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Left ventricular hypertrophy (LVH), a common sequella of hypertension, is associated with increased incidence of sudden cardiac death. The study reported herein measured the effect of melatonin on the heart in the setting of direct cardiac myocyte stimulation with isoproterenol, thus minimizing the role of autonomic output from the suprachiasmatic nucleus (SCN) and clarifying the effect of melatonin on LVH, an outcome of chromic hypertensions. Results show that daily injections of high dosages of melatonin do not affect heart weight:body weight or heart weight:tibia length ratios in the setting of isoproterenol-induced hypertrophy, suggesting that the cardiovascular effects of melatonin observed by others are not due primarily to a direct effect of melatonin on cardiac myocytes but to another mechanism, possibly melatonin modulation of SCN output. Melatonin has no effect on isoproterenol-induced LVH, suggesting that its cardiovascular effects are not due to a direct effect on cardiac myocytes. Melatonin has been found to have a significant effect on hypertension; however, in this study, one effect of extended hypertension, cardiac hypertrophy, which can ultimately lead to cardiac failure, was not affected, even by very large doses of melatonin in a chemically induced hypertrophy mouse model. It has been suggested that the effect of melatonin on hypertension is comparable to common antihypertensive agents.