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Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.

Lipopolysaccharide (LPS) is known to stimulate the synthesis and secretion of various proinflammatory cytokines in both the peripheral immune cells and the brain. Yet, the relative contribution of peripheral and central cytokines to the LPS-induced activation of the hypothalamo-pituitary-adrenal axis is still poorly understood. In this study, utilizing the push-pull perfusion technique of the rat brain, we attempted to characterize in detail the temporal profiles of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha after intravenous (i.v.) or intraperitoneal (i.p.) administration of LPS in both the general circulation and the hypothalamic paraventricular nucleus (PVN), which is the primary source of corticotropin releasing hormone (CRH). Temporal changes in plasma adrenocorticotropic hormone (ACTH) and CRH levels in the PVN were also monitored. We collected blood and perfusates every 30 min from 11:00 to 17:00 h. At 12:00 h, 1.0 or 2.5 mg/kg body weight of LPS was given via an i.v. or i.p. route, respectively. Peak ACTH response occurred 30 min after i.v. LPS and 1.5 h after ip LPS. Of the three cytokines measured in the plasma, TNF-alpha showed the fastest rise in synchrony with peak ACTH secretion after both i.v. and i.p. LPS. Although plasma IL-6 also showed a robust rise, its peak level occurred later than the ACTH peak. Elevation of plasma IL-1beta was the smallest among the three cytokines. CRH levels in the PVN reached their peaks 1 and 2.5 h after the ACTH peak following i.p. and i.v. LPS, respectively. Irrespective of the route of LPS administration, IL-6 and TNF-alpha levels in the PVN showed significant rises 1-2 h after the ACTH peak, but IL-1beta in the PVN did not significantly change during the entire period of observation. The results of the present study suggest that circulating TNF-alpha may play the most important role in triggering the early, peak phase of ACTH secretion after both i.v. and i.p. LPS. Although it is possible that brain TNF-alpha, IL-6, and circulating IL-6, may be involved in the later, protracted phase of ACTH secretion induced by LPS, IL-1beta in both the brain and peripheral circulation seems to play the smallest role in ACTH secretion. This is the first study to characterize the LPS-induced temporal changes in IL-1beta, IL-6, and TNF-alpha in both plasma and PVN simultaneously in conscious, freely moving rats.