Pierre Gachon

Uptake and release of two new Tc-99m labeled myocardial blood flow imaging agents in cultured cardiac cells

Two new neutral lipophilic 99mTc labeled molecules, chloro (methyboron (1-)-tris[1,2-cyclohexane-dionedioxime 91-)]-N,N′N″N‴N⁗) (SQ 30217) and Bis [1,2-cyclohexanedione dioximato (1-)-0]-[1,2-cyclohexanedione dioximato (2-)-0] borato (2-N,N′N″N‴N⁗) -chloro Tc (SQ 32014), were studied in cultures of beating myocardial cells of newborn rats. The uptake and release kinetics, the effects of various pH levels of the medium, and the effects of three metabolic inhibitors, i.e, ouabain, cyanide and iodoacetate were assessed. Results show that T1/2 of uptake were 2 min with both tracers, and T1/2 of release were 12 and 13 min with SQ 32014 and SQ 30217, respectively. The intra/extracellular tracer concentrations was about 15 times higher with SQ 30217 than with SQ 32014. Intracellular concentration was decreased for both tracers at high pH levels, and was only moderately modified otherwise, including in the presence of the metabolic inhibitors. It is concluded that both tracers present very interesting properties for myocardial blood flow imaging, although a higher contrast should be expected with SQ 30217 than with SQ 32014.

Effects of Two monocarboxylic Ionophores, Grisorixin and Alborixin, on Cardiovascular Function and Plasma Cation Concentrations in the Anesthetized Dog

Grisorixin and alborixin are two monocarboxylic ionophores of the nigericin group which carry potassium preferentially over sodium. We studies their cardiovascular effects in anesthetized digs. Grisorixin (2 mg/kg) and alborixin (1 mg/kg) produced a dramatic increase in ventricular contractile force (+250 and +320%, respectively) and in systolic and diastolic arterial pressures. At the same time, they induced a marked increase in plasma potassium in the coronary sinus and hepatic vein and a lesser increase in the renal and deep femoral veins. The concomitant modifications of the electrocardiogram were similar to those usually described in hyperkalemia, reflecting the effect of grisorixin and alborixin on plasma potassium. The parallel decrease in plasma sodium in the coronary sinus was more marked with alborixin than with grisorixin. These results suggest that the ionophores alter the intracellular ionic state of the myocardium, which may partly explain their positive inotropic effect and the greater effect of alborixin.

Comparative study of vascular effects of four calcium antagonists using a multi-organ functional imaging technique with thallium-201.

The vasoactive effects of calcium antagonist drugs were compared using a multi-organ functional imaging technique with thallium-201 (Tl-201). Four drugs were tested at two different doses: nifedipine (10 and 25 μ/kg), verapamil (100 and 250 μg/kg), diltiazem (100 and 250 μg/kg), and bepridil (2.5 and 10 mg/kg). Tl-201 was injected at three different times after drug administration to examine the time course of the effects of the drugs. The regions studied were heart, liver, kidneys, shoulder skeletal muscles, and lungs. The results showed marked changes in Tl-201 biodistribution in anesthetized dogs after administration of calcium antagonists. The major increases in count density were observed in heart and skeletal muscles, but the drug effects differed in intensity and duration. Nifedipine induced the largest variations in the doses used (136 and 153% in the heart 2 min after 10 and 25 μg/kg doses, respectively). Diltiazem and verapamil were most efficient at 250 μg/kg (134 and 115% at 2 min after injection, respectively). With bepridil the increases of cardiac and muscular uptakes of Tl-201 were transient and the 2.5 mg/kg dose induced a decrease of myocardial count density (84% at 5 min). The effects were less reproducible in the other organs studied.

Myocardial uptake of thallium-201 diethyldithiocarbamate (201TI-DDC) in cultured heart cells and in humans

We assessed the feasibility of SPECT imaging with 201Tl-diethyldithiocarbamate (201Tl-DDC), a new cerebral blood flow tracer with little redistribution, expecting to observe less extensive redistribution than with 201Tl-chloride. Myocardial sections were obtained in three patients presenting with documented coronary artery disease and injected at peak exercise with 100 MBq 201Tl-DDC. In two patients there was a clear redistribution phenomenon at four h after injection. In cultured myocardial cells of newborn rats, the uptake and washout of 201Tl-chloride and 201Tl-DDC were compared. The 201Tl-DDC uptake was lower than 201Tl-chloride (transmembrane gradients were respectively 89±10 and 4.1±0.2, mean±sem, n=14, P<0.001). After 2 h washout in a Tl free medium, the retention of 201Tl-chloride in the cells was 4% vs 19% for 201Tl-DDC. It is concluded that although myocardial imaging is feasible with 201Tl-DDC, this agent redistributes significantly with time.

MEASUREMENTS OF TL-201 UPTAKE AND OXIDATIVE METABOLISM IN CULTURED MYOCARDIAL CELLS

Cultures of myocardial cells were utilized under controlled conditions in order to measure simultaneously their Tl-201 uptake and oxidative metabolism. The cultures were prepared by trypsinization of the myocardium of two to four-day old newborn mice. The cells were placed into flasks and two days later were incubated with C14-glucose or C14-octanoate. The flasks were inserted in an apparatus in which recirculating air was passing through a vibrating reed electrometer for detection of the beta radiations of the C14-CO2 liberated by the radioactive substrates. The rate of oxidation was measured from the recording of this activity. Various drugs affecting the cardiac metabolism were injected in 22 flasks, i.e., potassium cyanide (KCN), an inhibitor of mitochondrial respiration (MR), 2–4 dinitrophenol (DNP), an uncoupler of MR, and grisorixin, a potassium ionophore. The flasks were finally incubated for five minutes with 100μCi of Tl-201. After washing, the remaining activity was counted and the amount of protein measured. The ratio of intra/extracellular Tl-201 activity (Tl i/o) was 35±9 in 12 controls. The changes in oxidation (Δ%) and the Tl i/o in the treated flasks were (m±sd;*p<0.05): Octanoate Glucose Δ% Tl i/o Δ% Tl i/o KCN −45±22* 27±11 −28±15* 31±4 DNP 10±52 35±10 37±23 41±10 Grisorixin −50±16* 20±5* −11±12 17±3* These results demonstrate that in tissue cultures the Tl-201 uptake was partially dependent on the oxidative metabolism.

Multi-organ functional imaging with thallium-201: A new noninvasive method for rapid assessment of vasoactive drugs

A new method for rapid and noninvasive assessment of vasoactive drugs is described, using scintigraphic imaging with thallium-201 in anesthetized dogs. The scintigraphic images were processed to evaluate the effects of the vasoactive agents studied upon the biodistribution of thallium-201 in the whole body of dogs. The calculation of the functional parameter was based upon the comparison of the cell by cell increase of the tracor uptake following two different injections: the first in the basal state, the second after treatment with a vasoactive drug. Six drugs were tested and their effects evaluated in heart, liver, lungs, kidneys, and skeletal muscles. The most marked effects on myocardium were observed with dipyridamole and the ionophore grisorixin, two coronary vasodilators, which induced a strong increase in the TI-201 myocardial uptake (168.9 +/- 31.6% and 194.9 +/- 34.2% respectively). The results obtained in the other organs with all the drugs tested were in accord with their known hemodynamic properties, and so confirm the usefulness of this method.