κ-Opioid receptor stimulation increases the expression of NA+-H+ exchange gene in the heart

Abstract

κ-opioid receptor (OR) stimulation increases intracellular pH (pHi) via activating the Na+-H+ exchange (NHE). In the present study, we determined the expression of the gene of NHE 1, the predominant NHE isoform in the heart, and intracellular pH (pHi) upon κ-OR stimulation in the rat heart. We found that 1μM U50,488H (trans-3,4-dichloro-N-methyl-N-(2-(1 pyrrolidinyl)cyclohexyl)benzeneacetamide), a selective κ-OR agonist, increased the expression of the NHE 1 gene. We also found that U50,488H dose-dependently increased pHi in the heart. The effects were abolished by 1 μM nor-binaltorphimine (nor-BNI), a selective κ-OR antagonist, indicating that the events were κ-OR mediated. The effects on both NHE 1 gene expression and pHi were also abolished by 5 μM chelerythrine and 5 μM BSM (bisyndolylmaleimide), protein kinase C (PKC) inhibitors, indicating that PKC mediated the actions. In addition, the effect of U50,488H on pHi was blocked by 10 μM EIPA (ethylisopropyl amiloride), a NHE 1 inhibitor, indicating that NHE 1 also mediated the action of U50,488H. The present study provides evidence for the first time that κ-OR stimulation increased the NHE 1 gene expression in the heart via a PKC dependent pathway. κ-OR stimulation also increases pHi via PKC and NHE in the heart.