Abstract
Objectives:The objective of this study was to investigate the effects of pentoxifylline (PTX), a drug that is mainly used for indications related to tissue hypoxia, on hypoxia-induced inhibition of skeletal muscle contractility and neuromuscular transmission in mice. We hypothesized that chronic PTX treatment alters skeletal muscle contractility and hypoxia-induced dysfunction.Materials and Methods:Mice were treated with 50 mg/kg PTX or saline intraperitoneally for a week. Following ether anesthesia, diaphragm muscles were removed; isometric muscle contractions and action potentials were recorded. Time to reach neuromuscular blockade and the rate of recovery of muscle contractility were assessed during hypoxia and re-oxygenation.Results:The PTX group displayed 90% greater twitch amplitudes (P < 0.01). Hypoxia depressed twitch contractions and caused neuromuscular blockade in both groups. However, neuromuscular blockade occurred earlier in PTX-treated animals (P < 0.05). Muscle contractures developed during hypoxia were more pronounced in the PTX group (P < 0.05). Re-oxygenation reduced contracture and indirect muscle contractions resumed. The rate of recovery of contractions was faster (P < 0.05) and the amplitude of contractions was greater (P < 0.01) in the PTX group. PTX treatment increased amplitude (P < 0.05) and shortened action potential (P < 0.05) without altering resting membrane potential, excitation threshold, and neurotransmitter release.Conclusion:Chronic PTX treatment increases diaphragm contractility, but amplifies hypoxia-induced contractile dysfunction in mice. These results may implicate important clinical consequences for clinical usage of PTX in hypoxia-related conditions.
Highlights
Hypoxia inhibits skeletal muscle contractility and causes neuromuscular blockade
Diaphragm muscles prepared from the control animals had twitch contraction amplitudes of 22.2 Ϯ 4.5 g/g and 10.0 Ϯ 1.4 g/g, upon direct and indirect stimulation, respectively
Muscles obtained from PTX-treated animals displayed about 90% greater contraction amplitudes for both types of stimulation [Figure 1, P Ͻ 0.01]
Summary
Hypoxia inhibits skeletal muscle contractility and causes neuromuscular blockade. Intracellular mechanisms of hypoxia-induced damage in skeletal muscle have not been fully elucidated. Impaired calcium (Ca2ϩ) buffering and decreased adenosine-5’-triphosphate (ATP) production in myocytes are known to participate in hypoxia-induced impairment of muscle function.[1]. Pentoxifylline (PTX), a xanthine-derived phosphodiesterase (PDE) inhibitor, is known to increase intracellular cyclic-adenosine monophosphate (cAMP) levels.[2] An increase in cAMP levels in muscle fibers results in the activation of protein kinase A (PKA) and facilitates synaptic transmission in the mammalian neuromuscular junction (NMJ).[3] Recent data showed that PTX administration decreases plasma levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha(TNF-␣), interleukin (IL)-1 , IL-10,[4] and down-regulates their production.[5] Recently, cytokines have been shown to impair contractile response in the skeletal muscle probably by affecting the nitrergic pathway or nitric oxide (NO) production.[6,7]
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