The influence of calcium antagonists on the adenine nucleotide metabolism in the guinea-pig working heart during ischaemia and reperfusion

J. G. Hugtenburg, M. J. Mathy, N. de Haan, J. J. Beckeringh, P. A. van Zwieten

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With the aim of gaining more insight into the metabolism of adenine nucleotides in working normoxic guinea-pigs and in hearts subjected to 45 min of global ischaemia and subsequent reperfusion for 25 min, we evaluated the effect of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and dipyridamole on the adenine nucleotide catabolite levels in these hearts. The drugs were applied at the concentrations that reduced the aortic dP/dt of normoxic working hearts by 10% (EC10) and 30% (EC30). In globally ischaemic hearts there was a large accumulation of adenine nucleotide catabolites. Inosine proved to be the major catabolite. The drugs, with the exception of bepridil, CERM 11956 and dipyridamole (3 μmol/l), decreased the accumulation of catabolites. In hearts treated with mioflazine and dipyridamole the amount of adenosine increased. A deficit in the balance between adenine nucleotides and catabolites indicated that in globally ischaemic hearts there was a large accumulation of inosine monophosphate. Indeed, a substantial amount of inosine monophosphate was determined in untreated hearts, and hearts treated with nifedipine (EC30) and mioflazine (EC10). During the first 5 min of reperfusion a large quantity of catabolites, mainly inosine, was washed out. During 20 min of subsequent reperfusion in untreated hearts and in nifedipine and mioflazine-treated hearts the efflux of catabolites returned to normoxic values. Similar to the effect in ischaemic hearts, in early perfusate from lidoflazine, mioflazine and dipyridamoletreated hearts the adenosine/inosine ratio was increased. An incomplete balance of adenine nucleotides and catabolites, as well as the presence of a considerable quantity of inosine monophosphate in mioflazine-treated hearts, suggests that adenosine suppresses the breakdown of inosine monophosphate upon reperfusion. A reduced efflux of catabolites and the presence of a considerable amount of inosine monophosphate in lidoflazine, mioflazine and dipyridamole-treated hearts does not lead to an increased synthesis of adenine nucleotides during 25 min of reperfusion. Calcium antagonists without nucleoside transport inhibitory activity exert only limited influence on the adenine nucleotide catabolism in globally ischaemic and reperfused guineapig hearts. The ineffectiveness of all drugs to enhance the adenine nucleotide levels in reperfused hearts seems to results from the incapacity of the adenine nucleotide metabolism to convert inosine monophosphate, nucleosides and hypoxanthine into adenine nucleotides.

Original languageEnglish
Pages (from-to)496-504
Number of pages9
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number5
Publication statusPublished - 1 May 1991


  • Adenine nucleotide metabolism
  • Calcium antagonists
  • Global ischaemia
  • Guinea-pig working heart
  • Nucleoside transport inhibition

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