Cardiac glycosides, calcium and the release of neurotransmitter from peripheral noradrenergic nerves

Summary

• 1. The requirement for external Ca (Ca_o) of neurotransmitter release evoked by cardenolides has been investigated in canine saphenous vein.

• 2. Basal efflux of³H-compounds from saphenous veins pre-loaded with³H-noradrenaline was the same in the absence as in the presence of Ca_o; Ca_o is not required for basal efflux of neurotransmitter.

• 3. Efflux of³H-compounds was increased by cardenolides. Both ACS and ouabain caused a similar maximum net efflux of³H suggesting that each evokes release from the same pool of³H compounds.

• 4. The similarity of the effects obtained with cardenolides to those obtained during exposure of saphenous vein preparations to potassium-free media suggests that³H-efflux is the result of Na, K-ATPase inhibition.

• 5. With ACS (ca. EC₅₀) the net efflux of³H-compounds early (<60 min) in the release period was greater in the absence of Ca_o than in its presence whereas at longer times the reverse was true; net efflux was less in the absence of Ca_o than in its presence. The difference in the³H-efflux pattern was paralleled qualitatively throughout by efflux of³H-noradrenaline.

• 6. The ACS-evoked efflux of³H-compounds in the presence and absence of Ca_o derives from sympathetic, noradrenergic nerves;³H present in extraneuronal tissues was not released by the cardenolide.

• 7. With ouabain (<EC₅₀) the total efflux of³H over a 75 min period was greater in the absence of Ca_o than in its presence. The reverse was found with ouabain (>EC₅₀): the total efflux of³H was less in the absence of Ca_o than in its presence.

• 8. In the presence of Ca_o the Ca-channel blocker VP reduced the total³H-efflux evoked by ouabain (>EC₅₀), but did not reduce that evoked by ouabain (<EC₅₀).

• 9. It is concluded that cardenolide evoked neurotransmitter efflux resulting from Na,K-ATPase inhibition is not dependent upon Ca_o although its presence, and subsequent entry via VP sensitive channels, does increase the magnitude of the efflux caused by higher concentrations of cardenolides. Whether a component of that efflux evoked by lower concentrations of cardenolides, (or higher concentrations over short time periods) depends on internal Ca stores or is independent of the cation, is not yet clear.