At 0.1-1 microM, U50488H, a kappa-opioid receptor agonist, inhibited the stimulatory effects of 1 microM isoprenaline, a beta-adrenoceptor agonist, on the electrically induced intracellular Ca2+ ([Ca2+](i)) transient and cAMP accumulation ("cross talk" between kappa-opioid receptors and beta-adrenoceptors) in the presence of 1 microM ICI118,551, a beta(2)-adrenoceptor antagonist in ventricular myocytes from both normoxic and chronically hypoxic rats. Pretreatment with 20 microg/ml cholera toxin increased the ADP-ribosylation of Gsalpha subunits and the electrically induced [Ca2+](i) transient in both normoxic and chronically hypoxic rats. The effects of cholera toxin were inhibited by 1 microM U50488H and the inhibitory effect of U50488H was attenuated in chronically hypoxic rats. Similarly, 1 microM forskolin also increased the electrically induced [Ca2+](i) transient and cAMP accumulation, which were both inhibited by U50488H, in both normoxic and chronically hypoxic rats. The inhibitory effects of 1 microM U50488H were significantly attenuated in chronically hypoxic rats. The results are novel findings, in that the "cross talk" between kappa-opioid receptors and beta-adrenoceptors is attenuated following chronic hypoxia. The attenuation may be due to decreased responses of Gs-protein and adenylyl cyclase to kappa-opioid receptor activation in addition to desensitization of the receptor itself.