[Biological rhythms, chronotherapy and nitrates]

Abstract

Mammalian biological functions are organized according to circadian rhythms (lasting about 24 hours). They are coordinated by a biological clock situated in the suprachiasmatic nuclei (SCN) of the hypothalamus. These rhythms persist under constant environmental conditions, demonstrating their endogenous nature. Several genes of the circadian rhythm have been cloned in N. Crassa, Drosophilus and Mice, allowing molecular analysis of circadian functioning. Some rhythms can be altered by disease and drug pharmacology can be influenced by the time of their administration during the day (chronopharmacology). The rhythms of disease and pharmacology can be taken into account to modulate treatment over the 24-hour period (chronotherapy). The knowledge of such rhythms appears particularly relevant for the understanding and/or treatment of hypertension and ischaemic coronary artery disease. In rats and in man, the circadian rhythm of systolic or diastolic blood pressure can be dissociated from the rest-activity cycle, suggesting that it is controlled by an oscillator which can function independently of the SCN, which could justify modification of treatment according to the anomalies of the blood pressure rhythm. The morning peak of myocardial infarction in man is due to the convergence of several risk factors, each of which has a 24-hour cycle: blood coagulability blood, BP, oxygen requirements and myocardial susceptibility to ischaemia. The existence of these rhythms, and the chronopharmacology of cardiovascular drugs such as nitrate derivatives, constitute clinical prerequisites for the chronotherapy of heart disease.