The effect of caffeine on prostaglandin output from the guinea-pig uterus.

1. Caffeine increased the outputs of prostaglandin F2 alpha (PGF2 alpha), PGE2 and 6-keto-PGF1 alpha from the guinea-pig uterus on days 7 and 15 of the oestrous cycle. The effect on PGE2 output depended on the age of the animals and was absent in younger guinea-pigs (< 4 months). Theophylline also stimulated the outputs of PGF2 alpha and 6-keto-PGF1 alpha, but not the output of PGE2, from the day 7 guinea-pig uterus. 2. The stimulatory effects of caffeine on the outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha from the guinea-pig uterus were not prevented by lack of extracellular calcium, ryanodine or ruthenium red (both inhibitors of calcium release via the ryanodine receptor), although the increase in PGF2 alpha output tended to be slower when extracellular calcium was absent. Also, ryanodine flattened and broadened the peak of increased PGF2 alpha release. 3. The calmodulin antagonists, W-7 and trifluoperazine, had no inhibitory effect on the caffeine-stimulated increases in uterine prostaglandin output. In fact, W-7 (but not trifluoperazine) greatly potentiated the action of caffeine on uterine PGF2 alpha output, but had little or no potentiating effect on the action of caffeine on uterine PGE2 and 6-keto-PGF1 alpha outputs. 4. TMB-8, an intracellular calcium antagonist, inhibited the increase in PGF2 alpha output produced by caffeine without preventing the increases in outputs of PGE2 and 6-keto-PGF1 alpha. 5. These studies suggest that caffeine stimulates uterine PGF2 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 increases in the synthesis and release of PGE2 and 6-keto-PGFI alpha. in the guinea-pig uterus induced by caffeine appear to involve mechanism(s) different from that which stimulates PGF2 alpha production.