Abstract
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. 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. 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. 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.
Highlights
Administration of a selective β1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction
We previously demonstrated in an experimental model of septic shock that isolated reduction in heart rate by ivabradine does not induce any change in inflammatory status [14]
Using an experimental model of septic shock, the purpose of the present study was to determine whether low doses of esmolol, which do not reduce heart rate, are associated with beneficial effects on: (1) in vivo left ventricular systolic function assessed by echocardiography, (2) ex vivo vascular responsiveness to phenylephrine (Phe) and vascular relaxation to acetylcholine (Ach) of the thoracic aorta and mesenteric artery and (3) systemic, cardiac and vascular inflammatory pathways
Summary
Administration of a selective β1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. In animals with experimental septic shock, a selective β1-blocker such as esmolol efficiently improves both cardiac and vascular functions [8,9,10,11,12,13] Most of these hemodynamic changes could be related to the pleiotropic effects of esmolol, including reduction in heart rate, and to downregulation of inflammatory pathways. Morelli et al observed a reduction in norepinephrine requirement in treated patients [10, 16] In these studies, the dose of esmolol was chosen to achieve a reduction in heart rate of approximately 20%. The authors hypothesize that the survival benefits are related to the modulation of inflammatory genes [17]
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