Cytokines play significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In this study, we examined the effects and possible mechanisms of interleukin-2 (IL-2) on contraction and the [Ca2+]i transient of enzymatically isolated ventricular myocytes with spectrofluorometry and video tracking. IL-2 (2.5-200 U/ml) depressed both the contraction and the [Ca2+]i transient in a dose-dependent manner. Pretreatment with the universal opioid receptor antagonist naloxone (10 nM), or a specific kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI, 10 nM), abolished the inhibitory effect of IL-2 on contraction and the [Ca2+]i transient; the specific delta-opioid receptor antagonist naltrindole (1 microM) had no effect. The effect of IL-2 was also abolished after pretreatment with pertussis toxin (PTX, 5 mg/l), but not by genistein (100 microM). Pretreatment with the phospholipase C inhibitor U73122 (5 microM) significantly inhibited the IL-2-induced depression of contraction and the [Ca2+]i transient. It is concluded that the effects of IL-2 on contraction and the [Ca2+]i transient of ventricular myocytes are mediated via the cardiac kappa opioid receptor, and the postreceptor signal transduction pathway includes a PTX-sensitive G protein and phospholipase C.