Influence of mioflazine on canine coronary blood flow and on adenine nucleotide and nucleoside content under normal and ischemic conditions.
Intravenous injection of mioflazine, a nucleoside transport antagonist, caused maximal coronary vasodilation in canine hearts. This was completely reversed by intravenous injection of the enzyme adenosine deaminase. Coronary vasodilation was induced again by the adenosine deaminase inhibitor EHNA [Erythro-9(2-hydroxy-3-nonyl)adenine]; however, without previous injection of mioflazine, EHNA did not produce coronary vasodilation. Mioflazine-induced coronary vasodilation was antagonized by theophylline, but it was not associated with increased plasma levels of adenosine. Under the influence of mioflazine, ischemic myocardium contained adenosine and inosine at a ratio of 65:30, which is the reverse of the control ratio. Total nucleoside content following mioflazine showed reduced nucleoside losses as compared with control. A significant amount of the accumulated adenosine is extracellular since it was accessible to exogenous adenosine deaminase. Reperfusion of ischemic myocardium did not result in increased rates of adenosine phosphorylation, another indicator of its extracellular accumulation. The data are best explained by assuming release of adenosine by mioflazine in addition to its known effect of inhibiting nucleoside transport. The adenosine release occurs most probably into the interstitial space where it occupies smooth muscle adenosine receptors. The existence of nonsymmetric transport (uptake is more inhibited than release) is postulated for the myocyte, as well as for the endothelial cell plasma membrane.
D000227:Adenine Nucleotides / Q000378:metabolism*; D000241:Adenosine / Q000097:blood; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000378:metabolism* / Q000503:physiopathology; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010879:Piperazines / Q000494:pharmacology*
D000227:Adenine Nucleotides; D002317:Cardiovascular Agents; D010879:Piperazines; D000255:Adenosine Triphosphate; C041518:mioflazine; D000241:Adenosine