Attenuated [Ca2+]i and [pH]i responses to kappa-opioid receptor stimulation in the heart of rats subjected to chronic hypoxia

Abstract

In the present study WC determined the [Ca2+]i and [PH]i responses to k-opioid receptor stimulation in the hypertrophied right heart induced by chronic hypoxia. U50,488H, a selective k-opioid receptor agonist, at IO - 30 µM, dose-dependently decreased the electrically-induced [CA2+]i transient. 20 µM U50,488H also increased the [pH]i. The effects of the k-opioid receptor agonist at 20 µM were completely abolished by 5 µM nor-binaltorphimine (nor-BNI), a selective K-opioid receptor antagonist and I µM calphostin C, a specific inhibitor of protein kinase C (PKC). We further investigated the [Ca2+]i and [pH]i responses to activation of PKC, known to mediate the actions of k-opioid receptor stimulation. PMA, an activator of PKC, at 0.01 - 1 µM also dose-dependently decreased the electrically-induced [Ca2+]i transient and at 0. 1 µM it increased the [pH]i. The effects of 0.1 µM PMA were abolished by 1 µM calphostin C. The effect of 0.1 µM PMA on [pH]i was also blocked by EIPA, a potent Na+-H+ exchange (NHE) blocker. In the right hypertrophied heart of rat subjected to hypoxia for 4 weeks, the effects of U50,488H and PMA on [Ca2+]i transient and [pH]i were significantly attenuated and completely abolished, respectively. The responses to The results demonstrated for the first time that the [Ca2+]i transient and [pH]i responses to k-opioid receptor stimulation were impaired in the heart of rats subjected to chronic hypoxia, which may be due to impaired PKC functions. (Supported by a grant from the Institute of Cardiovascular Science and Medicine)