A new concept for donor heart preservation: Nucleoside transport inhibition

Flameng, Willem; Möllhoff, T.; Sukehiro, S; Minten, J; Belle, H. Van; Janssen, P. A. J.

doi:10.1016/0022-2828(90)91821-n

Cited by 5 publications

(6 citation statements)

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“…We observed, in line with literature [6,[27][28][29], that reperfusion was unable to restore basal levels of cardiac adenine nucleotide content (Fig. 5A).…”

Section: Energy Metabolismsupporting

confidence: 80%

“…These data suggest that ATP degradation to purines during ischemia could slow high-energy phosphate restoration during reperfusion with delayed mechanical and metabolic cardiac recovery (stunned myocardium; ref. [27]). Our findings also emphasize the specificity ofpurine release to characterize the occurrence of myocardial ischemic conditions [33], where lactate release seems to be inadequate as a marker (Figs.…”

Section: Energy Metabolismmentioning

confidence: 99%

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Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia

et al. 1996

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We studied the effect of 12-36 min of global ischemia followed by 36 min of reperfusion in Langendorffperfused rabbit hearts (n = 26). Metabolism was determined in terms of peak and total release ofpurines (adenosine, inosine, hypoxanthine), lactate and noradrenaline during reperfusion; and myocardial content of nucleotides (ATP, ADP, AMP), glycogen and noradrenaline at the end of reperfusion. An inverse relationship (r = -0.79) existed between duration of ischemia and developed pressure post-ischemia. Early during reperfusion, after 12 min of ischemia, the purine concentration (peak release) increased 100x (p < 0.01), that of lactate and noradrenaline 10x (p < 0.05). Total purine release rose with progression of the ischemic period (30x after 36 min ofischemia; p < 0.01), concomitant with a reduction in nucleotide content. Lactate release was independent from the duration of ischemia, although glycogen had declined by 30% (p < 0.01) after 36 rain ofischemia. The acid insoluble glycogen fraction, which presumably contains proglycogen, increased substantially during short-term ischemia. Peak noradrenaline increased 100x and 200x (p < 0.05) after 24 and 36 min ofischemia, respectively. Total noradrenaline release due to various periods of ischemia mirrored its peak release. Function recovery was inversely related to total purine and noradrenaline effiux (both r = -0.81); it correlated with tissue nucleotide content (r = 0.84). In conclusion, larger amounts of noradrenaline are released only after a substantial drop in myocardial ATR During severe ischemia ATP consumption more than limited ATP production by anaerobic glycolysis, is a key factor affecting recovery on subsequent reperfusion. In contrast to lactate efflux, purine and noradrenaline release are useful markers of ischemic and reperfusion damage. (Mol Cell Biochem 160/161:187-194, 1996)

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“…We observed, in line with literature [6,[27][28][29], that reperfusion was unable to restore basal levels of cardiac adenine nucleotide content (Fig. 5A).…”

Section: Energy Metabolismsupporting

confidence: 80%

Section: Energy Metabolismmentioning

confidence: 99%

Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia

et al. 1996

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“…We have also screened a variety of analogues of draflazine and have identified functional groups important for ENT1 versus ENT2 selectivity in the mouse, as well as chemical features that contribute to hENT1 versus mENT1 binding affinity [20,34]. These structure-activity data, in conjunction with the amino acid sequences of mENT1 and mENT2 determined in the present study, will assist in the delineation of the protein domains involved in the binding of draflazine, and other cardioprotective agents, to nucleoside transporters [11,35,36].…”

Section: Resultsmentioning

confidence: 80%

Molecular cloning and functional characterization of inhibitor-sensitive (mENT1) and inhibitor-resistant (mENT2) equilibrative nucleoside transporters from mouse brain

Kiss

Farah

Kim

et al. 2000

Biochemical Journal

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Mammalian cells express at least two subtypes of equilibrative nucleoside transporters, i.e. ENT1 and ENT2, which can be distinguished functionally by their sensitivity and resistance respectively to inhibition by nitrobenzylthioinosine. The ENT1 transporters exhibit distinctive species differences in their sensitivities to inhibition by dipyridamole, dilazep and draflazine (human mouse rat). A comparison of the ENT1 structures in the three species would facilitate the identification of the regions involved in the actions of these cardioprotective agents. We now report the molecular cloning and functional expression of the murine (m)ENT1 and mENT2 transporters. mENT1 and mENT2 encode proteins containing 458 and 456 residues respectively, with a predicted 11-transmembrane-domain topology. mENT1 has 88 % and 78 % amino acid identity with rat ENT1 and human ENT1 respectively ; mENT2 is more highly conserved, with 94 % and 88 % identity with rat ENT2 and human ENT2 respectively. We have also isolated two additional distinct cDNAs that encode proteins similar to mENT1 ; these probably represent distinct mENT1 isoforms or alternative splicing products. One cDNA encodes a protein with two additional amino acids

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“…Draflazine has also been reported to prevent catecholamine-induced myocardial damage . The pharmacological profile of draflazine appears to be advantagous as a compound for cardiac protection, and could be useful as an additional compound in cardioplegic solutions (Flameng et al, 1991). In cardiac transplantation, the availability of donor hearts is markedly limited by the time for which the heart can be kept in cardioplegia for transportation.…”

Section: Introductionmentioning

confidence: 99%

Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium

Böhm

Weinhold

Schwinger

et al. 1994

British J Pharmacology

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1 The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation.2 Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol 1' Ca21) human atrial trabeculae and ventricular papillary muscle strips. 4 Draflazine, at concentrations up to 100 lmolI 1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5 The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 ftmol V'.6 Draflazine could be a useful agent for cardiopreservation because it does not produce cardiodepressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.

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A new concept for donor heart preservation: Nucleoside transport inhibition

Cited by 5 publications

References 0 publications

Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia

Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia

Molecular cloning and functional characterization of inhibitor-sensitive (mENT1) and inhibitor-resistant (mENT2) equilibrative nucleoside transporters from mouse brain

Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium

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