Abstract
BackgroundVentilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction. Recent data show that renin-angiotensin system is involved in diaphragmatic skeletal muscle atrophy after MV. In particular, angiotensin-II can induce marked diaphragm muscle wasting, whereas angiotensin-(1–7) (Ang-(1–7)) could counteract this activity. This study was designed to evaluate the effects of the treatment with Ang-(1–7) in a rat model of VIDD with neuromuscular blocking agent infusion. Moreover, we studied whether the administration of A-779, an antagonist of Ang-(1–7) receptor (Mas), alone or in combination with PD123319, an antagonist of AT2 receptor, could antagonize the effects of Ang-(1–7).MethodsSprague-Dawley rats underwent prolonged MV (8 h), while receiving an iv infusion of sterile saline 0.9% (vehicle) or Ang-(1–7) or Ang-(1–7) + A-779 or Ang-(1–7) + A-779 + PD123319. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis, quantitative real-time PCR, and Western blot analysis.ResultsMV resulted in a significant reduction of diaphragmatic contractility in all groups of treatment. Ang-(1–7)-treated rats showed higher muscular fibers cross-sectional area and lower atrogin-1 and myogenin mRNA levels, compared to vehicle treatment. Treatment with the antagonists of Mas and Ang-II receptor 2 (AT2R) caused a significant reduction of muscular contractility and an increase of atrogin-1 and MuRF-1 mRNA levels, not affecting the cross-sectional fiber area and myogenin mRNA levels.ConclusionsSystemic Ang-(1–7) administration during MV exerts a protective role on the muscular fibers of the diaphragm preserving muscular fibers anatomy, and reducing atrophy. The involvement of Mas and AT2R in the mechanism of action of Ang-(1–7) still remains controversial.
Highlights
Ventilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction
Systemic response We found no difference in survival in all experimental groups: all rats survived the 8 h of MV, except two rats (one in vehicle and one in Ang-(1–7) group) that were sacrificed after 7 h because of hypotension
The mean blood pressure was similar between groups at the beginning of the experiment, whereas at the end of the MV it was significantly higher in Ang-(1–7) + A-779 + PD compared to the other two treatment groups (Table 1)
Summary
Ventilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction. Several experimental and clinical studies have shown a rapid muscular atrophy and contractile dysfunction in the diaphragm during prolonged MV [4], through the reduction of protein synthesis, the increase of proteolysis, and the activation of oxidative stress. Prolonged MV results in oxidative damage to the diaphragm through the generation of reactive oxygen species and their derivatives that have a significant effect on the contraction of the skeletal muscle [6]. During prolonged MV, the oxidative modification of diaphragm contractile proteins leads to less efficient activation of diaphragm fibers induced by calcium [7]
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