Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium.
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 l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-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 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.
Klinik III für Innere Medizin, Universität zu Köln, Germany.
M
M
Böhm
C
C
Weinhold
R H
RH
Schwinger
J
J
Müller-Ehmsen
D
D
Böhm
H
H
Reichenspurner
B
B
Reichart
E
E
Erdmann
D000328:Adult; D000345:Affinity Labels; D000368:Aged; D002217:Carbachol / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D033703:Nucleoside Transport Proteins; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000345:Affinity Labels; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D010879:Piperazines; C072040:draflazine; D010660:Phenylisopropyladenosine; D013868:Thioinosine; D004176:Dipyridamole; D002217:Carbachol; C001789:4-nitrobenzylthioinosine