Effect of indomethacin on cyclic AMP phosphodiesterase activity in myometrium from pregnant rhesus monkeys

Our results indicate that indomethacin inhibits cyclic AMP phosphodiesterase in the myometrium of the pregnant rhesus monkey under in vitro as well as in vivo conditions. Kinetic data on extracts of myometrium from pregnant rhesus monkeys indicated two cyclic AMP phosphodiesterase activities. The apparent K_m value for the high affinity enzyme averaged 3.9 μM and for the low affinity enzyme 23 μM; the V_max values averaged 0.56 and 1.4 nmoles cyclic AMP hydrolized per mg protein min^?1 respectively. When indomethacin was added to the myometrial extracts, the activity of the high K_m phosphodiesterase was competitively inhibited, with an average K_i of 200 μM; the low K_m enzyme was noncompetitively inhibited with an average K_i of 110 μM. Experiments on myometrial slices demonstrated that 10 μM indomethacin potentiated the effect of PGE₁ and epinephrine on cyclic AMP levels, presumably by inhibiting the phosphodiesterase activity. The uterine relaxing effect of indomethacin is generally attributed to the inhibition of prostaglandin synthetase activity. However, treatment of pregnant rhesus monkeys with therapeutic doses of indomethacin resulted in a significant inhibition of myometrial cyclic AMP phosphodiesterase activity in association with uterine relaxation and prolongation of gestation.