-13) demonstrates significant norepinephrine-sparing properties in managing sepsis-induced shock.
- APL-13 may mitigate the adverse effects associated with prolonged exogenous catecholamine administration.
- The findings suggest APL-13 as a promising therapeutic agent for septic shock.
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).
Conclusion:
APL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.
