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Cardioprotection, attenuated systemic inflammation, and survival benefit of ß1-adrenoceptor blockade in severe sepsis in rats*

Ackland, Gareth L. PhD, FRCA; Yao, Song T. PhD; Rudiger, Alain MD; Dyson, Alex Msc; Stidwill, Ray Bsc; Poputnikov, Dmitry PhD; Singer, Mervyn MD, FRCP; Gourine, Alexander V. PhD

doi: 10.1097/CCM.0b013e3181c03dfa
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Objective: To explore the hypothesis that beta-1 adrenoreceptor blockade may be protective through the attenuation of sympathetic hyperactivity and catecholaminergic inflammatory effects on cardiac and hepatic function.

Design: Prospective, randomized, controlled study.

Setting: Animal laboratory in a university medical center.

Subjects: Male adult Wistar rats.

Interventions: Peripheral β1-adrenoceptor blockade through daily intraperitoneal injection (metoprolol, 100 mg·kg−1; atenolol, 6 mg·kg−1) or central nervous system β1-adrenoceptor blockade (intracerebroventricular metoprolol, 25 μg) to achieve ∼20% heart rate reduction in rats for 2 days before or after the induction of lethal endotoxemia, cecal ligation and puncture, or fecal peritonitis.

Measurements and Main Results: Peripheral β1-adrenoceptor blockade established for 2 days before lethal endotoxemia markedly improved survival in both metoprolol-treated (n = 16; log rank test, p = .002) and atenolol-treated (n = 15; p = .03) rats. Overall mortality in cecal ligation and puncture was similar between metoprolol (40%; n = 10) and saline (50%; n = 10) pretreatment (p = .56), but the median time to death was increased by 33 hrs in metoprolol-treated rats (p = .03). Metoprolol pretreatment reduced hepatic expression of proinflammatory cytokines and lowered plasma interleukin-6 (both p < .05). Myocardial protein expression of interleukin-18 and monocyte chemoattractant protein-1, key mediators of cardiac dysfunction in sepsis, were also reduced (p < .05). Peripheral β1-adrenoceptor blockade commenced 6 hrs after lethal endotoxemia or fecal peritonitis did not improve survival. However, arterial blood pressure was preserved and left ventricular contractility restored similar to that found in nonseptic controls. Central nervous system β1-adrenoceptor blockade (metoprolol) did not reduce plasma cytokines or mortality, despite enhancing parasympathetic tone.

Conclusions: Peripheral β1-adrenoceptor blockade offers anti-inflammatory and cardioprotective effects, with mortality reduction if commenced before a septic insult. Its role in sepsis should be explored further.

From the Centre for Anaesthesia (GLA), Critical Care and Pain Medicine, University College London, UK; Neuroscience, Physiology and Pharmacology (GLA, DP, AVG), University College London, UK; Department of Neuroendocrinology (STY), University of Bristol, UK; and Department of Medicine (GLA, AR, AD, RS, MS), Bloomsbury Institute of Intensive Care Medicine, and Wolfson Institute of Biomedical Research, University College London, UK.

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This study was supported, in part, by Academy Medical Sciences/Health Foundation Clinician Scientist Award, Intensive Care Society UK; Centre for Anaesthesia, Pain Management and Critical Care, University College London (GLA); Wellcome Trust Senior Fellow (AVG), Medical Research Council UK; and The Wellcome Trust (MS, AD). This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centre's funding scheme.

Work was undertaken at laboratories in University College London.

The authors have not disclosed any potential conflicts of interest.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins