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, 20 (1), 407

Effects of Low Doses of Esmolol on Cardiac and Vascular Function in Experimental Septic Shock

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Effects of Low Doses of Esmolol on Cardiac and Vascular Function in Experimental Septic Shock

Chaojie Wei et al. Crit Care.

Abstract

Background: Administration of a selective β1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. Certain experimental data also indicate that esmolol exerts systemic anti-inflammatory and beneficial effects on vascular tone. Thus, the present study aimed to determine whether a non-chronotropic dose of esmolol maintains its protective cardiovascular and anti-inflammatory effects in experimental septic shock.

Methods: Four hours after cecal ligation and puncture (CLP), Wistar male rats were randomly allocated to the following groups (n = 8): CLP, CLP + E-1 (esmolol: 1 mg.kg-1.h-1), CLP + E-5 (esmolol: 5 mg.kg-1.h-1), CLP + E-18 (esmolol: 18 mg.kg-1.h-1). An additional eight rats underwent sham operation. All rats received a continuous infusion of saline, analgesic and antibiotics 4 hours after the surgery. Assessment at 18 hours included in vivo cardiac function assessed by echocardiography and ex vivo vasoreactivity assessed by myography. Circulating cytokine levels (IL-6 and IL-10) were measured by ELISA. Cardiac and vascular protein expressions of p-NF-κB, IκBα, iNOS, p-AKT/AKT and p-eNOS/eNOS were assessed by western blotting.

Results: CLP induced tachycardia, hypotension, cardiac output reduction, hyperlactatemia and vascular hypo-responsiveness to vasopressors. Compared to CLP animals, heart rate was unchanged in CLP + E-1 and CLP + E-5 but was reduced in CLP + E-18. Stroke volume, cardiac output, mean arterial pressure and lactatemia were improved in CLP + E-1 and CLP + E-5, while vascular responsiveness to phenylephrine was only improved in CLP + E-5 and CLP + E-18. Plasma IL-6 levels were decreased in all esmolol groups. p-NF-κB was decreased in both cardiac and vascular tissues in CLP + E-5 and CLP + E-18.

Conclusion: In experimental septic shock, low doses of esmolol still improved cardiac function and vasoreactivity. These benefits appear to be associated with a modulation of inflammatory pathways.

Keywords: Esmolol; Heart function; Inflammation; Sepsis; Vasoreactivity.

Figures

Fig. 1
Fig. 1
Vasoreactivity evaluated by myography. Ex vivo vascular responsiveness to phenylephrine and concentration–response curves to acetylcholine in rat thoracic aorta and mesenteric resistance arteries from sham, cecal ligation and puncture (CLP) and CLP + esmolol (CLP + E) groups (n = 8 per group). a and c Contraction of the vessel (in mN.mm−1) as a function of increasing concentrations of phenylephrine (Phe) expressed as log of Phe [M, mole/L]. b and d Relaxation of the vessel (in percent) as a function of increasing concentrations of acetylcholine (Ach) expressed as log of Ach [M, mole/L]. Circles, squares and triangles represent median; upper edges of error bars represent the 75th percentile in each group; *p < 0.05. *Sham vs. CLP, CLP vs. CLP + E-5 and CLP vs. CLP + E-18 (b). *Sham vs. CLP, CLP vs. CLP + E-1 and CLP vs. CLP + E-18 (d). E-1 esmolol 1 mg.kg−1.h−1, E-5 esmolol 5 mg.kg−1.h−1, E-18 esmolol 18 mg.kg−1.h−1. a and b aorta and c and d mesenteric arteries
Fig. 2
Fig. 2
Assessment of circulatory pro-inflammatory/anti-inflammatory cytokine levels of IL-6 (a), and IL-10 (b) as measured by ELISA. Data are expressed as concentration (pg.ml−1); black lines indicate medians ± interquartile range (in color). Sham, n = 7; all other groups, n = 8. *p < 0.05.CLP cecal ligation and puncture, E-1 esmolol 1 mg.kg−1.h−1, E-5 esmolol 5 mg.kg−1.h−1, E-18 esmolol 18 mg.kg−1.h−1
Fig. 3
Fig. 3
Western blot analysis of protein expression in the heart. Western blots revealing phosphorylated AKT (p-AKT) (a), phosphorylated endothelial nitric oxide synthase (p-eNOS) (b), nuclear factor - κB (NF-κB) (c), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) (d) and inducible nitric oxide synthase (iNOS) (e). Proteins were obtained from heart lysates (n = 8) prepared from all experimental rat groups. A typical western blot is shown below each histogram. Densitometric analysis (n = 8) was used to calculate the normalized protein ratio. Data are expressed as median ± interquartile range. Upper edges of error bars represent the 75th percentile in each group. *p < 0.05. CLP cecal ligation and puncture, E-1 esmolol 1 mg.kg−1.h−1, E-5 esmolol 5 mg.kg−1.h−1, E-18 esmolol 18 mg.kg−1.h−1
Fig. 4
Fig. 4
Western blot analysis of protein expression in the thoracic aorta. Western blots revealing phosphorylated AKT (p-AKT) (a), phosphorylated endothelial nitric oxide synthase (p-eNOS) (b), nuclear factor-κB (NF-κB) (c), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) (d) and inducible nitric oxide synthase (iNOS) (e). Proteins were obtained from thoracic aorta lysates (n = 8) prepared from all experimental rat groups. A typical western blot is shown below each histogram. Densitometric analysis (n = 8) was used to calculate the normalized protein ratio. Data are expressed as median ± interquartile range. Upper edges of error bars represent the 75th percentile in each group. *p < 0.05. CLP cecal ligation and puncture, E-1 esmolol 1 mg.kg−1.h−1, E-5 esmolol 5 mg.kg−1.h−1, E-18 esmolol 18 mg.kg−1.h−1

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