Changes in creatine phosphate, inorganic phosphate, and the purine pattern in dog hearts with time of coronary artery occlusion and effect thereon of mioflazine, a nucleoside transport inhibitor

Abstract

A detailed analysis was made of the changes in canine myocardium, with time of occlusion, in several important metabolites such as creatine phosphate and adenosine triphosphate (luminometry), inorganic phosphate (spectrophotometry), and most of the purines and nicotinamide adenine dinucleotide (high performance liquid chromatography). Within 1 min there was a significant reduction in creatine phosphate and a significant increase in inorganic phosphate, adenosine diphosphate, and adenosine monophosphate. A decrease in adenosine triphosphate became apparent after 4 min, concomitant with a progressive rise in the nucleosides, which reached almost 50% of the total purines after 64 min of occlusion. The formation of hypoxanthine was detectable in 50% only of all animals, suggesting a lack of active nucleoside phosphorylase in the others. Nicotinamide adenine dinucleotide, although decreasing slightly, was by far the most constant of all variables measured during at least 30 min of ischaemia. Therefore, this component is suggested to be a useful internal standard, thus minimising analytical and biological variations. Mioflazine, a potent nucleoside transport inhibitor (I50 3 X 10(-8) mol X litre-1), when given orally at 2.5 mg X kg-1, did not affect any of the changes with the exception of the nucleosides, where the drug completely inverts the adenosine to inosine ratio. The contribution of adenosine to the total nucleosides changed from 20% in the controls to 80% with treatment during at least 16 min of occlusion, there being no overlap between the groups. It is concluded therefore that adenosine is not deaminated in the cell where it is produced. It is not yet clear how this notable effect of mioflazine could be linked to its remarkable protective effect against ischaemia.

Oral pretreatment with mioflazine completely changes the pattern and remarkably prolongs the accumulation of nucleosides in ischemic and reperfused myocardium

“…Eight were pretreated 150 min before LAD occlusion with 2.5 mg. kg 1 orally of mioflazine (R 51 469 -Janssen Pharmaceutica, Beerse, Belgium) and the others served as controls. Further preparation and LAD occlusion was done as described previously (3,15). Control transmural needle biopsies were taken from the non-occluded area, one before ischemia and one at the end of the experiment.…”

“…In most animals this procedure was repeated a second time and from several dogs a sample could be obtained after a third 8-min occlusion. The biopsies were processed and analysed for the different metabolites, exactly as described earlier (15). The final results are expressed as Ixmoles.…”

“…Since it is a potent and specific nucieoside transport inhibitor (15), one would expect mioflazine to affect nucleoside release during ischemia and inhibit its removal upon reperfusion. In a previous study in dogs (15), treated orally at 2.5 mg. kg -1, 150 rain before LAD occlusion, a remarkable and drastic change in the ratio between ADO and INO in the ischemic tissue was observed.…”

Cytotoxic Nucleosides and Parasitic Diseases: A New Therapeutic Approach

“…NBMPR, on the other hand, is unlikely to be tested in humans despite its effectiveness as a transport inhibitor and host protector since it is a nonproprietary drug. Recently we explored a number of derivatives of mioflazine, a new cardioprotective drug, 24 and it appears that some of these will be useful for host protection in selected species, with potential for oral administration and long duration of action.…”

Effect of D,L‐carnitine on the response of the isolated heart of the rat to ischaemia and reperfusion: relation to mitochondrial function

“…Myocardial ischaemia is associated with the intracelshown to exert deleterious effects on isolated mitolular accumulation of various factors known to be chondria including inhibition of oxidative phosassociated with tissue injury, including long-chain phorylation and adenine nucleotide (ADP/ATP) acyl CoA (Opie, 1979;Piper & Das, 1987), inorganic translocase activity (Opie, 1979;Shug, 1979;Ferrari phosphate (Pi) (van Belle et al, 1986) and free radet al., 1988). Various investigators have shown that icals (Garlick et al, 1987).…”