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The Selective Rat Toxicant Norbormide Blocks KATP Channels in Smooth Muscle Cells But Not in Insulin-Secreting Cells.
- Source :
- Frontiers in Pharmacology; 5/23/2019, pN.PAG-N.PAG, 11p
- Publication Year :
- 2019
-
Abstract
- Norbormide is a toxicant selective for rats to which it induces a widespread vasoconstriction. In a recent paper, we hypothesized a role of ATP-sensitive potassium (K<subscript>ATP</subscript>) channels in norbormide-induced vasoconstriction. The current study was undertaken to verify this hypothesis by comparing the effects of norbormide with those of glibenclamide, a known K<subscript>ATP</subscript> channel blocker. The whole-cell patch-clamp method was used to record K<subscript>ATP</subscript> currents in myocytes freshly isolated from the rat and mouse caudal artery and from the rat gastric fundus, as well as in insulin-secreting pancreatic beta cells (INS-1 cells). Smooth muscle contractile function was assessed on either rat caudal artery rings or gastric fundus strips. Molecular modeling and docking simulation to K<subscript>ATP</subscript> channel proteins were investigated in silico. Both norbormide (a racemic mixture of endo and exo isomers) and glibenclamide inhibited K<subscript>ATP</subscript> currents in rat and mouse caudal artery myocytes, as well as in gastric fundus smooth muscle cells. In rat INS-1 cells, only glibenclamide blocked K<subscript>ATP</subscript> channels, whereas norbormide was ineffective. The inhibitory effect of norbormide in rat caudal artery myocytes was not stereo-specific as both the endo isomers (active as vasoconstrictor) and the exo isomers (inactive as vasoconstrictor) had similar inhibitory activity. In rat caudal artery rings, norbormide-induced contraction was partially reverted by the K<subscript>ATP</subscript> channel opener pinacidil. Computational approaches indicated the SUR subunit of K<subscript>ATP</subscript> channels as the binding site for norbormide. K<subscript>ATP</subscript> channel inhibition may play a role in norbormide-induced vasoconstriction, but does not explain the species selectivity, tissue selectivity, and stereoselectivity of its constricting activity. The lack of effect in INS-1 cells suggests a potential selectivity of norbormide for smooth muscle K<subscript>ATP</subscript> channels. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 16639812
- Database :
- Complementary Index
- Journal :
- Frontiers in Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 136617793
- Full Text :
- https://doi.org/10.3389/fphar.2019.00598