Alteration of norepinephrine release from [3h]-norepinephrine preloaded basilar artery by naphthalenesulfonamides.
The effects of W-7, W-5, No. 233, and chlorpromazine on sympathetic nerve transmitter efflux were compared in superfused canine basilar arterial preparations preloaded with [3H]-norepinephrine. In vitro experiments suggest that these agents are selective calmodulin antagonists. The electrical transmural stimulation-induced efflux of tritium was reduced by W-7 and W-5, although they were unexpectedly equipotent since W-5 is a chloride-deficient derivative of W-7 and has a lower affinity for calmodulin than does W-7. The median inhibitory concentration (IC50) of W-7 for stimulation-induced efflux was 3.4 X 10(-6) M. The addition of No. 233 at relatively high concentrations (3 X 10(-5) M and 5 X 10(-5) M) caused a reduction in stimulation-induced efflux. Chlorpromazine produced a dual effect on the efflux: enhancement at low concentrations (below 1 X 10(-6) M) and reduction at high concentrations. The IC50 values of No. 233 and chlorpromazine were 3.5 X 10(-5) M and 2.5 X 10(-5) M, respectively. The additions of these four agents also caused a significant elevation in the spontaneous basal efflux of tritium from the preparations. The concentrations of the agents that elevated the spontaneous efflux to the level of half the stimulation-induced efflux were closely fitted to the IC50 values for stimulation-induced efflux. This finding indicates that the elevation in spontaneous efflux is directly proportional to the reduction in electrical stimulation-induced efflux. From these findings, it is concluded that naphthalenesulfonamides including W-7 have a direct effect on sympathetic nerve terminals which is independent of the effect on calmodulin.
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001488:Basilar Artery / Q000378:metabolism* / Q000502:physiology; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002746:Chlorpromazine / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium
D002147:Calmodulin; D013449:Sulfonamides; D014316:Tritium; C017967:W 7; C024987:N(2)-dansyl-L-arginine-4-t-butylpiperidine amide; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D001120:Arginine; D002746:Chlorpromazine; D009638:Norepinephrine