Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats* Critical care medicine [Crit Care Med] Journal article

OBJECTIVE:: To explore the relationship of increased plasma catecholamines and poor outcomes in septic patients and the consequences of reducing sympathetic drive in sepsis. The beta1-adrenergic receptor blockade may be protective through the attenuation of catecholaminergic inflammatory effects on cardiac and hepatic function and reduced sympathetic hyperactivity.
DESIGN:: Prospective, randomized, controlled study.
SETTING:: Animal laboratory in a university medical center.
SUBJECTS:: Male adult Wistar rats.
INTERVENTIONS:: Peripheral beta1-adrenoceptor blockade through daily intraperitoneal injection (metoprolol, 100 mgkg; atenolol, 6 mgkg) or central nervous system beta1-adrenoceptor blockade (intracerebroventricular metoprolol, 25 mug) to achieve approximately 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 beta1-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 reduced 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 beta1-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 beta1-adrenoceptor blockade (metoprolol) did not reduce plasma cytokines or mortality, despite enhancing parasympathetic tone.
CONCLUSIONS:: Peripheral beta1-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.

Critical care medicine [Crit Care Med]