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 (KATP) 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 KATP channel blocker. The whole-cell patch-clamp method was used to record KATP 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 KATP channel proteins were investigated in silico. Both norbormide (a racemic mixture of endo and exo isomers) and glibenclamide inhibited KATP 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 KATP 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 KATP channel opener pinacidil. Computational approaches indicated the SUR subunit of KATP channels as the binding site for norbormide. KATP 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 KATP channels.
Highlights
Norbormide, a selective rat toxicant, induces a lethal effect in rats but has little or no effect in non-rat species, including humans, and for this reason, it has been marketed for many years as an eco-sustainable pesticide (Roszkowski, 1965)
The effect of norbormide on KATP channels was assessed in vascular and non-vascular single cells and single INS-1 cells
The KATP channel opener pinacidil (10 μM) activated an inward current that was significantly antagonized by the KATP channel blocker glibenclamide (10 μM; Figure 2A and B)
Summary
Norbormide, a selective rat toxicant, induces a lethal effect in rats but has little or no effect in non-rat species, including humans, and for this reason, it has been marketed for many years as an eco-sustainable pesticide (Roszkowski, 1965). Norbormide Blocks KATP Channels toxicant induces a marked and irreversible vasoconstriction of rat peripheral vessels by targeting a receptor abundantly and/or selectively expressed in the rat peripheral artery myocytes (Bova et al, 2001). In rat conduit arteries (i.e., aorta), in rat non-vascular muscles, and in all muscles from non-rat species, norbormide, at concentrations partially overlapping those that induce vasoconstriction in rats, shows vasorelaxant properties, attributed to an inhibitory effect on CaV1.2 channels (Bova et al, 2003). Only the endo isomers show rat-specific vasoconstrictor activity, being lethal to rats (Poos et al, 1966) These observations indicate that the contractile activity of norbormide is species- and tissue-selective and stereo-specific, suggesting the existence of a highly specific target for this compound in rat vessels
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