Impaired [Ca2+]i and pHiresponses to κ-opioid receptor stimulation in the heart of chronically hypoxic rats

Abstract

κ-Opioid receptor (κ-OR) stimulation with U50,488H, a selective κ-OR agonist, or activation of protein kinase C (PKC) with 4-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, decreased the electrically induced intracellular Ca2+ ([Ca2+]i) transient and increased the intracellular pH (pHi) in single ventricular myocytes of rats subjected to 10% oxygen for 4 wk. The effects of U50,488H were abolished by nor-binaltorphimine, a selective κ-OR antagonist, and calphostin C, a specific inhibitor of PKC, while the effects of PMA were abolished by calphostin C and ethylisopropylamiloride (EIPA), a potent Na+/H+exchange blocker. In both right hypertrophied and left nonhypertrophied ventricles of chronically hypoxic rats, the effects of U50,488H or PMA on [Ca2+]i transient and pHi were significantly attenuated and completely abolished, respectively. Results are first evidence that the [Ca2+]i and pHi responses to κ-OR stimulation are attenuated in the chronically hypoxic rat heart, which may be due to reduced responses to PKC activation. Responses to all treatments were the same for right and left ventricles, indicating that the functional impairment is independent of hypertrophy. κ-OR mRNA expression was the same in right and left ventricles of both normoxic and hypoxic rats, indicating no regional specificity.