Inhibitors of nonselective cation channels in cells of the blood-brain barrier.
In the antiluminal membrane of isolated capillaries of rat and porcine brain (blood-brain barrier) nonselective cation channels with g = 31 pS were observed in cell-excised membrane patches. The channel inactivated by decreasing cytosolic Ca2+ below 1 microM and was inhibited by 1 mM ATP on the intracellular side. Anions and divalent cations did not pass the channel, but Na+ and K+ were equally permeant. Like the nonselective cation channel of rat exocrine pancreatic cells, the channel in cerebral capillary endothelial cells was inhibited reversibly by derivatives of diphenylamine-2-carboxylate (DPC), like 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC, ki = 1 microM), and flufenamic acid (ki = 4.9 microM). 4'-methyldiphenylamine-2-carboxylic acid (4-MDPC), 5-chloro-2(3-trifluormethylphenylamino)-3-nitrobenzoic acid, and 5-nitro-2-(3-phenylpropylamino)-2-carboxylic acid (NPPB), as well as the antiinflammatory drug ((Z)-5-chloro2,3-dihydro-3-(hydroxy-2-thienylmethylene)-2-ox o-1H-indole-1- carboxamide (Tenidap)) had a relatively low blocking potency (ki > 10 microM). Gadolinium (10 microM), a blocker of stretch-activated channels, inhibited the nonselective cation channel potently.
Popp
R
R
Max-Planck-Institut für Biophysik, Kennedyallee, Frankfurt, FRG.
Englert
H C
HC
Lang
H J
HJ
Gögelein
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001812:Blood-Brain Barrier; D002118:Calcium / Q000378:metabolism; D002196:Capillaries / Q000502:physiology*; D002412:Cations / Q000378:metabolism; D002560:Cerebrovascular Circulation; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005439:Flufenamic Acid; D007211:Indoles / Q000494:pharmacology; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009579:Nitrobenzoates / Q000494:pharmacology; D000078183:Oxindoles; D011188:Potassium / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002412:Cations; D007211:Indoles; D007473:Ion Channels; D009579:Nitrobenzoates; D000078183:Oxindoles; D062367:ortho-Aminobenzoates; C059537:3',5-dichlorodiphenylamine-2-carboxylic acid; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D005439:Flufenamic Acid; D000255:Adenosine Triphosphate; C001209:fenamic acid; C062866:tenidap; D004159:Diphenylamine; D012964:Sodium; D011188:Potassium; D002118:Calcium