Adverse Effects of Circadian Disorganization on Mood and Molecular Rhythms in the Prefrontal Cortex of Mice.

Disturbance of the daily cycles in sleep and wakefulness induced by conditions such as shift work and jet lag can increase the risk of affective disorders including anxiety and depression. The way such circadian disorganization disrupts the regulation of mood, however, is not well understood. More specifically, the impact of circadian disorganization on the daily rhythms of the neuronal function that controls mood remains unclear. We therefore investigated the effects of circadian disorganization on expression rhythms of clock genes as well as immediate early genes (IEGs) in several mood-controlling regions of the brain. To introduce circadian disorganization of behaviors, we exposed male C57BL/6J mice to chronic reversal of the light-dark cycle and we found a marked negative mood phenotype in these mice. Importantly, the most adverse effect of circadian disorganization on expression rhythms of clock and IEGs was observed in the prefrontal cortex (PFC) when compared to that in other mood-related areas of the brain. Dysregulation of molecular rhythms in the PFC is therefore suggested to be associated with the development of mood disorders in conditions including shift work and jet lag.

Management of Bilateral Partial Anomalous Pulmonary Venous Connection.

Bilateral partial anomalous venous connections are rare. Here, we present a patient who underwent the modified Warden procedure to reroute the superior vena cava with the partial anomalous veins to the left atrium and reconstruct the innominate vein and superior vena cava with a polytetrafluoroethylene conduit to the right atrial appendage. The procedure was successfully performed without using foreign materials in the pulmonary venous route. Furthermore, it prevented the obstruction of blood flow.

Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice.

The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart-specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals.

Evidence for a histaminergic input from the ventral tuberomammillary nucleus to the solitary tract nucleus involved in arterial pressure regulation.

The tuberomammillary nucleus (TMN) of the posterior hypothalamus has a high density of histaminergic neurons, the projection fibers of which are present in many areas of the brain, including the nucleus tractus solitarius (NTS), which controls arterial pressure (AP). In this study, we investigated whether the TMN-NTS pathway is involved in central cardiovascular regulation. Bicuculline, a gamma-aminobutyric acid type A (GABAA) receptor antagonist, was microinjected into the ventral TMN of anesthetized rats and its effects on AP and heart rate (HR) were observed. We also evaluated the effect of cetirizine, an H1 receptor antagonist, microinjected into the NTS on cardiovascular responses induced by electrical stimulation of the TMN Both AP and HR increased following bicuculline microinjection into the ventral TMN Similar pressor and tachycardic responses were observed after electrical stimulation of the ventral TMN Microinjection of cetirizine into the NTS partially inhibited the pressor response but had no effect on HR Finally, the treadmill test was associated with a high level of c-Fos expression in both ventral TMN and NTS neurons. These results suggest that the TMN-NTS pathway is involved in regulation of AP, presumably under a high-arousal phase, such as that during exercise.

Estimation of the Compatibility of Blend Composites of Resins by Measuring the Fluorescent Spectra.

The effects of adding desipramine-containing fluorescence polymer (poly(10,11-dihydro-5-[3-(N-methylamino)propyl]dibenz[b,f]azepine-2,8-diyl-alt-9,9-didodecylfluorene-2,7-diyl, PAzep-Fl) to resins were investigated. When composites were prepared by a reactive blend of poly(lactic acid) (PLA), PAzep-Fl, and diisocyanate, the molecular weight of the obtained composite was larger than that of the composite, which was blended without PAzep-Fl; this suggested that chemical bonding occured between PLA and PAzep-Fl via diisocyanate. The effects of adding PAzep-Fl in two kinds of resins/lysine triisocyanate (LTI) blend were also investigated. The addition of LTI to resins/PAzep-Fl blend composites afforded a shorter wavelength shift of the fluorescence λmax due to the release of the aggregation of PAzep-Fl by LTI. This suggested that the compatibility of two kinds of resins could be estimated by this simple method. The addition of PAzep-Fl to PLA/poly(ε-caprolactone) (PCL)/LTI blends improved the impact strength because of chemical bond formation between PAzep-Fl and the resins (PLA and PCL) via LTI.

Fate of Hancock valve in tricuspid position 36 years after implantation.

Mid- to long-term durability of bioprosthesis in tricuspid position is acceptable. However, little is known about more extended long-term structural valve changes of Hancock valve. In present report, we describe Hancock valve images 36 years after implantation.

Modified Damus-Kaye-Stansel Procedure Subsequent to Pulmonary Artery Banding.

Both the Damus-Kaye-Stansel procedure and pulmonary artery banding provide an effective palliative technique in certain subsets of patients, but this combination of procedures is potentially hazardous in pulmonary valve geometry. This is a matter of vital concern, especially in patients whose pulmonary arteries have to work after operations as the major systemic output routes. In this report, we present a novel surgical modification that builds a systemic output route without causing valve deformities.

The circadian clock maintains cardiac function by regulating mitochondrial metabolism in mice.

Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene Bmal1 results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac Bmal1 function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.

Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade.

OBJECTIVE: Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR). METHODS: We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence. RESULTS: Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan. CONCLUSION: ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.

Renal denervation prevents stroke and brain injury via attenuation of oxidative stress in hypertensive rats.

BACKGROUND: Although renal denervation (RD) is shown to reduce blood pressure significantly in patients with resistant hypertension, the benefit of RD in prevention of stroke is unknown. We hypothesized that RD can prevent the incidence of stroke and brain injury in hypertensive rats beyond blood pressure lowering. METHODS AND RESULTS: High-salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP) were divided into 4 groups: (1) control; (2) sham operation; (3) bilateral RD; and (4) hydralazine administration to examine the effect of RD on stroke and brain injury of SHRSP. RD significantly reduced the onset of neurological deficit and death in SHRSP, and this protection against stroke by RD was associated with the increase in cerebral blood flow (CBF), the suppression of blood-brain barrier disruption, the limitation of white matter (WM) lesions, and the attenuation of macrophage infiltration and activated microglia. Furthermore, RD significantly attenuated brain oxidative stress, and NADPH oxidase subunits, P67 and Rac1 in SHRSP. On the other hand, hydralazine, with similar blood pressure lowering to RD, did not significantly suppress the onset of stroke and brain injury in SHRSP. Furthermore, RD prevented cardiac remodeling and vascular endothelial impairment in SHRSP. CONCLUSIONS: Our present work provided the first experimental evidence that RD can prevent hypertensive stroke and brain injury, beyond blood pressure lowering, thereby highlighting RD as a promising therapeutic strategy for stroke as well as hypertension.

Long-term renal denervation normalizes disrupted blood pressure circadian rhythm and ameliorates cardiovascular injury in a rat model of metabolic syndrome.

BACKGROUND: Although renal denervation significantly reduces blood pressure in patients with resistant hypertension, the role of the renal nerve in hypertension with metabolic syndrome is unknown. We investigated the impact of long-term renal denervation on SHR/NDmcr-cp(+/+) (SHRcp) rats, a useful rat model of metabolic syndrome, to determine the role of the renal nerve in hypertension with metabolic syndrome. METHODS AND RESULTS: SHRcp rats were divided into (1) a renal denervation (RD) group and (2) a sham operation group (control) to examine the effects of long-term RD on blood pressure circadian rhythm, renal sodium retention-related molecules, the renin-angiotensin-aldosterone system, metabolic disorders, and organ injury. RD in SHRcp rats not only significantly reduced blood pressure but also normalized blood pressure circadian rhythm from the nondipper to the dipper type, and this improvement was associated with an increase in urinary sodium excretion and the suppression of renal Na(+)-Cl(-) cotransporter upregulation. RD significantly reduced plasma renin activity. RD significantly prevented cardiovascular remodeling and impairment of vascular endothelial function and attenuated cardiovascular oxidative stress. However, RD failed to ameliorate obesity, metabolic disorders, and renal injury and failed to reduce systemic sympathetic activity in SHRcp rats. CONCLUSIONS: By including the upregulation of the Na(+)-Cl(-) cotransporter, the renal sympathetic nerve is involved in the disruption of blood pressure circadian rhythm as well as hypertension in metabolic syndrome. Thus, RD seems to be a useful therapeutic strategy for hypertension with metabolic syndrome.

Novel mechanism for disrupted circadian blood pressure rhythm in a rat model of metabolic syndrome--the critical role of angiotensin II.

BACKGROUND: This study was performed to determine the characteristics and mechanism of hypertension in SHR/NDmcr-cp(+/+) rats (SHRcp), a new model of metabolic syndrome, with a focus on the autonomic nervous system, aldosterone, and angiotensin II. METHODS AND RESULTS: We measured arterial blood pressure (BP) in SHRcp by radiotelemetry combined with spectral analysis using a fast Fourier transformation algorithm and examined the effect of azilsartan, an AT1 receptor blocker. Compared with control Wistar-Kyoto rats (WKY) and SHR, SHRcp exhibited a nondipper-type hypertension and displayed increased urinary norepinephrine excretion and increased urinary and plasma aldosterone levels. Compared with WKY and SHR, SHRcp were characterized by an increase in the low-frequency power (LF) of systolic BP and a decrease in spontaneous baroreflex gain (sBRG), indicating autonomic dysfunction. Thus, SHRcp are regarded as a useful model of human hypertension with metabolic syndrome. Oral administration of azilsartan once daily persistently lowered BP during the light period (inactive phase) and the dark period (active phase) in SHRcp more than in WKY and SHR. Thus, angiotensin II seems to be involved in the mechanism of disrupted diurnal BP rhythm in SHRcp. Azilsartan significantly reduced urinary norepinephrine and aldosterone excretion and significantly increased urinary sodium excretion in SHRcp. Furthermore, azilsartan significantly reduced LF of systolic BP and significantly increased sBRG in SHRcp. CONCLUSIONS: These results strongly suggest that impairment of autonomic function and increased aldosterone in SHRcp mediate the effect of angiotensin II on circadian blood pressure rhythms.

Transcriptome of the NTS in exercise-trained spontaneously hypertensive rats: implications for NTS function and plasticity in regulating blood pressure.

The nucleus tractus solitarii (NTS) controls the cardiovascular system during exercise, and alteration of its function may underlie exercise-induced cardiovascular adaptation. To understand the molecular basis of the NTS's plasticity in regulating blood pressure (BP) and its potential contribution to the antihypertensive effects, we characterized the gene expression profiles at the level of the NTS after long-term daily wheel running in spontaneously hypertensive rats (SHRs). Genome-wide microarray analysis was performed to screen for differentially expressed genes in the NTS between exercise-trained (12 wk) and control SHRs. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes database revealed that daily exercise altered the expression levels of NTS genes that are functionally associated with metabolic pathways (5 genes), neuroactive ligand-receptor interactions (4 genes), cell adhesion molecules (3 genes), and cytokine-cytokine receptor interactions (3 genes). One of the genes that belonged to the neuroactive ligand-receptor interactions category was histamine receptor H(1). Since we confirmed that the pressor response induced by activation of this receptor is increased after long-term daily exercise, it is suggested that functional plasticity in the histaminergic system may mediate the facilitation of blood pressure control in response to exercise but may not be involved in the lowered basal BP level found in exercise-trained SHRs. Since abnormal inflammatory states in the NTS are known to be prohypertensive in SHRs, altered gene expression of the inflammatory molecules identified in this study may be related to the antihypertensive effects in exercise-trained SHRs, although such speculation awaits functional validation.

Outcomes of one-lung Fontan operation: a retrospective multicenter study in Japan.

BACKGROUND: The Fontan operation for patients with one available lung is an extremely challenging situation. However, few reports are available on this procedure. The purpose of this study was to describe outcomes of one-lung Fontan operation. METHODS: A retrospective multicenter study was performed. Twelve of 1,142 patients whose data were recorded here underwent one-lung Fontan operation between September 1989 and October 2009. Preoperative, operative, and postoperative data were reviewed. RESULTS: Median age at operation was 3.5 years (range, 1.0 to 22.8), the preoperative mean pulmonary pressure was 11.5±3.3 mm Hg (range, 7.0 to 18.0), the ventricular ejection fraction was 58%±13% (range, 39 to 76), and end-diastolic ventricular pressure was 7.5±3.5 mm Hg (range, 1.0 to 12.0). The available lung was right in 9 patients and left in 3 patients. Eleven patients underwent a two-staged Fontan completion. Extracardiac conduit total cavopulmonary connection, intraatrial extracardiac conduit total cavopulmonary connection, and atriopulmonary connection were performed in 10 patients, 1 patient, and 1 patient, respectively. The estimated actuarial survival was 83% at 1 year, 73% at 5 years, and 73% at 10 years. Impaired ventricular function was found to be a significant risk factor for mortality by univariate analysis (43.0%±9.5% versus 64.0%±9.5%, p<0.01), but not by multivariate analysis. CONCLUSIONS: One-lung Fontan operation can be performed with an acceptable midterm to long-term mortality rate in patients without impaired ventricular function. Thus, absence of one lung itself is not a contraindication to the Fontan operation.

Integration of metabolic and cardiovascular diurnal rhythms by circadian clock.

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.

Acute reductions in blood flow restricted to the dorsomedial medulla induce a pressor response in rats.

OBJECTIVES: The brainstem nucleus of the solitary tract (nucleus tractus solitarii, NTS) is a pivotal region for regulating the set-point of arterial pressure, the mechanisms of which are not fully understood. Based on evidence that the NTS exhibits O2-sensing mechanisms, we examined whether a localized disturbance of blood supply, resulting in hypoxia in the NTS, would lead to an acute increase in arterial pressure. METHODS: Male Wistar rats were used. Cardiovascular parameters were measured before and after specific branches of superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and would produce stagnant hypoxia. Hypoxyprobe-1, a marker for detecting cellular hypoxia in the post-mortem tissue, was used to reveal whether vessel occlusion induced hypoxia within the NTS. RESULTS: Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata including the NTS region showed an approximately 60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS as revealed using hypoxyprobe-1. Arterial pressure increased and this response was pronounced significantly in both magnitude and duration when baroreceptor reflex afferents were sectioned. CONCLUSION: These results suggest that localized hypoxia in the NTS increases arterial pressure. We suggest this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. Whether this physiological mechanism has any relevance to neurogenic hypertension is discussed.

Histamine receptor H1 in the nucleus tractus solitarii regulates arterial pressure and heart rate in rats.

Axons of histamine (HA)-containing neurons are known to project from the posterior hypothalamus to many areas of the brain, including the nucleus tractus solitarii (NTS), a central brain structure that plays an important role in regulating arterial pressure. However, the functional significance of NTS HA is still not fully established. In this study, we microinjected HA or 2-pyridylethylamine, a HA-receptor H(1)-specific agonist, into the NTS of urethane-anesthetized Wister rats to identify the potential functions of NTS HA on cardiovascular regulation. When HA or H(1)-receptor-specific agonist was bilaterally microinjected into the NTS, mean arterial pressure (MAP) and heart rate (HR) were significantly increased, whereas pretreatment with the H(1)-receptor-specific antagonist cetirizine into the NTS significantly inhibited the cardiovascular responses. The maximal responses of MAP and HR changes induced by HA or H(1)-receptor-specific agonist were dose dependent. We also confirmed gene expression of HA receptors in the NTS and that the expression level of H(1) mRNA was higher than that of the other subtypes. In addition, we found that H(1) receptors are mainly expressed in neurons of the NTS. These findings suggested that HA within the NTS may play a role in regulating cardiovascular homeostasis via activation of H(1) receptors expressed in the NTS neurons.

Contributions of vascular inflammation in the brainstem for neurogenic hypertension.

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that primary hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1, were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat: SHR) compared to normotensive Wistar Kyoto (WKY) rats. We have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Despite the inflammatory state in the NTS of SHR, transcripts of some inflammatory molecules such as chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3 were down-regulated in the NTS of SHR compared to WKY rats. This may be compensatory to avoid further strong inflammatory activity. More importantly, we found that down-regulation of Ccl5 in the NTS of SHR may be pro-hypertensive since microinjection of Ccl5 into the NTS of SHR decreased arterial pressure but was less effective in WKY rats. Leukocyte accumulation of the NTS microvasculature may also induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger release of pro-inflammatory molecules which via paracrine signaling may affect central neural cardiovascular activity conducive to neurogenic hypertension. All told, we suggest that vascular inflammation within the brainstem contributes to neurogenic hypertension by multiple pathways.

Down-regulation of chemokine Ccl5 gene expression in the NTS of SHR may be pro-hypertensive.

OBJECTIVES: Recent studies have demonstrated that pro-inflammatory molecules such as junctional adhesion molecules-1 are highly expressed in the nucleus tractus solitarii (NTS) of the spontaneously hypertensive rat (SHR), compared to normotensive rats (Wistar-Kyoto rats: WKY), suggesting that the NTS of SHR may exhibit an abnormal inflammatory state. In the present study, we tested whether gene expression of inflammatory markers such as cytokines and chemokines is altered in the NTS of SHR and whether this contributes to the hypertensive phenotype in the SHR. METHODS: We have performed RT Profiler PCR arrays in the NTS of SHR and WKY, which were designed to specifically target major cytokines/chemokines and their receptors. To validate PCR array results quantitative RT-PCR was performed. Microinjection studies using anesthetized rats were also carried out to examine whether validated inflammatory molecules exhibit functional roles on cardiovascular regulation at the level of the NTS. RESULTS: Five inter-related transcripts were identified to be differentially expressed between the NTS of SHR and WKY. They include chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3. All of them were down-regulated in the NTS of SHR compared to WKY. Moreover, we found that the protein Ccl5 microinjected into the NTS significantly decreased baseline arterial pressure and that the response was greater in the SHR compared to the WKY (-33.2±3.2 vs. -8.8±1.6 mmHg, P<0.001), demonstrating that its down-regulation in the NTS may contribute to hypertension in the SHR. CONCLUSION: We suggest that gene expression of specific chemokines may be down-regulated to protect further inflammatory reactions in the NTS of SHR at the expense of arterial hypertension.

Metabolic cycles are linked to the cardiovascular diurnal rhythm in rats with essential hypertension.

BACKGROUND: The loss of diurnal rhythm in blood pressure (BP) is an important predictor of end-organ damage in hypertensive and diabetic patients. Recent evidence has suggested that two major physiological circadian rhythms, the metabolic and cardiovascular rhythms, are subject to regulation by overlapping molecular pathways, indicating that dysregulation of metabolic cycles could desynchronize the normal diurnal rhythm of BP with the daily light/dark cycle. However, little is known about the impact of changes in metabolic cycles on BP diurnal rhythm. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that feeding-fasting cycles could affect the diurnal pattern of BP, we used spontaneously hypertensive rats (SHR) which develop essential hypertension with disrupted diurnal BP rhythms and examined whether abnormal BP rhythms in SHR were caused by alteration in the daily feeding rhythm. We found that SHR exhibit attenuated feeding rhythm which accompanies disrupted rhythms in metabolic gene expression not only in metabolic tissues but also in cardiovascular tissues. More importantly, the correction of abnormal feeding rhythms in SHR restored the daily BP rhythm and was accompanied by changes in the timing of expression of key circadian and metabolic genes in cardiovascular tissues. CONCLUSIONS/SIGNIFICANCE: These results indicate that the metabolic cycle is an important determinant of the cardiovascular diurnal rhythm and that disrupted BP rhythms in hypertensive patients can be normalized by manipulating feeding cycles.