Impaired [Ca2+](i) and pH(i) responses to kappa-opioid receptor stimulation in the heart of chronically hypoxic rats

kappa-Opioid receptor (kappa-OR) stimulation with U50,488H, a selective kap pa-OR agonist, or activation of protein kinase C (PKC) with 4-phorbol 12-my ristate 13-acetate (PMA), an activator of PKC, decreased the electrically i nduced intracellular Ca2+ ([Ca2+](i)) transient and increased the intracell ular pH (pH(i)) in single ventricular myocytes of rats subjected to 10% oxy gen for 4 wk. The effects of U50,488H were abolished by nor-binaltorphimine , a selective kappa-OR antagonist, and calphostin C, a specific inhibitor o f PKC, while the effects of PMA were abolished by calphostin C and ethyliso propylamiloride (EIPA), a potent Na+/H+ exchange blocker. In both right hyp ertrophied and left nonhypertrophied ventricles of chronically hypoxic rats , the effects of U50,488H or PMA on [Ca2+](i) transient and pHi were signif icantly attenuated and completely abolished, respectively. Results are firs t evidence that the [Ca2+](i) and pH(i) responses to kappa-OR stimulation a re attenuated in the chronically hypoxic rat heart, which may be due to red uced responses to PKC activation. Responses to all treatments were the same for right and left ventricles, indicating that the functional impairment i s independent of hypertrophy. kappa-OR mRNA expression was the same in righ t and left ventricles of both normoxic and hypoxic rats, indicating no regi onal specificity.