Chloride channel inhibition

Cromolyn, nedocromil Alters function of delayed chloride channels inhibits inflammatory cell activation Prevents acute bronchospasm Asthma (other routes used for ocular, nasal, and gastrointestinal allergy) Aerosol t duration 6-8 h t Toxicity. Cough not absorbed so other toxicities are minimal... 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

Forshaw PJ, Lister T, Ray DE (1993) Inhibition of a neuronal voltage-dependent chloride channel by the type II pyrethroid, deltamethrin. Neuropharmacology 32 105-111... 

Schwiebert, E. M., D. C. Gruenert, W. B. Guggino, and B. A. Stanton. 1995. G protein G alpha i-2 inhibits outwardly rectifying chloride channels in human airway epithelial cells. Am J Physiol 269(2 Pt l) C451-6. 

Schwartz-Bloom RD, CookTA, Yu X. (1996). Inhibition of GABA-gated chloride channels in brain by the arachidonic acid metabolite, thromboxane A2. Neuropharmacology. 35(9-10) 1347-53. 

One proposed mechanism for toxaphene-induced neurotoxicity is that it acts as a noncompetitive y-aminobutyric acid (GABA) antagonist at the chloride channel in brain synaptosomes. Substances that bind to the GABA-regulated chloride channel induce convulsions by inhibiting chloride flux thus allowing brain cells to depolarize and fire spontaneously. ... 

Nedocromil modify inflammation preventive treatment to exercise or provocative/known allergen Mechanisms anti-inflammatory block early and late reaction to allergen interfere with chloride channel function, stabilize mastcell membrane inhibit release of mediators from eosinophils and epithelial cells inhibit acute response to exercise, cold air and SO2 ... 

Another suggested mechanism of action involves the chloride channel. As discussed previously, the chloride channel is intimately associated with neuronal inhibition, and its activity appears to be modulated at many different sites. Caffeine can compete for binding at the benzodiazepine site and would therefore be expected to reduce chloride conductance. Thus, caffeine may act functionally like the analeptic stimulants that limit chloride channel activation. 

A. Analeptic stimulants, such as pentylenetetrazol and picrotoxin, act by inhibiting chloride influx at the GABAa receptor-chloride channel complex. This antagonism can occur through interaction with one of several binding sites or allosteric modifiers of receptor-channel function. 

The main action of BZs occurs at the y-aminobuteric acid A (CABAa) receptors. The CABA receptors have been classified into three subtypes, CABA, CABAg, and CABA. The CABAg slow receptors are composed of seven transmembrane subunits that activate second messenger systems. CABA and CABA receptors mediate fast synaptic inhibition via transmittergated chloride ion channels (Chebib and Johnston, 1999). Each CABA and CABA receptor consists of five subunits with four transmembrane domains, which combine together to form a chloride channel (Chebib and Johnston, 1999). 

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