Attenuated "cross talk" between κ-opioid receptors and β-adrenoceptors in the heart of chronically hypoxic rats

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