Pharmacological Profile of U-37883A, a Channel Blocker of Smooth Muscle-Type ATP-Sensitive K Channels.
U-37883A (PNU-37883A, guanidine; 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl hydrochloride) was originally developed as a potential diuretic with specific binding in kidney and vascular smooth muscle rather than in brain or pancreatic beta cells. U-37883A inhibits ATP-sensitive K(+) channels (K(ATP) channels) in vascular smooth muscle at submicromolar concentrations whilst even at high concentrations (> or =10 microM) it has no inhibitory effect at pancreatic, cardiac or skeletal K(ATP) channels. Thus, it is generally thought that U-37883A is a selective inhibitor of vascular smooth muscle K(ATP) channels. Approximately one decade ago, K(ATP) channels were cloned and found to consist of at least two subunits: an inwardly-rectifying K(+) channel six family (K(ir)6.x; K(ir)6.1 and K(ir)6.2) which forms the ion conducting pore and a modulatory sulphonylurea receptor (SUR.x; SUR1, SUR2A, and SUR2B) that accounts for several pharmacological properties. It is generally believed that different combinations of K(ir)6.x and SUR.x determine the molecular properties of K(ATP) channels. Thus, K(ir)6.2/SUR1 channel represents the pancreatic beta-cell K(ATP) channel, K(ir)6.2/SUR2A channel is thought to represent the cardiac K(ATP) channel, whereas K(ir)6.1/SUR2B channel is likely to represent the vascular smooth muscle K(ATP) channel. Recent molecular studies have shown that U-37883A selectively suppresses the activity of recombinant K(ATP) channels which contain K(ir)6.1 subunits in the channel pore unit. It was thus thought that U-37883A was a selective pharmacological tool which could be used to investigate the activity of vascular smooth muscle K(ATP) channels. However, due to its multiple pharmacological actions on several ion channels and poor tissue selectivity, U-37883A should not be viewed as a selective blocker of smooth muscle K(ATP) channels.
Teramoto
Noriyoshi
N
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Japan. noritera@linne.med.kyushu-u.ac.jp
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*
D004232:Diuretics; D009025:Morpholines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C082658:U 37883A; D000218:Adamantane