THE EFFECT OF CAFFEINE ON PROSTAGLANDIN OUTPUT FROM THE GUINEA-PIG UTERUS

1 Caffeine increased the outputs of prostaglandin F-2 alpha, (PGF(2 al pha), PGE(2) and 6-keto-PGF(1 alpha), from the guinea-pig uterus on da ys 7 and 15 of the oestrous cycle. The effect on PGE(2) output depende d on the: age of the animals and was absent in younger guinea-pigs (<4 months). Theophylline also stimulated the outputs of PGF, and 6-keto- PGF(1 alpha), but not the output of PGE(2), from the day 7 guinea-pig uterus. 2 The stimulatory effects of caffeine on the outputs of PGF(2 alpha), PGE(2) and 6-keto-PGF(1 alpha), from the guinea-pig uterus wer e not prevented by lack of extracellular calcium, ryanodine or rutheni um red (both inhibitors of calcium release via the ryanodine receptor) , although the increase in PGF(2 alpha) output tended to be slower whe n extracellular calcium was absent. Also, ryanodine flattened and broa dened the peak of increased PGF(2 alpha), release. 3 The calmodulin an tagonists, W-7 and trifluoperazine, had no inhibitory effect on the ca ffeine-stimulated increases in uterine prostaglandin output. In fact, W-7 (but not trifluoperazine) greatly potentiated the action of caffei ne on uterine PGF(2 alpha), output, but had little or no potentiating effect on the action of caffeine on uterine PGE(2) and 6-keto-PGF(1 al pha) outputs. 4 TMB-8, an intracellular calcium antagonist, inhibited the increase in PGF(2), output produced by caffeine without preventing the increases in outputs of PGE(2) and 6-keto-PGF(1 alpha). 5 These s tudies suggest that caffeine stimulates uterine PGF(2 alpha) synthesis and release by a mechanism dependent upon intracellular calcium, but this mechanism is not mediated by activation of any of the three well- characterized ryanodine receptors or by calmodulin. Furthermore, the i ncreases in the synthesis and release of PGE(2) and 6-keto-PGF(1 alpha ) in the guinea-pig uterus induced by caffeine appear to involve mecha nism(s) different from that which stimulates PGF(2 alpha), production.