Reverse Na+/Ca2+-exchange mediated Ca2+-entry and noradrenaline release in Na+-loaded peripheral sympathetic nerves

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Abstract

[3H]noradrenaline ([3H]NA) released from sympathetic nerves in the isolated main pulmonary artery of the rabbit was measured in response to field stimulation (2 Hz, 1 ms, 60 V for 3 min) in the presence of uptake blockers (cocaine, 3 × 10−5 M and corticosterone, 5 × 10−5 M). The [3H]NA-release was fully blocked by the combined application of the selective and irreversible ‘N-type’ voltage-sensitive Ca2+-channel (VSCC)-blocker ω-conotoxin (ω-CgTx) GVIA (10−8 M) and the ‘non-selective’ VSCC-blocker aminoglycoside antibiotic neomycin (3 × 10−3 M). Na+-loading (Na+-pump inhibition by K+-free perfusion) was required to elicit further NA-release after blockade of VSCCs (ω-CgTx GVIA + neomycin). In K+-free solution, in the absence of functioning VSCCs (ω-CgTx GVIA + neomycin), the fast Na+-channel activator veratridine (10−5 M) further potentiated the nerve-evoked release of [3H]NA. This NA-release was significantly inhibited by KB-R7943, and fully blocked by Symbol. 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 Symbol.

It is concluded that in Na+-loaded sympathetic nerves, in which the VSCCs are blocked, the reverse Na+/Ca2+-exchange-mediated Ca2+-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.

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