Influence of calcium channel inhibitors on the myocardial uptake and retention of technetium 99m N-NOET, a new myocardial perfusion imaging agent: a study on isolated perfused rat hearts.
BACKGROUND
Technetium 99m N-NOET is a new myocardial perfusion imaging agent currently in phase III clinical trials in Europe. In vitro studies on newborn rat cardiomyocytes have shown that calcium inhibitors, such as verapamil or diltiazem, inhibit its cellular uptake by 40%. To determine whether such a specificity exists ex vivo, we studied the effect of verapamil, diltiazem, and nifedipine on the myocardial uptake and retention of Tc-99m N-NOET in isolated perfused rat hearts.


RESULTS
After a 15-minute baseline period, rat hearts were perfused with 0.5 micromol/L verapamil (n = 6), 0.75 micromol/L diltiazem (n = 6), or 0.1 micromol/L nifedipine (n = 6) for 10 minutes before the injection of a bolus (40 microCi/250 microL) of the tracer. Control hearts were perfused with either 1.5 mmol/L calcium (same concentration as in the treated groups; n = 7) or 0.75 mmol/L calcium (same contractility as in the treated groups; n = 6). Myocardial activity of Tc-99m N-NOET was monitored for 30 minutes. The functional parameters of the hearts were recorded throughout the experiments. Calcium inhibitors induced a 40% to 55% decrease in maximal first derivative of left ventricular pressure (dP/dt) (0.0001<P< .001 versus control, calcium 1.5 mmol/L). After 30 minutes, tracer retention was 51.6%+/-6.1% injected dose (ID)/g and 54.2%+/-10.2% ID/g for control hearts perfused with 1.5 mmol/L and 0.75 mmol/L calcium, respectively (P = not significant). Myocardial activity of Tc-99m N-NOET was not modified in hearts perfused with verapamil (50.0%+/-4.1% ID/g), diltiazem (47.2%+/-8.7% ID/g), or nifedipine (51.7%+/-3.4% ID/g; P = not significant versus control hearts perfused with 1.5 mmol/L or 0.75 mmol/L calcium).


CONCLUSIONS
Verapamil, diltiazem, and nifedipine were not responsible for any variations in Tc-99m N-NOET uptake and retention in the isolated rat-heart model. This might be explained by the binding of the tracer to endothelial cells, which do not present voltage-dependent calcium channels.
Riou
L
L
Laboratoire d'Etude de Radiopharmaceutiques, Faculté de Médecine, Université Joseph Fourier, Grenoble, France.
Ghezzi
C
C
Pasqualini
R
R
Fagret
D
D
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D013859:Thiocarbamates / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013859:Thiocarbamates; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; C093922:technetium Tc 99m, bis(N-ethoxy-N-ethyldithiocarbamato)nitrido-