Effect of κ-opioid receptor agonist U50488H on ventricular arrhythmias induced by ET-1 in rats

AIM: To investigate the effect of κ-opioid receptor agonist U50488H on arrhythmia induced by endothelin-1(ET-1) and the underlying mechanism.METHODS: Rats were randomly divided into seven groups(six rats in each group): control group,U50488H group,U50488H+nor-BNI(a selective κ-opioid receptor antagonist) group,nor-BNI group,ET-1 group,ET-1+U50488H group and ET-1+U50488H+nor-BNI group.Heart rate(HR),arterial blood pressure(ABP),left ventricular pressure(LVP),systolic function(+LVdp/dtmax) and diastolic function(-LVdp/dtmax) were examined.Arrhythmia score and mortality were determined and expressions of ET-1,ET-1 recepter(ETRA),and c-Src protein tyrosine kinase were assessed.RESULTS: U50488H significantly attenuated the increase in ABP,LVP and ±LVdp/dtmax and reduced the incidence of ventricular arrhythmias and animal mortality induced by ET-1(P<0.01).U50488H also downregulated myocardial ET-1 mRNA(P<0.01) and c-Src protein tyrosine kinase expressions(P<0.05).In addition,ET-1 stimulated phosphorylation of c-Src protein tyrosine kinase,which was reversed by U50488H(P<0.05).The effect of U50488H was abolished by nor-BNI,a selective κ-opioid receptor antagonist.CONCLUSION: κ-opioid receptor agonist U50488H reduces ET-1 induced arrhythmia.Effects may be related to the inhibition of the expression of ET-1 and its downstream molecule c-Src protein tyrosine kinase.