Inhibitory effect of a toxin okadaic acid, isolated from the black sponge on smooth muscle and platelets.
1. Effects of okadaic acid, a toxin isolated from marine sponges, on smooth muscle contraction and platelet activation were examined. 2. Contractions in rabbit aorta induced by high concentrations of K+ and noradrenaline were inhibited by 0.1-1 microM okadaic acid in a concentration-dependent manner. Spontaneous rhythmic contractions as well as high K+-induced contraction in guinea-pig taenia caeci were also inhibited by 1 microM okadaic acid. 3. High K+-induced contraction in rabbit aorta was accompanied by increased Ca2+ influx measured with 45Ca2+ and increased cytosolic Ca2+ [( Ca2+]cyt) measured with fura-2-Ca2+ fluorescence. Okadaic acid inhibited the contraction without inhibiting Ca2+ influx and produced only a small decrease in [Ca2+]cyt. 4. In a saponin-skinned taenia, Ca2+-induced contraction was not inhibited but rather potentiated by okadaic acid. 5. Okadaic acid, 1 microM, inhibited aggregation, ATP release and increased in [Ca2+]cyt induced by thrombin in washed rabbit platelets. Okadaic acid itself did not change the platelet activities. 6. Okadaic acid did not change the cyclic AMP content of rabbit aorta although the inhibitory effects of okadaic acid were similar to those of cyclic AMP. 7. Although the mechanism of the inhibitory effect of okadaic acid was not clarified in the present experiments, it is suggested that okadaic acid acts by inhibiting protein phosphatases resulting in an indirect activation of cyclic AMP-dependent protein phosphorylation.
Karaki
H
H
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
Mitsui
M
M
Nagase
H
H
Ozaki
H
H
Shibata
S
S
Uemura
D
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D003106:Colon / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004988:Ethers, Cyclic / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D019319:Okadaic Acid; D010975:Platelet Aggregation Inhibitors; D011161:Porifera / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002132:Calcium Radioisotopes; D004988:Ethers, Cyclic; D010975:Platelet Aggregation Inhibitors; D014662:Vasoconstrictor Agents; D019319:Okadaic Acid; D011189:Potassium Chloride; D000242:Cyclic AMP; D002118:Calcium; D009638:Norepinephrine