Effect of omega-conotoxin GVIA on noradrenaline release from postganglionic sympathetic neurones in rabbit aorta.
The aim of the present work was to examine the effect of the selective N-type calcium blocking agent omega-conotoxin GVIA on stimulation-evoked release of noradrenaline from sympathetic nerves in rabbit isolated aorta with regard to stimulation frequency, extracellular Ca2+ concentration, and transmitter uptake. Rings of rabbit isolated aorta were preloaded with (-)-3H-noradrenaline and the fractional 3H-overflow evoked by electrical-field stimulation was determined by liquid scintillation spectrometry. Omega-conotoxin GVIA (3 x 10(-10)-3 x 10(-8) M) did not alter the spontaneous 3H-outflow. Omega-conotoxin GVIA (3 x 10(-10)-3 x 10(-8) M) caused a slowly developing reduction of stimulation-evoked 3H-overflow at 1 and 30 Hz. The Emax for the omega-conotoxin-induced inhibition was less (70%) at 30 Hz than that (96%) seen at 1 Hz. Short-term incubation with omega-conotoxin GVIA caused a subsequent steady-state inhibition. The inhibitory action of omega-conotoxin GVIA (3 x 10(-10)-3 x 10(-9) M) was inversely related to the extracellular Ca2+ concentration (6.5 x 10(-4)-2.7 x 10(-3) M). Cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M), neuronal and extraneuronal uptake inhibitors, respectively, did not alter the inhibitory effect of omega-conotoxin GVIA (3 x 10(-9) M) on 3H-overflow evoked by stimulation at a frequency of either 1 or 30 Hz. It is concluded that omega-conotoxin GVIA acts on prejunctional N-type calcium channels to inhibit stimulation-evoked noradrenaline release from sympathetic neurone terminals in rabbit aorta. At a high frequency, another subtype calcium channel may possibly be involved. The action of omega-conotoxin GVIA is independent of neuronal and extraneuronal uptake mechanisms for noradrenaline, but dependent on the amount of Ca2+ to be transported across the neurilemma from the extracellular space into the neurone.
Nedergaard
O A
OA
Department of Pharmacology, School of Medicine, Odense University, Denmark. oa.nedergaard@winsloew.sdu.dk
D000818:Animals; D001013:Aorta, Thoracic / Q000294:innervation*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium; D020866:omega-Conotoxin GVIA / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D014179:Neurotransmitter Uptake Inhibitors; D014316:Tritium; D020866:omega-Conotoxin GVIA; D003042:Cocaine; D002118:Calcium; D003345:Corticosterone; D009638:Norepinephrine