Reverse Na(+)/Ca(2+)-exchange mediated Ca(2+)-entry and noradrenaline release in Na(+)-loaded peripheral sympathetic nerves.
[(3)H]noradrenaline ([(3)H]NA) released from sympathetic nerves in the isolated main pulmonary artery of the rabbit was measured in response to field stimulation (2Hz, 1ms, 60V for 3min) in the presence of uptake blockers (cocaine, 3 x10(-5)M and corticosterone, 5 x10(-5)M). The [(3)H]NA-release was fully blocked by the combined application of the selective and irreversible 'N-type' voltage-sensitive Ca(2+)-channel (VSCC)-blocker omega-conotoxin (omega-CgTx) GVIA (10(-8)M) and the 'non-selective' VSCC-blocker aminoglycoside antibiotic neomycin (3x10(-3)M). Na(+)-loading (Na(+)-pump inhibition by K(+)-free perfusion) was required to elicit further NA-release after blockade of VSCCs (omega-CgTx GVIA+neomycin). In K(+)-free solution, in the absence of functioning VSCCs (omega-CgTx GVIA+neomycin), the fast Na(+)-channel activator veratridine (10(-5)M) further potentiated the nerve-evoked release of [(3)H]NA. This NA-release was significantly inhibited by KB-R7943, and fully blocked by Ca(o)(2+)-removal. However, Li(+)-substitution was surprisingly ineffective. The non-selective K(+)-channel blocker 4-aminopyridine (4-AP, 10(-4)M) also further potentiated the nerve-evoked release of NA in K(+)-free solution. This potentiated release was concentration-dependently inhibited by KB-R7943, significantly inhibited by Li(+)-substitution and abolished by Ca(o)(2+)-removal. It is concluded that in Na(+)-loaded sympathetic nerves, in which the VSCCs are blocked, the reverse Na(+)/Ca(2+)-exchange-mediated Ca(2+)-entry is responsible for transmitter release on nerve-stimulation. Theoretically we suppose that the fast Na(+)-channel and the exchanger proteins are close to the vesicle docking sites.
Török
Tamás L
TL
Department of Pharmacodynamics, Semmelweis University, H-1445 Budapest, Nagyvárad-tér 4, Hungary. tortam@net.sote.hu
Rácz
Dániel
D
Sáska
Zsuzsanna
Z
Dávid
Adám Z
AZ
Tábi
Tamás
T
Zillikens
Stefan
S
Nada
Somaia A
SA
Klebovich
Imre
I
Gyires
Klára
K
Magyar
Kálmán
K
D000320:Adrenergic Fibers / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011651:Pulmonary Artery / Q000294:innervation / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D014701:Veratridine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D026902:Potassium Channel Blockers; D062687:Sodium Channel Agonists; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D014701:Veratridine; D012964:Sodium; D002118:Calcium; D009638:Norepinephrine