Abstract
Guanidine has been used with some success to treat myasthenia gravis and myasthenic syndrome because it increases acetylcholine release at nerve terminals through K+, Na+ and Ca2+ channels-involving mechanisms. Currently, guanidine derivatives have been proposed for treatment of several diseases. Studies aimed at providing new insights to the drug are relevant. Experimentally, guanidine (10 mM) induces on mouse phrenic nerve-diaphragm (PND) preparations neurotransmission facilitation followed by blockade and a greatest secondary facilitation after its removal from bath. Herein, we hypothesized that this peculiar triphasic response may differ in muscles with distinct twitch/metabolic characteristics. Morphological alterations and contractile response of PND, extensor digitorum longus (EDL) and soleus (SOL) preparations incubated with guanidine (10 mM) for 15, 30, 60 min were analyzed. Guanidine concentrations of 5 mM (for PND and EDL) and 1 mM (for EDL) were also tested. Guanidine triphasic effect was only observed on PND regardless the concentration. The morphological alterations in muscle tissue varied along time but did not impede the PND post-wash facilitation. Higher doses (20–25 mM) did not increase EDL or SOL neurotransmission. The data suggest a complex mechanism likely dependent on the metabolic/contractile muscle phenotype; muscle fiber types and density/type of ion channels, sarcoplasmic reticulum and mitochondria organization may have profound impact on the levels and isoform expression pattern of Ca2+ regulatory membrane proteins so reflecting regulation of calcium handling and contractile response in different types of muscle.
Highlights
The contractile response of skeletal muscle can be affected by a variety of substances which can act directly either on the neurotransmission or contractile apparatus, inhibiting and/or facilitating the muscular response
Twenty minutes after guanidine removal by washing the preparation, the increase in the contractile response still remained 150% above that observed before guanidine administration and in relation to that presented by preparations incubated with Tyrode only (Figure 1A,B)
Panels B (PND), D (EDL) and F (SOL) display the myographic isometric twitch record of preparations incubated with guanidine (G)
Summary
The contractile response of skeletal muscle can be affected by a variety of substances which can act directly either on the neurotransmission or contractile apparatus, inhibiting and/or facilitating the muscular response Some of these substances are from animal [1,2,3,4] or plant origin [5,6,7]; others are synthetic products such as tetraethylammonium, aminopyridines and guanidine. The decline of quantal content was shown to vary across NMJs of different muscle fiber types during repetitive stimulation, indicating that the underlying mechanism of synaptic delivery is in line with their contractile characteristics [26]. The discussion of the results considered the characteristics of each muscle and the pharmacological/ultrastructural effects already described for guanidine on diaphragm after 60 min incubation The elucidation of these issues will contribute to shed light on the guanidine pharmacological interaction with phenotypically different skeletal muscles and their neurotransmission mechanisms. The use of depolarizing drugs affecting K+, Na+ and Ca2+ channels-dependent cellular events can be excellent tools for determining cell mechanisms, which results in either therapeutic benefits or undesirable side-effects
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