Archives of Toxicology

, Volume 78, Issue 1, pp 34–39 | Cite as

Cardiovascular effects of the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning

  • Marloes J. A. Joosen
  • Tjerk J. H. Bueters
  • Herman P. M. van Helden
Organ Toxicity and Mechanisms
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Abstract

Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 µg/kg s.c., ~2×LD50) in rats is completely prevented by treatment with the adenosine A1 receptor agonist N 6-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A1 receptor antagonist 8-p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A1 receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.

Keywords

Sarin Organophosphate Cardiovascular effects Adenosine A1 receptor N6-Cyclopentyladenosine (CPA) 8-p-Sulphophenyltheophylline (8-PST) 
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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Marloes J. A. Joosen
    • 1
  • Tjerk J. H. Bueters
    • 1
  • Herman P. M. van Helden
    • 1
  1. 1.Research Group Medical CountermeasuresTNO Prins Maurits LaboratoryRijswijkThe Netherlands

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