Effects of the muscarinic agonist, 5-methylfurmethiodide, on contraction and electrophysiology of Ascaris suum muscle.
Contraction and electrophysiological effects of 5-methylfurmethiodide (MFI), a selective muscarinic agonist in mammals, were tested on Ascaris suum muscle strips. In a contraction assay, MFI produced weak contraction and was less potent than levamisole and acetylcholine. Atropine (3microM) a non-selective muscarinic antagonist in mammalian preparations, did not affect contractions produced by MFI. Mecamylamine (3microM) a nicotinic antagonist in A. suum preparations, blocked the MFI contractions indicating that MFI had weak nicotinic agonist actions. In two-micropipette current-clamp experiments MFI, at concentrations greater than 10microM, produced concentration-dependent depolarizations and small increases in membrane conductance. The depolarizing effects were not abolished by perfusing the preparation in a calcium-free Ascaris Ringer solution to block synaptic transmission, suggesting that MFI effects were mediated by receptors on the muscle and were calcium-independent. A high concentration of mecamylamine, 30microM, only reduced the depolarizing responses by 42%, indicating that MFI also had effects on non-nicotinic receptors. Three non-nicotinic effects in the presence of 30microM mecamylamine were identified using voltage-clamp techniques: (i) MFI produced opening of mecamylamine-resistant non-selective-cation channel currents; (ii) MFI inhibited opening of voltage-activated potassium currents; and (iii) MFI increased the threshold of voltage-activated calcium currents. We suggest that a drug that is more selective for voltage-activated potassium currents, without effects on other channels like MFI, may be exploited pharmacologically as a novel anthelmintic or as an agent to potentiate the action of levamisole. In a larval migration assay we demonstrated that 4-aminopyridine (4-AP: a potassium channel blocker) potentiated the effects of levamisole but MFI did not.
Trailovic
Sasa M
SM
Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011-1250, USA.
Verma
Saurabh
S
Clark
Cheryl L
CL
Robertson
Alan P
AP
Martin
Richard J
RJ
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017165:Ascaris suum / Q000187:drug effects / Q000502:physiology*; D004594:Electrophysiology; D066298:In Vitro Techniques; D009116:Muscarine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques
D000871:Anthelmintics; D018721:Muscarinic Agonists; C008446:5-methylfurtrethonium; D009116:Muscarine