Ionophores stimulate prostaglandin and thromboxane biosynthesis

Abstract

The role of Ca in triggering PG and thromboxane synthesis was studied in several systems with ionophores of different ion specificities. Divalent cationophore A23187 [2-[(3.beta.,9.alpha.,11.beta.-trimethyl)-8-(2-pyrrolecarboxymethyl)-1,7-dioxaspiro[6.6]undecyl-2.beta.-methyl]-5-methylamino-benzoxazole-4-carboxylic-acid] stimulates PG and thromboxane production by washed human platelets in a concentration-dependent manner (0.3-9 .mu.M). A23187 also induces an antimycin A-insensitive burst in oxygen utilization which is partially blocked by 5 mM aspirin or 10 .mu.M indomethacin. Under these conditions, A23187 (up to 10 .mu.M) does not appear to damage platelet membranes since it does not cause appreciable loss of lactate dehydrogenase or .beta.-glucuronidase. Mono- and divalent cationophore X537A [lasalocid] stimulates platelet thromboxane B2 production and oxygen utilization, but monovalent cationophores nigericin, monensin A, A204 and valinomycin have no effect. Synthesis of PG E2, D2 and F2.alpha. by rat renal medulla mince is stimulated by 1 and 5 .mu.M A23187 without changes in tissue ATP content, lactate output or K+ efflux. X537A, monensin A and nigericin (all 5 .mu.M) stimulate PG output and K+ efflux from renal medulla, while 5 .mu.M valinomycin or A204 has no effect on either. None of the ionophores stimulates renomedullary PG production if Ca is omitted from the incubation medium. A23187 stimulates PG production by human lymphoma cells, rat stomach and trachea preparations and guinea pig polymorphonuclear leukocytes. A major role for Ca2+ in stimulating PG and thromboxane biosynthesis is suggested, and PG and/or thromboxane release may partially mediate some previously described effects of ionophores on cells and tissues.