Characterization of KATP-channels in rat basilar and middle cerebral arteries: Studies of vasomotor responses and mRNA expression

Oct 18, 2005European journal of pharmacology

Properties of energy-sensitive potassium channels in rat brain arteries: effects on blood vessel movement and gene activity

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Abstract

Strong mRNA expression of K+ channel subunits was found in rat basilar and middle cerebral arteries.

Both the basilar and middle cerebral arteries exhibited high levels of mRNA for the inward-rectifying K+ channel subunits Kir6.1 and Kir6.2, along with SUR1 and SUR2B.
K+ channel openers induced relaxation in arteries precontracted with prostaglandin F2alpha, with P-1075 showing the highest potency.
The relaxation responses to certain K+ channel openers were significantly stronger in basilar arteries compared to middle cerebral arteries.
Removal of the endothelium decreased the sensitivity of basilar arteries to several K+ channel openers, indicating a possible endothelial role in K+ channel function.
The maximum relaxation response to P-1075 was notably greater in basilar arteries with endothelium than in those without.
The pharmacological properties align with K(ATP) channels likely being composed of SUR2B paired with either Kir6.1 or Kir6.2, suggesting a distinct role of endothelial K(ATP) channels in basilar arteries.

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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.

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Characterization of KATP-channels in rat basilar and middle cerebral arteries: Studies of vasomotor responses and mRNA expression

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