Impact Of Dopamine Agonist Administration On Myocardial Ischemic Injury In Mice

Objective: Rotigotine and ropinirole are non-ergot dopamine receptor agonists that can improve motor function in PD patients.Rotigotine extended-release microsphere(Ro MS)is an extended-release intramuscular formulation that exhibits sustained release of rotigotine compared to common dosage forms,and has been carried out clinical trials in USA and China.It has been reported there were cases of myocardial ischemia caused by ergot dopamine receptor agonists in the process of treating PD.The purpose of the study is to observe the effects of non-ergoline dopamine receptor agonists therapy on myocardial ischemic injury in mice,to know whether ropinirole,rotigotine,Ro MS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with these drugs.Methods: A mouse model of myocardial ischemia was established using isoproterenol.The mice were pretreated with ropinirole,rotigotine,Ro MS before inducing myocardial ischemic injury,to mimic the situation in clinical practice.The effects of non-ergoline dopamine receptor agonists on the degree of myocardial ischemic injury were studied by evaluating troponin I(c TNI)levels,creatine kinase-MB(CK-MB)activity,and histopathological changes in cardiomyocytes.The dopamine receptor blocker haloperidol or chlorpromazine was used to further investigate the effects of ropinirole,rotigotine,Ro MS on myocardial ischemic injury.Furthermore,serum ropinirole and rotigotine concentrations were also assayed.Results: The results showed that concentrations of ropinirole in plasma peaked at 2 h after administration.At 12 h,ropinirole was eliminated from blood.Pre-treatment with ropinirole could attenuate the myocardial necrosis,the vacuolar degeneration,the edema and the inflammatory cells infiltration accompanied with reduced troponin I level and CK-MB activity.The dopamine receptor antagonist haloperidol may diminish the cardioprotective effect of ropinirole administration.While myocardial ischemia occurred during rotigotine or Ro MS administration,troponin I levels and CK-MB activity were decreased,and ischemia-induced histopathological changes in cardiomyocytes were alleviated.The effects of rotigotine were maintained only 12 h and after that no protective effect was observed.Ro MS releases slowly and continuously into the circulation following intramuscular injection.The effects of Ro MS were maintained 14 d after a single Ro MS administration.These results of alleviating myocardial damage were basically consistent with the blood concentration of rotigotine and Ro MS.When combined with chlorpromazine,the protective effects of rotigotine on myocardial ischemic injury were eliminated,and the protective effects of Ro MS were also partially abolished.Conclusion: In an animal model of myocardial ischemia,pretreatment with ropinirole,rotigotine,or Ro MS did not deteriorate,but could alleviate cardiomyocyte injury.Furthermore,Ro MS pretreatment showed long-term and continuous protective effects on cardiomyocyte injury if myocardial ischemia occured.Innovation: The present study demonstrated that non-ergoline dopamine receptor agonists in the treatment of Parkinson's disease,could reduce cardiomyocyte injury if myocardial ischemia occurs.Ropinirole,rotigotine,Ro MS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.