A Dopamine D 1/5 Receptor Antagonist, SCH23390, Prevents Stress-Induced Sudden Death in Cardiomyopathic Hamsters

Abstract

Stress is known to have an impact on the development of life-threatening cardiovascular dysfunction. We have previously demonstrated that repeated exposure to cold-immobilization stress had lethal effects on cardiomyopathic Syrian hamsters (BIO 14.6), and that stress-induced sudden death was prevented by daily treatment with propranolol, suggesting an important role of sympathetic nerves in the etiology of stress-induced cardiac sudden death. In an attempt to clarify further the mechanisms of the sudden death, in the present study we investigated the effects of D 1/5 receptor blockade by SCH23390 on the sudden death of cardiomyopathic hamsters. In accordance with our previous results, repeated exposure for 5 days to cold-immobilization stress induced a lethal effect in the cardiomyopathic hamsters but not in control healthy hamsters. SCH23390 (0.1–10 mg/kg, IP), administered just before the exposure for 5 consecutive days, dose-dependently and significantly prevented the lethal effects of the stress. Furthermore, it was demonstrated that the drug significantly reduced the increase in the weights of the adrenal and kidneys observed in the stressed-cardiomyopathic hamsters. On the other hand, specific D 2 antagonist haloperidol (0.1–10 mg/kg) failed to prevent the stress-induced sudden death and minimally affected the increase in organ weights. Correctively, these results suggest that D 1/5 receptors had an important role in the etiology of stress-induced cardiac sudden death of the cardiomyopathic hamsters, and provide the first experimental evidence of the potential therapeutic values of D 1/5 antagonists against cardiac sudden death associated with stress.