Characterization of K(ATP)-channels in rat basilar and middle cerebral arteries: studies of vasomotor responses and mRNA expression.
Changes in the activity of K+ channels represent a major mechanism that regulates vascular tone. Cerebrovascular adenosine 5'-triphosphate-sensitive K+(K(ATP)) channels were characterized in studies of the molecular expression and vasomotor reactivity to different K(ATP) channel openers in rat basilar and middle cerebral arteries. Both arteries showed strong mRNA expression of the subunits of the pore-forming inward-rectifying K+ channel type 6.1 (Kir6.1), Kir6.2 and the connected sulfonylurea receptor (SUR) subunits, SUR1 and SUR2B, while only weak bands for SUR2A were seen. The K(ATP) channel openers induced relaxation of prostaglalndin F2alpha-precontracted isolated basilar and middle cerebral arteries with the order of potency N-Cyano-N-(1,1-dimethylpropyl)-N''-3pyridylguanidine (P-1075)>levcromakalim>N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (ZM226600)>pinacidil>diazoxide. The responses induced by levcromakalim, ZM226600 and diazoxide were significantly more potent in basilar arteries than in middle cerebral arteries, while pinacidil and P-1075 were equipotent. Endothelium removal decreased (P<0.05) the sensitivity (pIC50) of basilar arteries, but not of middle cerebral arteries, to pinacidil, levcromakalim, P-1075 and ZM226600. The maximum relaxant response to P-1075 was stronger (P<0.005) in basilar arteries with endothelium than without endothelium. Correlation of the relaxant potency of K(ATP) channel openers in rat basilar and middle cerebral arteries with historical measurements of affinity obtained in COS-7 cell lines expressing either SUR1, SUR2A or SUR2B showed that vasodilatation by K(ATP) channel openers correlated with binding to either the SUR2A or the SUR2B subunit. Glibenclamide was a blocker of relaxation induced by pinacidil, levcromakalim, P-1075 and ZM226600 in basilar arteries. Only a weak antagonistic effect of glibenclamide on pinacidil-, levcromakalim- and ZM226600-induced relaxations was found in middle cerebral arteries. The subunit profile and the observed pharmacological properties suggest that the K(ATP) channels expressed in rat basilar and middle cerebral artery are likely to be composed of SUR2B co-associated with Kir6.1 or Kir6.2. In basilar arteries, but not in middle cerebral arteries, endothelial K(ATP) channels may be involved.
Jansen-Olesen
Inger
I
Department of Neurology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600 Glostrup, Copenhagen, Denmark. ijo@tdcadsl.dk
Mortensen
Camilla Holbech
CH
El-Bariaki
Najat
N
Ploug
Kenneth Beri
KB
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009930:Organic Chemicals / Q000378:metabolism / Q000494:pharmacology; D020110:Pinacidil / Q000378:metabolism / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D005905:Glyburide; D006146:Guanidines; D054086:KATP Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009930:Organic Chemicals; D020110:Pinacidil; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011725:Pyridines; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat; C102234:levochromakalim; C092520:uK-ATP-1 potassium channel; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine