vored those species that are able to anticipate the con- comitant rhythmic environmental changes, which in mammals has led to the development of a specialized brain region dedicated to this function, the ‘biological clock’, located in the suprachiasmatic nucleus in the hy- pothalamus (SCN). The heart is the driving force for the delivery of oxygen and nutrients, for the disposal of waste and for the distribution of heat. These circulatory demands change greatly over the day and night, and the ability to anticipate these changing demands would obvi- ously be very beneficial to the survival of the individual. The number of cardiovascular incidents follows a daily rhythm with maximum risk in the early morning, which cannot be totally explained by a daily rhythm in exoge- nous factors such as activity and body position. Rather, this could be attributed to circadian changes in blood pressure, vascular tone, catecholamines, platelet aggre- gation and heart rate (HR) (Kranz et al., 1996). Recent findings suggest a compromised cardiovascular antici- pation to the activity period in patients with essential hy- pertension, possibly leading to increased risk of cardio- vascular incidents in the early morning (Muller et al., 1989; Goncharuk et al., 2001, 2002; Stergiou et al., 2002). In this review we discuss the neural and neuroendocrine mechanism by which the SCN could control the cardio- vascular system, to allow such anticipation to oncoming demands. Two properties of the SCN were used to deter- mine the role of the biological clock in cardiovascular regulation. Firstly, the ability of the SCN to generate an endogenous circadian rhythm in cardiovascular activity was studied. This was possible by recording the heart rate under conditions that exclude the effect of ‘masking’ factors such as behavioral activity and light. Secondly, stimulation of the biological clock was used as a tool to investigate the influence of the SCN on the cardiovascu- lar system. Two stimuli were applied: light as the day sig- nal and melatonin as the night signal for the biological clock. For light exposure, our central hypothesis was: nocturnal light induces day-time physiology and behav- ior via the SCN, both in nocturnal and diurnal species. These experimental findings will be discussed in relation with the preliminary findings of a blood pressure reduc- tion after repeated nightly melatonin treatment in patients with essential hypertension. Finally, we will discuss the requirement for regional differentiation in the output of the SCN via the autonomous nervous system to explain the diversity of expression profiles of circadian rhythms. Biol. Chem., Vol. 384, pp. 697 – 709, May 2003 · Copyright © by Walter de Gruyter · Berlin · New York Frank A.J.L. Scheer*, Andries Kalsbeek and Ruud M. Buijs Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Brain Research, NL-1105Amsterdam AZ, The Netherlands *Corresponding author The risk for cardiovascular incidents is highest in the early morning, which seems partially due to endoge- nous factors. Endogenous circadian rhythms in mammalian physiology and behavior are regulated by the suprachiasmatic nucleus (SCN). Recently, ana- tomical evidence has been provided that SCN func- tioning is disturbed in patients with essential hyper- tension. Here we review neural and neuroendocrine mechanisms by which the SCN regulates the cardio- vascular system. First, we discuss evidence for an endogenous circadian rhythm in cardiac activity, both in humans and rats, which is abolished after SCN le- sioning in rats. The immediate impact of retinal light exposure at night on SCN-output to the cardiovascu- lar system, which signals ‘day’ in both diurnal (hu- man) and nocturnal (rat) mammals with opposite ef- fects on physiology, is discussed. Furthermore, we discuss the impact of melatonin treatment on the SCN and its potential medical relevance in patients with essential hypertension. Finally, we argue that re- gional differentiation of the SCN and autonomous nervous system is required to explain the multitude of circadian rhythms. Insights into the mechanisms by which the SCN affects the cardiovascular system may provide new strategies for the treatment of dis- ease conditions known to coincide with circadian rhythm disturbances, as is presented for essential hy- pertension. Key words: Autonomous nervous system / Biological clock / Circadian / Hormones / Light. Introduction From the beginning, life on earth has been exposed to sunlight in a daily rhythm as determined by the earth’s rotation, which has dictated the life of all organisms. Through millions of years, evolutionary pressure has fa- Review Cardiovascular Control by the Suprachiasmatic Nucleus: Neural and Neuroendocrine Mechanisms in Human and Rat