Previously, we have shown that bradykinin elicits the production of prostaglandin E2 (PGE2) in human synovial cells only after pre-exposure of the cells to IL-1. The observation that calcium ionophores, but not a variety of physiologic receptor-mediated agonists, can mimic bradykinin in its synergy with IL-1 led us to hypothesize that the ability of bradykinin to induce prostanoid synthesis was a result of its selective ability (among physiologic agonists) to raise the cytosolic free ionized calcium concentration ([Ca2+]i) levels of synovial cells. Extending this hypothesis, it follows that the relative potency of an agonist in inducing PGE2 production from IL-1-treated cells should be dependent on its ability to raise [Ca2+]i. In these studies, we have confirmed the potent ability of bradykinin to elevate [Ca2+]i in resting human synovial cells. That the effect of bradykinin on [Ca2+]i was mediated through the previously described synovial cell kinin receptor was confirmed by a pharmacologic profile consistent with a high affinity B2 kinin receptor. Furthermore, the relative specificity and potency of the PGE2 response of bradykinin in IL-1-treated cells was paralleled, in resting cells, by a similar pattern in the [Ca2+]i response. Finally, IL-1 had no direct effect on [Ca2+]i levels, nor did it alter agonist-induced elevations in [Ca2+]i. We conclude that the potency of a receptor-mediated agonist in inducing prostanoid synthesis in synovial cells is dependent on its ability to raise [Ca2+]i. However, this effect is not enough, in and of itself, to induce prostanoid synthesis; the concomitant induction by IL-1 of a PG-generating enzyme is also required.