Presence and vascular pharmacology of KATP channel subtypes in rat central and peripheral tissues

Abstract

K(ATP) channel openers are vasodilators and induce headache in normal subjects. We previously identified the Kir6.1/SUR2B K(ATP) channel subtype in major cerebral and dural arteries of rat, pig and man. We hypothesized that craniovascular Kir6.1/SUR2B K(ATP) channels mediate the headache-inducing effects of K(ATP) channel openers and that a Kir6.1/SUR2B specific blocker might be effective in the treatment of primary headaches such as migraine. Since K(ATP) channels are ubiquitous, we characterized the K(ATP) channel subtypes in major rat cranial and peripheral arteries and organs in order to understand the possible adverse effects of a Kir6.1/SUR2B blocker. We studied the mRNA expression of K(ATP) channel subunits in rat femoral, mesenteric, renal, coronary, basilar, middle cerebral and middle meningeal arteries and in tissue from rat heart, brain, liver, colon, lung, kidney and pancreas. We also studied the effects and potencies of a panel of synthetic K(ATP) channel openers and their potential inhibition by the Kir6.1 subunit-specific K(ATP) channel blocker PNU-37883A in segments of the arteries mounted in a wire myograph. Our studies suggest that Kir6.1/SUR2B forms the major functional K(ATP) channel complex in rat cranial and peripheral arteries. The mRNA transcripts of SUR1 and Kir6.2 subunits were predominantly found in brain, pancreas and heart, while SUR2A mRNA was merely detected within the heart. K(ATP) channel blockers highly specific for the SUR2B subunit may have no adverse CNS and cardiac effects and will not affect insulin release in the pancreas. However, a SUR2B blocker may not discriminate between cranial and peripheral arteries.