Lymphocytes sensitize rat isolated atria to the inotropic and chronotropic effects of sodium arachidonate.

Abstract

Normal human lymphocytes (4 X 10(5) ml-1) incubated with sodium arachidonate (8 X 10(-7)M) (NaA-L) induced a strong enhancement of the tension and frequency of spontaneously beating rat atria. Normal human lymphocytes (L) or NaA alone at 8 X 10(-7)M did not modify this contractile activity. Between 2 X 10(-6)M to 1 X 10(-5)M NaA alone increased the tension of the atria without effect on the rate. In the presence of L (4 X 10(5) ml-1) the dose-response curve to NaA shifted to the left, the potency and the efficiency of NaA were enhanced and the chronotropic action was triggered. Inhibitors of cyclo-oxygenase (indomethacin 1 X 10(-6)M or acetylsalicylic acid (ASA) 1.8 X 10(-4)M) completely blocked the positive inotropic effect induced by NaA alone. Inhibitors of lipoxygenase/s (nordihydroguaiaretic acid (NDGA) 1 X 10(-5)M or 5,8,11,14-eicosatetraynoic acid (ETYA) 1 X 10(-7)M did not modify this effect. Indomethacin and ASA did not block the positive inotropic and chronotropic effects of the lower concentration of NaA-L and significantly reduced the inotropic effect of the higher ones. NDGA and ETYA shifted to the right the inotropic and chronotropic dose-response curve to NaA-L. FPL-55712 (1 X 10(-7)M), the slow reacting substance of anaphylaxis (SRS-A) antagonist, significantly reduced the overall inotropic and chronotropic effect of NaA-L. Direct contact of NaA-L with the atria was not necessary. Cell-free supernatants of L exposed to NaA increased the tension and the frequency of beating rat atria. 7 The stimulatory effect of NaA-L supernatants did not occur if rat atria had been previously incubated with NDGA 1 x 10-5 M. On the other hand, the generation of stimulatory products from NaA-L was not prevented by preincubating L with 1 x 10-5 M NDGA. Hence SRS-A and/or other oxidative metabolites of arachidonic acid were produced by the atria. 8 These results suggest that NaA-L react in vitro with spontaneous beating rat atria, inducing inotropic and chronotropic effects. Moreover, the stimulatory action of NaA itself was potentiated by L. These reactions involved a balance between cyclo-oxygenase and lipoxygenase oxidative products with a central role for SRS-A.