BACKGROUND: We sought to elucidate the effects of dexmedetomidine, a selective alpha2-adrenergic receptor agonist, on the regulation of pulmonary inflammation in ventilator-induced lung injury (VILI) in a rat model. METHODS: A total of 64 adult male Sprague-Dawley rats were assigned to receive either standard ventilation (tidal volume 10 mL/kg; respiratory rate 50 breaths/minute), high-tidal volume ventilation (HVT: tidal volume 20 mL/kg; respiratory rate 50 breaths/minute), HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour), or HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour) and yohimbine (the alpha2-adrenergic receptor antagonist) (n = 8 in each group). The doses of dexmedetomidine were chosen to correspond to 1, 5 and 10 times the clinical dose (0.5 microg/kg per hour). After maintaining ventilation for 4 hours, rats were sacrificed and pulmonary inflammatory changes as well as the upregulation of pulmonary inflammatory molecules were evaluated. RESULTS: Histological and arterial blood gas analyses confirmed that HVT induced significant lung injury. HVT also significantly increased the pulmonary concentrations of chemokines (e.g. macrophage inflammatory protein-2), cytokines (e.g. tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), inducible nitric oxide synthase/nitric oxide, cyclooxygenase-2/prostaglandin E2. Dexmedetomidine at the dose of 5.0 microg/kg per hour, but not at 0.5 and 2.5 microg/kg per hour, significantly attenuated the effects of HVT. Moreover, these effects of dexmedetomidine were significantly attenuated by yohimbine. CONCLUSION: Dexmedetomidine at clinically relevant doses had no significant effect in attenuating VILI. In contrast, dexmedetomidine at a dose approximately 10 times higher than the clinical dose significantly attenuated VILI. These effects of dexmedetomidine were mediated, at least in part, by the alpha2-adrenergic receptor.
BACKGROUND: We sought to elucidate the effects of dexmedetomidine, a selective alpha2-adrenergic receptor agonist, on the regulation of pulmonary inflammation in ventilator-induced lung injury (VILI) in a rat model. METHODS: A total of 64 adult male Sprague-Dawley rats were assigned to receive either standard ventilation (tidal volume 10 mL/kg; respiratory rate 50 breaths/minute), high-tidal volume ventilation (HVT: tidal volume 20 mL/kg; respiratory rate 50 breaths/minute), HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour), or HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour) and yohimbine (the alpha2-adrenergic receptor antagonist) (n = 8 in each group). The doses of dexmedetomidine were chosen to correspond to 1, 5 and 10 times the clinical dose (0.5 microg/kg per hour). After maintaining ventilation for 4 hours, rats were sacrificed and pulmonary inflammatory changes as well as the upregulation of pulmonary inflammatory molecules were evaluated. RESULTS: Histological and arterial blood gas analyses confirmed that HVT induced significant lung injury. HVT also significantly increased the pulmonary concentrations of chemokines (e.g. macrophage inflammatory protein-2), cytokines (e.g. tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), inducible nitric oxide synthase/nitric oxide, cyclooxygenase-2/prostaglandin E2. Dexmedetomidine at the dose of 5.0 microg/kg per hour, but not at 0.5 and 2.5 microg/kg per hour, significantly attenuated the effects of HVT. Moreover, these effects of dexmedetomidine were significantly attenuated by yohimbine. CONCLUSION:Dexmedetomidine at clinically relevant doses had no significant effect in attenuating VILI. In contrast, dexmedetomidine at a dose approximately 10 times higher than the clinical dose significantly attenuated VILI. These effects of dexmedetomidine were mediated, at least in part, by the alpha2-adrenergic receptor.
Authors: Michael A Smith; Maho Hibino; Bonnie A Falcione; Katherine M Eichinger; Ravi Patel; Kerry M Empey Journal: Ann Pharmacother Date: 2013-11-04 Impact factor: 3.154
Authors: Keliana O'Mara; Peter Gal; John Wimmer; J Laurence Ransom; Rita Q Carlos; Mary Ann V T Dimaguila; Christie C Davanzo; McCrae Smith Journal: J Pediatr Pharmacol Ther Date: 2012-07