NITRIC OXIDE-MEDIATED EFFECTS OF INTERLEUKIN-6 ON [CA2+](I) AND CELL CONTRACTION IN CULTURED CHICK VENTRICULAR MYOCYTES

Cytokines have significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In th e present study, we examined both the early and delayed effects of int erleukin-6 (IL-6) on cultured chick embryo ventricular myocytes. Expos ure of these cells to human recombinant IL-6 significantly decreased p eak systolic [Ca2+](i) (71.0+/-0.6% of the control value) and the ampl itude of cell contraction (66.0+/-7.4% of the control value) within a few minutes. Pretreatment with N-G-monomethyl-L-arginine (L-NMMA) or m ethylene blue completely inhibited the IL-6-induced early changes. Sub sequent addition of L-arginine reversed the effects of L-NMMA. The lev els of cGMP were significantly increased after 30 minutes of exposure to IL-6 (134.4+/-9.1% of the control value). Pretreatment with L-NMMA or EGTA significantly inhibited the IL-6-induced early elevation of cG MP. These results suggest that IL-6 acutely decreases intracellular Ca 2+ transients and depresses cell contraction by nitric oxide (NO)-cGMP -mediated pathway. Therefore, IL-6 may enhance the Ca2+-dependent cons titutive NO synthase activity in cardiac myocytes. On the other hand, 24-hour exposure to IL-6 also increased the levels of cGMP (159.0+/-22 .8% of the control value) regardless of pretreatment with EGTA. These delayed increases in cGMP were also shown to be coupled with decreases in intracellular Ca2+ transients and the amplitude of cell contractio n. Thus, IL-6 may induce Ca2+-independent NO synthase in cardiac myocy tes. Together with the previous reports that have suggested the possib le roles of IL-6 in myocardial stunning or endotoxic shock, this negat ive inotropic effect of IL-6 may contribute to these clinical settings .