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A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure.

Abstract
A(3) adenosine receptor (AR) activation and inhibition worsen and improve, respectively, renal function after ischemia-reperfusion (I/R) injury in rats. We sought to further characterize the role of A(3) ARs in modulating renal function after either I/R or myoglobinuric renal injury. A(3) knockout mice had significantly lower plasma creatinines compared with C57 controls 24 h after I/R or myoglobinuric renal injury. C57 control mice pretreated with the A(3) AR antagonist [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5 dicarboxylate] or agonist [0.125 mg/kg N(6)-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (IB-MECA)] demonstrated improved or worsened renal function, respectively, after I/R or myoglobinuric renal injury. Higher doses of IB-MECA were lethal in C57 mice subjected to renal ischemia. H(1) but not H(2) histamine receptor antagonist prevented death in mice pretreated with IB-MECA before renal ischemia. Improvement in renal function was associated with significantly improved renal histology. In conclusion, preischemic A(3) AR activation (0.125 mg/kg IB-MECA) exacerbated renal I/R injury in mice. Mice lacking A(3) ARs or blocking A(3) ARs in wild-type mice resulted in significant renal protection from ischemic or myoglobinuric renal failure.
AuthorsH Thomas Lee, Ayuko Ota-Setlik, Hua Xu, Vivette D D'Agati, Marlene A Jacobson, Charles W Emala
JournalAmerican journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 284 Issue 2 Pg. F267-73 (Feb 2003) ISSN: 1931-857X [Print] United States
PMID12388399 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1
  • N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
  • p-Methoxy-N-methylphenethylamine
  • Histamine
  • Adenosine
Topics
  • Acute Kidney Injury (pathology, physiopathology, prevention & control)
  • Adenosine (analogs & derivatives, pharmacology, toxicity)
  • Animals
  • Genotype
  • Histamine (blood)
  • Ischemia (metabolism, pathology, physiopathology)
  • Kidney (pathology, physiopathology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout (genetics)
  • Myoglobinuria (metabolism, physiopathology)
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1 (drug effects)
  • Reference Values
  • Renal Circulation
  • Reperfusion Injury (metabolism, pathology)
  • p-Methoxy-N-methylphenethylamine (pharmacology, toxicity)

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