1. This experiment was designed to pharmacologically characterize a novel calcium channel blocker, AE0047. 2. After 1-hr treatment with each drug (10(-6) M), K(+)-induced contraction in rat aortic ...strip was clearly depressed by nifedipine and manidipine and slightly depressed by AE0047. After a wash out of the preparation in drug-free medium, the inhibition of K(+)-induced contraction by nifedipine or manidipine was abolished or unchanged, respectively. In contrast, AE0047-produced inhibition was reinforced with time after removal of the drug. 3. A cell membrane depolarization-induced 45Ca uptake into tissue was depressed completely by nifedipine, but, if it was washed out, merely 20% inhibition of control remained. AE0047-produced inhibition became prominent after drug removal. Manidipine did not have the same inhibitory effect after wash out. 4. A receptor-binding study indicated that affinity of AE0047 and manidipine for the dihydropyridine-sensitive Ca channel receptor was lower than that of nifedipine. AE0047, unlike nifedipine and manidipine, inhibited 3HPN200-110 binding more strongly when a 4-hr preincubation was used than without extended incubation. 5. The drug molecule of AE0047 was highly partitioned into the lipid bilayer of the synaptosome in canine cerebral cortices. In the synaptic membrane and liposomes, both prepared from canine cerebral cortices, the respective partition coefficients of the drug were 6997 +/- 2309 and 422 +/- 28 against 1395 +/- 161 and 24 +/- 2 of nitrendipine. 6. AE0047 showed slower onset of inhibition against K(+)-induced contraction and enhanced Ca influx compared with manidipine and nifedipine. These results may suggest that AE0047 requires a long period of time to occupy the dihydropyridine-sensitive sites within the Ca channel, which was detected by decreased specific 3HPN200-110 binding, and to inhibit K(+)-induced Ca influx into rat aorta.
Torasemide is a loop diuretic with potent and long lasting natriuretic action. Since the diuretic action of torasemide was not affected by several experimental disease models, this agent seems to be ...useful as the anti-edematous agent. In the present study, we examined the anti-edematous effect of torasemide in vascular permeability increased model, hind paw edematous model and pleural fluid increased model, and compared with those of furosemide. Oral administration of torasemide (0.3 - 10 mg/kg) and furosemide (1 - 30 mg/kg) elicited a dose-dependent increase in urine volume and urinary excretion of electrolytes. Torasemide and furosemide inhibited dose-relatedly the increase of vascular permeability induced by histamine, carrageenin-induced hind paw edema and increase of pleural fluid induced by carrageenin, and those potency of torasemide were approximately 10 times greater than those of furosemide. These results suggest that loop diuretic torasemide is useful as the anti-edematous agent.
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