Mechanisms of noradrenaline release in the anoxic heart of the rat.
OBJECTIVE
The aim was to examine the time course of exocytotic and "spontaneous" noradrenaline overflow and the influence of an Uptake1 inhibitor, desipramine, in rat hearts subjected to anoxic and substrate-free perfusion.


METHODS
Hearts were perfused with a constant flow and exocytotic noradrenaline overflow was elicited either by electrical stimulation of the left stellate ganglion or by K+ depolarisation. Noradrenaline overflow was measured by HPLC.


RESULTS
Energy depletion for a period of 30 min resulted in an enhanced spontaneous noradrenaline overflow and a progressive decline in the nerve stimulation induced noradrenaline overflow. However, noradrenaline overflow induced by 40 mM K+ was enhanced by three- to fourfold in the energy depleted conditions. During anoxia, desipramine (0.3 microM) inhibited the spontaneous noradrenaline overflow and partly increased, in the early phase of anoxia, noradrenaline overflow by nerve stimulation, but showed no effect on K+ induced overflow. Further experiments showed that K+ at 10 mM failed to evoke noradrenaline overflow in normoxic hearts but induced a significant overflow in energy depleted hearts, either in the presence or absence of desipramine; quantities of noradrenaline overflow in response to 10-40 mM K+ were substantially higher in anoxia. This difference in noradrenaline overflow caused by K+ during normoxia and anoxia was partly narrowed by desipramine which enhanced overflow in normoxia.


CONCLUSIONS
"Spontaneous" and exocytotic noradrenaline release coexist within the 30 min period of anoxia but their responses to Uptake1 inhibitor differ. K(+)-induced noradrenaline overflow was markedly augmented by energy depletion due to a combination of failed neuronal reuptake and enhanced exocytosis.
Du
X J
XJ
Baker Medical Research Institute, Prahran, Victoria, Australia.
Dart
A M
AM
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D005089:Exocytosis / Q000187:drug effects; D005728:Ganglia, Sympathetic / Q000502:physiology; D006321:Heart / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D011188:Potassium; D003891:Desipramine; D009638:Norepinephrine