Role of nucleoside transport inhibition and endogenous adenosine in prevention of catecholamine induced death in rabbits.
OBJECTIVE
R 75,231, a potent and specific nucleoside transport inhibitor, largely prevents cardiac damage and death in catecholamine challenged rabbits. The major biochemical effect of nucleoside transport inhibition in ischaemic and reperfused myocardium is a prolonged accumulation of adenosine. The cardioprotection by R 75,231 may be explained if it can be shown that endogenous adenosine plays a role in catecholamine cardiotoxicity and if nucleoside transport inhibition is required for the cardioprotective effect of R 75,231.


METHODS
Several groups of rabbits were infused with catecholamines until death. Changes in survival with time of infusion by coinfusion of aminophylline and/or treatment with R 75,231 and its two stereoenantiomers were assessed.


RESULTS
Treatment with R 75,231 postponed the time to reach 50% mortality threefold after challenge with adrenaline or noradrenaline. Draflazine, the (-)-enantiomer of R 75,231, was also effective, whereas the (+)-enantiomer, which is devoid of any effect on the transporter, was not cardioprotective. The cardioprotective effect of R 75,231 was dependent on the extent and duration of ex vivo inhibition of the transporter in blood. Co-infusion of aminophylline with adrenaline significantly accelerated the rate of mortality.


CONCLUSIONS
Nucleoside transport inhibition is the major, if not the only, determinant for efficacy of R 75,231 and draflazine as cardioprotective agents. Taken together with the evidence for a role of endogenous adenosine, the benefit from nucleoside transport inhibition in this model may be the result of prolonged accumulation of endogenous adenosine.
Van Belle
H
H
Department of Biochemistry, Janssen Research Foundation, Beerse, Belgium.
Ver Donck
K
K
Verheyen
W
W
D000241:Adenosine / Q000502:physiology*; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine; D009705:Nucleosides / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits
D009705:Nucleosides; D010879:Piperazines; C072040:draflazine; D000628:Aminophylline; D000241:Adenosine; D009638:Norepinephrine; D004837:Epinephrine