BRADYKININ IS A POTENT AND RELATIVELY SELECTIVE STIMULUS FOR CYTOSOLIC CALCIUM ELEVATION IN HUMAN SYNOVIAL-CELLS

Previously, we have shown that bradykinin elicits the production of pr ostaglandin E(2) (PGE(2)) in human synovial cells only after pre-expos ure of the cells to IL-1. The observation that calcium ionophores, but not a variety of physiologic receptor-mediated agonists, can mimic br adykinin in its synergy with IL-1 led us to hypothesize that the abili ty of bradykinin to induce prostanoid synthesis was a result of its se lective ability (among physiologic agonists) to raise the cytosolic fr ee ionized calcium concentration ([Ca2+](i)) levels of synovial cells. Extending this hypothesis, it follows that the relative potency of an agonist in inducing PGE(2) production from IL-1-treated cells should be dependent on its ability to raise [Ca2+](i). In these studies, we h ave 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 hi gh affinity B-2 kinin receptor. Furthermore, the relative specificity and potency of the PGE(2) 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, n or did it alter agonist-induced elevations in [Ca2+](i). We conclude t hat 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-genera ting enzyme is also required.