K(ATP) channel expression and pharmacological in vivo and in vitro studies of the K(ATP) channel blocker PNU-37883A in rat middle meningeal arteries.
OBJECTIVE
Dilatation of cerebral and dural arteries causes a throbbing, migraine-like pain, indicating that these structures are involved in migraine. Clinical trials suggest that adenosine 5'-triphosphate-sensitive K(+) (K(ATP)) channel opening may cause migraine by dilatating intracranial arteries, including the middle meningeal artery (MMA). We studied the K(ATP) channel expression profile in rat MMA and examined the potential inhibitory effects of the K(ATP) channel blocker PNU-37883A on K(ATP) channel opener-induced relaxation of the rat MMA, using the three K(ATP) channel openers levcromakalim, pinacidil and P-1075.


METHODS
mRNA and protein expression of K(ATP) channel subunits in the rat MMA were studied by quantitative real-time PCR and western blotting, respectively. The in vivo and in vitro effects of the K(ATP) channel drugs on rat MMA were studied in the genuine closed cranial window model and in myograph baths, respectively.


RESULTS
Expression studies indicate that inwardly rectifying K(+) (Kir)6.1/sulphonylurea receptor (SUR)2B is the major K(ATP) channel complex in rat MMA. PNU-37883A (0.5 mg kg(-1)) significantly inhibited the in vivo dilatory effect of levcromakalim (0.025 mg kg(-1)), pinacidil (0.38 mg kg(-1)) and P-1075 (0.016 mg kg(-1)) in rat MMA. In vitro PNU-37883A significantly inhibited the dilatory responses of the three K(ATP) channel openers in rat MMA at 10(-7) and 3 x 10(-7) M.


CONCLUSIONS
We suggest that Kir6.1/SUR2B is the major functional K(ATP) channel complex in the rat MMA. Furthermore, we demonstrate the potent in vivo and in vitro blocking potentials of PNU-37883A on K(ATP) channel opener-induced relaxation of the rat MMA.
Ploug
K B
KB
Department of Neurology and Danish Headache Center, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark. KEBEPL01@glo.regionh.dk
Boni
L J
LJ
Baun
M
M
Hay-Schmidt
A
A
Olesen
J
J
Jansen-Olesen
I
I
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D019806:Cromakalim / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004232:Diuretics / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects*; D018715:Microscopy, Video; D009025:Morpholines / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D020110:Pinacidil / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000096:biosynthesis; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents / Q000494:pharmacology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000218:Adamantane; D019806:Cromakalim; D004232:Diuretics; D006146:Guanidines; D054086:KATP Channels; D009025:Morpholines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020110:Pinacidil; D026902:Potassium Channel Blockers; 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; C092520:uK-ATP-1 potassium channel; C082658:U 37883A; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine