ABSTRACT
Patients with spinal cord injury (SCI) usually develop lower urinary tract dysfunctions, including detrusor overactivity which is also known to be a risk factor for upper urinary tract dysfunction. Antimuscarinic agents, such as propiverine, have been used clinically for the treatment of detrusor overactivity. Also, propiverine has been known to possess antagonistic activity against L-type Ca2+ channels and transient receptor potential vanilloid subtype 1 (TRPV1), in addition to activity against muscarinic receptors. These mechanisms of action may contribute to improving detrusor overactivity in SCI. We therefore investigated the effects of antagonists of these mechanisms on non-voiding contraction (NVC) in SCI rats that are similar to clinical cases of detrusor overactivity, and considered whether these action mechanisms contribute to the incidence of NVC in SCI. Cystometry was performed in rats 4 weeks after spinal transection. Urinary functions were evaluated before and after intravenous administration of propiverine and specific antagonists for muscarinic receptors (atropine), L-type Ca2+ channels (verapamil), and TRPV1 (capsazepine). Propiverine markedly decreased the amplitude pressure of NVC in SCI rats, which was partially inhibited by atropine. Verapamil also suppressed the amplitude pressure of NVC to the same degree as propiverine. NVC disappeared almost completely after C-fiber desensitization, although capsazepine exerted no evident effects. These findings suggest that muscarinic receptors, L-type Ca2+ channels, and C-fiber afferent nerves contribute to the incidence of detrusor overactivity in SCI, and a drug that has multiple antagonistic effects, such as propiverine, is very effective for the treatment of lower urinary tract dysfunctions in SCI.
Subject(s)
Benzilates/antagonists & inhibitors , Spinal Cord Injuries/drug therapy , Urinary Bladder, Overactive/drug therapy , Animals , Atropine/pharmacology , Benzilates/therapeutic use , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Female , Muscarinic Antagonists/therapeutic use , Rats , Spinal Cord Injuries/complications , Urinary Bladder/drug effects , Urinary Bladder, Overactive/complications , Verapamil/pharmacologyABSTRACT
Muscarinic agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M(1), M(2), and M(4) receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
Subject(s)
Muscarinic Agonists/chemical synthesis , Muscarinic Agonists/pharmacology , Nervous System Diseases/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Animals , Benzilates/antagonists & inhibitors , Benzilates/chemistry , Binding, Competitive , CHO Cells , Carbachol/pharmacology , Cell Line , Colforsin/antagonists & inhibitors , Colforsin/pharmacology , Cricetinae , Cyclic AMP/metabolism , Humans , Hypothermia/chemically induced , Male , Mice , Models, Molecular , Muscarinic Agonists/metabolism , Pyridines/chemistry , Pyridines/metabolism , Radioligand Assay , Rats , Rats, Long-Evans , Receptors, Muscarinic/metabolism , Thiadiazoles/chemistry , Thiadiazoles/metabolismABSTRACT
1. Muscarinic acetylcholine receptors in a plasma-membrane fraction derived from mouse neuroblastoma clone NIE-115 bind [3-3H]quinuclidinyl benzilate according to the Law of Mass Action (Kdissociation 40 pM, h0.96). 2. Antagonist and agonist binding to the receptor was studied by displacement of [3-3H]quinuclidinyl benzilate with non-radioactive ligands. The data show good agreement with similar data obtained on rat brain and ideal smooth muscle [Birdsall & Hulme (1976) J. Neurochem. 27, 7-16] indicating that the receptor is very similar in these three tissues.
Subject(s)
Neuroblastoma/metabolism , Receptors, Cholinergic/metabolism , Receptors, Muscarinic/metabolism , Animals , Benzilates/antagonists & inhibitors , Benzilates/metabolism , Binding Sites , Cell Membrane/metabolism , Clone Cells/metabolism , Mice , Neoplasms, Experimental/metabolism , Quinuclidines/metabolismSubject(s)
Acridines/pharmacology , Cholinesterase Inhibitors/pharmacology , Gastrointestinal Motility/drug effects , Heart/drug effects , Muscle Contraction/drug effects , Acetylcholinesterase , Allosteric Regulation , Amines/pharmacology , Animals , Benzilates/antagonists & inhibitors , Binding Sites/drug effects , Cholinesterases , Depression, Chemical , Heart Rate/drug effects , In Vitro Techniques , Kinetics , Physostigmine/pharmacology , Quinuclidines/antagonists & inhibitors , Rats , Stimulation, Chemical , Tubocurarine/antagonists & inhibitorsABSTRACT
1 The synthesis of tritium labelled propylbenzilylcholine mustard ([(3)H]-PrBCM; N-2'-chloroethyl-N-[2'', 3''-(3)H(2)] propyl-2-aminoethyl benzilate) is described.2 The uptake by muscle strips was measured and shown to be considerably increased by previous immersion of the muscle in distilled water.3 A considerable part of the uptake is inhibited selectively by atropine, but not by nicotinic antagonists. A number of muscarinic agonists also inhibit uptake and their apparent affinity constants have been determined.4 The uptake by atropine-sensitive sites is temperature-insensitive, whereas the other sites are temperature-sensitive. Recovery is highly temperature-sensitive and there is good agreement between recovery of sensitivity to agonists and loss of radioactivity from the muscle.
