INFLUENCE OF CALCIUM ON THE EFFECTS OF OKADAIC ACID AND ITS INTERACTION WITH CAFFEINE AND THEOPHYLLINE IN RAT MYOMETRIUM

The effects of okadaic acid (OA), a monocarboxylic acid produced by ma rine dinoflagellates belonging to the genera Dinophysis and Prorocentr um, and their interactions with theophylline and caffeine were studied on the rat-isolated uterus in a calcium-containing medium and a calci um-free medium in the presence of 10(-3) M EGTA. Okadaic acid (5x10(-6 ) to 5x10(-5) M) induced a concentration-dependent contraction of the rat-isolated uterus corresponding, with 5x10(-5) M, to 142.3+/-6.1% (n = 7) of the contraction induced by oxytocin 10(-6) M. The time to pea k tension was inversely proportional to the maximum effect produced. T he contraction was not sustained and was followed by a concentration-d ependent decrease in tone. In a Ca2+-free medium containing 10(-3) M E GTA the contractile effects of OA were significantly inhibited or redu ced. A 30 min pretreatment with theophylline (3x10(-3) M) or caffeine (2x10(-2) M) significantly reduced, in a Ca2+-containing medium, the m aximum contractile effect of OA 10 and/or 2x10(-5) M and shortened the relative time to peak tension. In a Ca2+-free medium containing 10(-3 ) M EGTA, only the second effect was observed. With a 1 min pretreatme nt and in a Ca2+-containing medium, theophylline 3x10(-3) M and caffei ne 10(-2) M did not modify the maximum effect of OA 10(-5) M but short ened the time to peak tension. The same concentrations of the xanthine s potentiated the E(max) of OA 5x10(-6) M in the Ca2+-containing mediu m or in a Ca2+-free medium containing 10(-3) M EGTA. Okadaic acid 10(- 6) M used as 30 min pretreatment versus OA 10(-5) M and 2x10(-5) M beh aved like caffeine or theophylline. These results suggest that the OA- induced contraction of the rat uterine smooth muscle is partly effecte d by transmembrane calcium movements which can be inhibited in an O-Ca 2+-10(-3) M EGTA solution or by theophylline or caffeine. This contrac tion also involves mobilization of Ca2+ from an intracellular pool whi ch is also xanthine-sensitive. The latter effect seems to be important in inducing the contractile effect. This study does not exclude the p ossibility of other mechanisms being involved in the contraction induc ed by OA.