Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model

Abstract

Olprinone represents a potential therapy for cases of respiratory failure with diaphragmatic fatigability resulting from inhibition of neutrophil activation.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Since in septic patients cAMP stores were found depleted (54), the authors also speculated that phosphodiesterase inhibition would alleviate fatigue patterns. Using the PDE inhibitor olprinone, both MPO activity and fatigue were restored similarly towards control levels, indicating a crucial involvement of activated neutrophils or macrophages within septic tissue to contribute to downstream muscle weakness and increased fatigability, probably through their cytokine release patterns of IL-1 and TNF-␣ or free radicals (94,224,488). In chronic inflammatory conditions of polymyositis and dermatomyositis, muscle weakness in patients was correlated with a strong expression of IL-1␣ in patient muscle tissues (516).…”

“…Trains of tetanic stimulations (50 Hz for 2 s every 10 s for 5 min) were applied. Times to half decrement of the first peak tetanic tension (T 50 ) as fatigability index revealed an almost 50% shorter T 50 indicative of massive fatigue (488). This fatigue was associated with a marked increase in myeloperoxidase activity (MPO) as an index of neutrophil activation in septic muscle tissue.…”

Olprinone decreases elevated concentrations of cytokine-induced neutrophil chemoattractant-1 in septic rats

“…Therefore, we have focused on neutrophil migration and activation associated with organ dysfunction in septic rats. Our previous study showed that the degree of diaphragmatic fatigability paralleled MPO activity in the diaphragm [7]. This suggests that neutrophil activation is essential for the development of diaphragmatic fatigability.…”

“…It has been suggested that the diaphragmatic fatigability associated with abdominal sepsis is induced by activated neutrophils in diaphragmatic muscle in which myeloperoxidase (MPO) activity is increased [7].…”

“…Direct and indirect evidence also suggests that ARDS following abdominal sepsis is accompanied by diaphragmatic fatigability, which may be associated with cyclic adenosine monophosphate (cAMP) depletion in diaphragmatic muscle [6]. In addition to the alteration of cAMP content in muscle, neutrophil activation was demonstrated to contribute to the development of diaphragmatic fatigability under abdominal septic conditions, while the intraperitoneal administration of olprinone, a phosphodiesterase (PDE) inhibitor, was shown to improve diaphragmatic contractility and to inhibit neutrophil activation induced in a rat model of abdominal sepsis, although it remains unclear whether olprinone mo dulated cytokine activation at sites of infl ammation [7].…”