K+ channel openers activate brain sulfonylurea-sensitive K+ channels and block neurosecretion.
Vascular K+ channel openers such as cromakalim, nicorandil, and pinacidil potently stimulate 86Rb+ efflux from slices of substantia nigra. This 86Rb+ efflux is blocked by antidiabetic sulfonylureas, which are known to be potent and specific blockers of ATP-regulated K+ channels in pancreatic beta cells, cardiac cells, and smooth muscle cells. K0.5, the half-maximal effect of the enantiomer (-)-cromakalim, is as low as 10 nM, whereas K0.5 for nicorandil is 100 nM. These two compounds appear to have a much higher affinity for nerve cells than for smooth muscle cells. Openers of sulfonylurea-sensitive K+ channels lead to inhibition of gamma-aminobutyric acid release. There is an excellent relationship between potency to activate 86Rb+ efflux and potency to inhibit neurotransmitter release.
Schmid-Antomarchi
H
H
Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 Centre National de la Recherche Scientifique, Valbonne, France.
Amoroso
S
S
Fosset
M
M
Lazdunski
M
M
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D019806:Cromakalim; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001578:Benzopyrans; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011758:Pyrroles; D013453:Sulfonylurea Compounds; D019806:Cromakalim; D005680:gamma-Aminobutyric Acid; D012413:Rubidium