Involvement of D1 dopamine receptor in the nucleus of the solitary tract of rats in stress-induced hypertension and exercise.

OBJECTIVE: Chronic stress can cause hypertension, whereas daily exercise promotes healthy well being through destressing. Although the nucleus of the solitary tract (NTS) is involved in the development of hypertension, the molecular and physiological mechanisms of stress and exercise remain unclear. In this study, we tested whether gene expression in the NTS is altered by stress and daily exercise and whether this is involved in cardiovascular regulation. METHODS: We have performed RT2 Profiler PCR arrays targeting a panel of neurotransmitter receptor genes in the NTS of Wistar rats subjected to chronic restraint stress (1 h a day over 3 weeks) with or without voluntary wheel exercise. We also performed immunohistochemistry to determine whether the identified molecules were expressed at the protein level. Additionally, microinjection studies in anesthetized rats were performed to examine whether validated molecules exhibit physiological roles in cardiovascular regulation of the NTS. RESULTS: We observed that blood pressure was significantly increased by stress and the increase was suppressed by exercise. Using PCR analysis, we determined that the expression levels of four genes in the NTS, including the dopamine receptor D1 gene (Drd1), were significantly affected by stress and suppressed by exercise. We also examined dopamine D1 receptor (D1R) expression in NTS neurons and found significantly greater expression in the stressed than nonstressed animals. Furthermore, the microinjection of a D1R agonist into the NTS in anesthetized rats induced hypotensive effects. CONCLUSION: These results suggest that NTS D1R plays a role in the counteracting processes of stress-induced hypertension.

Association between flexibility activity and blood-pressure change among older adults in Japan: A 5-year longitudinal study.

This longitudinal study examined the relationship between flexibility-activity and blood-pressure (BP) change among older adults in Japan. Our study included 452 older adults who took part in our survey in both 2012/2013 and 2017/2018. The seated systolic blood pressure (SBP) and diastolic BP (DBP) were measured both at baseline and at the 5 years follow-up. The frequencies of the different physical activities at baseline were assessed using a questionnaire. A generalized linear mixed model was used to estimate the non-standardized coefficient (B) of BP change associated with flexibility activity, after adjustments for sex, age, body mass index, smoking status, alcohol consumption, antihypertensive medication use, history of heart disease, walking time, and muscle-strengthening activity as a fixed-effect, and area of residence as a random-effect. Higher flexibility-activity frequency was significantly associated with reduced SBP (B = -0.77 [95% confidence intervals = -1.36, -0.18], p for linear trend = 0.01, p for quadratic trend = 0.85) and DBP (-0.33 [-0.71, 0.05], p for linear trend = 0.09, p for quadratic trend = 0.04). Engaging in flexibility activity for 3 days per week was significantly associated with a reduction in DBP (B = -4.16, 95% CI [-7.53, -0.79], p = 0.02) compared with that in the reference group (0 days per week). Interaction tests were not significant between basic variables (sex, age, BMI, and antihypertensive medication) and flexibility. In conclusion, higher flexibility activity frequency was associated with a reduction in BP in older adults. Future longitudinal and interventional studies should examine the effects of flexibility activity on cardiovascular disease prevention.

Impact of exercise on brain-bone marrow interactions in chronic stress: potential mechanisms preventing stress-induced hypertension.

We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.NEW & NOTEWORTHY Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.

Implication of the Central Nucleus of the Amygdala in Cardiovascular Regulation and Limiting Maximum Exercise Performance During High-intensity Exercise in Rats.

To date, the mechanism of central fatigue during high-intensity exercise has remained unclear. Here we elucidate the central mechanisms of cardiovascular regulation during high-intensity exercise with a focus on the hypothesis that amygdala activation acts to limit maximum exercise performance. In the first of three experiments, we probed the involvement of the central nucleus of the amygdala (CeA) in such regulation. Wistar rats were subjected to a maximum exercise test and their total running time and cardiovascular responses were compared before and after bilateral CeA lesions. Next, probing the role of central pathways, we tested whether high-intensity exercise activated neurons in CeA and/or the hypothalamic paraventricular nucleus (PVN) that project to the nucleus tractus solitarius (NTS). Finally, to understand the potential autonomic mechanisms affecting maximum exercise performance, we measured the cardiovascular responses in anesthetized rats to electrical microstimulation of the CeA, PVN, or both. We have found that (1) CeA lesions resulted in an increase in the total exercise time and the time at which an abrupt increase in arterial pressure appeared, indicating an apparent suppression of fatigue. (2) We confirmed that high-intensity exercise activated both the PVN-NTS and CeA-NTS pathways. Moreover, we discovered that (3) while stimulation of the CeA or PVN alone both induced pressor responses, their simultaneous stimulation also increased muscle vascular resistance. These results are evidence that cardiovascular responses during high-intensity exercise are affected by CeA activation, which acts to limit maximum exercise performance, and may implicate autonomic control modulating the PVN-NTS pathway via the CeA.

Conditional Regulation of Blood Pressure in Response to Emotional Stimuli by the Central Nucleus of the Amygdala in Rats.

Humans and animals can determine whether a situation is favorable to them and act accordingly. For this, the autonomic tuning of the cardiovascular system to supply energy to active skeletal muscles through the circulatory system is as important as motor control. However, how the autonomic cardiovascular responses are regulated in dynamically changing environments and the neuronal mechanisms underlying these responses remain unclear. To resolve these issues, we recorded the blood pressure and heart rate of head-restrained rats during dynamically changing appetitive and aversive classical conditioning tasks. The rats displayed various associations between conditioned stimuli and unconditioned stimuli in appetitive (sucrose water), neutral (no outcome), and aversive (air puff) blocks. The blood pressure and heart rate in the appetitive block gradually increased in response to the reward-predicting cue and the response to the actual reward vigorously increased. The reward-predictive response was significantly higher than the responses obtained in the neutral and aversive condition blocks. To investigate whether the reward-predictive pressor response was caused by orofacial movements such as anticipatory licking behavior, we separately analyzed high- and low-licking trials. The conditioned pressor response was observed even in trials with low-licking behaviors. Blood pressure and heart rate responses to the air puff-predicting cue in the aversive block were not significantly different from the responses in the neutral block. The conditioned blood pressure response rapidly changed with condition block switching. Furthermore, to examine the contribution of the amygdala as an emotion center to these conditioned responses, we bilaterally microinjected a GABAA receptor agonist, muscimol, into the central nucleus of the amygdala. Pharmacological inactivation of the central nucleus of the amygdala significantly decreased the reward-predictive pressor responses. These results suggest that the blood pressure is adaptively and rapidly regulated by emotional conditioned stimuli and that the central nucleus of the amygdala participates in regulating the pressor response in dynamically changing situations.

Estradiol-dependent gene expression profile in the amygdala of young ovariectomized spontaneously hypertensive rats.

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.

Connectome analysis of male world-class gymnasts using probabilistic multishell, multitissue constrained spherical deconvolution tracking.

In athletes, long-term intensive training has been shown to increase unparalleled athletic ability and might induce brain plasticity. We evaluated the structural connectome of world-class gymnasts (WCGs), as mapped by diffusion-weighted magnetic resonance imaging probabilistic tractography and a multishell, multitissue constrained spherical deconvolution method to increase the precision of tractography at the tissue interfaces. The connectome was mapped in 10 Japanese male WCGs and in 10 age-matched male controls. Network-based statistic identified subnetworks with increased connectivity density in WCGs, involving the sensorimotor, default mode, attentional, visual, and limbic areas. It also revealed a significant association between the structural connectivity of some brain structures with functions closely related to the gymnastic skills and the D-score, which is used as an index of the gymnasts' specific physical abilities for each apparatus. Furthermore, graph theory analysis demonstrated the characteristics of brain anatomical topology in the WCGs. They displayed significantly increased global connectivity strength with decreased characteristic path length at the global level and higher nodal strength and degree in the sensorimotor, default mode, attention, and limbic/subcortical areas at the local level as compared with controls. Together, these findings extend the current understanding of neural mechanisms that distinguish WCGs from controls and suggest brain anatomical network plasticity in WCGs resulting from long-term intensive training. Future studies should assess the contribution of genetic or early-life environmental factors in the brain network organization of WCGs. Furthermore, the indices of brain topology (i.e., connection density and graph theory indices) could become markers for the objective evaluation of gymnastic performance.

Regional brain gray matter volume in world-class artistic gymnasts.

The relationship between long-term intensive training and brain plasticity in gymnasts has recently been reported. However, the relationship between abilities in different gymnastic events and brain structural changes has not been explored. This study aimed to evaluate the correlation between world-class gymnasts (WCGs)' specific abilities in different gymnastics events and their gray matter (GM) volume. Ten right-handed Japanese male WCGs and 10 right-handed gender- and age-matched controls with no history of gymnastic training participated in this study. Whole brain three-dimensional T1-weighted images (magnetization-prepared rapid gradient-echo sequence) with 0.90 mm3 voxels were obtained using a 3 T-MRI scanner from each subject. Volume-based morphometry (VolBM) was used to compare GM volume differences between WCGs and controls. We then explored the correlation between specific gymnastic abilities using different gymnastic apparatuses, and GM volume. Significantly higher GM volumes (false discovery rate-corrected p < 0.05) in the inferior parietal lobule, middle temporal gyrus, precentral gyrus, rostral middle frontal gyrus, and superior frontal gyrus were demonstrated in WCGs, compared with controls using VolBM. Moreover, significant positive correlations were observed between brain regions and the difficulty scores for each gymnastic event, for example, rings and inferior parietal lobule and parallel bars and rostral middle frontal gyrus. These results may reflect the neural basis of an outstanding gymnastic ability resulting from brain plasticity in areas associated with spatial perception, vision, working memory, and motor control.

Potential Role of the Amygdala and Posterior Claustrum in Exercise Intensity-dependent Cardiovascular Regulation in Rats.

Tuning of the cardiovascular response is crucial to maintain performance during high-intensity exercise. It is well known that the nucleus of the solitary tract (NTS) in the brainstem medulla plays a central role in cardiovascular regulation; however, where and how upper brain regions form circuits with NTS and coordinately control cardiovascular responses during high-intensity exercise remain unclear. Here focusing on the amygdala and claustrum, we investigated part of the mechanism for regulation of the cardiovascular system during exercise. In rats, c-Fos immunostaining was used to examine whether the amygdala and claustrum were activated during treadmill exercise. Further, we examined arterial pressure responses to electrical and chemical stimulation of the claustrum region. We also confirmed the anatomical connections between the amygdala, claustrum, and NTS by retrograde tracer injections. Finally, we performed simultaneous electrical stimulation of the claustrum and amygdala to examine their functional connectivity. c-Fos expression was observed in the amygdala and the posterior part of the claustrum (pCL), but not in the anterior part, in an exercise intensity-dependent manner. pCL stimulation induced a depressor response. Using a retrograde tracer, we confirmed direct projections from the amygdala to the pCL and NTS. Simultaneous stimulation of the central nucleus of the amygdala and pCL showed a greater pressor response compared with the stimulation of the amygdala alone. These results suggest the amygdala and pCL are involved in different phases of exercise. More speculatively, these areas might coordinately tune cardiovascular responses that help maintain performance during high-intensity exercise.

Trpv4 involvement in the sex differences in blood pressure regulation in spontaneously hypertensive rats.

Arterial pressure (AP) is lower in premenopausal women than in men of a similar age. Premenopausal women exhibit a lower sympathetic activity and a greater baroreceptor reflex; however, mechanisms controlling sex differences in blood pressure regulation are not well understood. We hypothesized that different neuronal functions in the cardiovascular centers of the brains of men and women may contribute to the sex difference in cardiovascular homeostasis. Our previous studies on male spontaneously hypertensive rats (SHRs) and their normotensive counterparts, Wistar Kyoto (WKY) rats, revealed that the gene-expression profile of the nucleus tractus solitarius (NTS), a region of the medulla oblongata that is pivotal for regulating the set point of AP, is strongly associated with AP. Thus, we hypothesized that gene-expression profiles in the rat NTS are related to sex differences in AP regulation. Because female SHRs clearly exhibit lower AP than their male counterparts of a similar age, we investigated whether SHR NTS exhibits sex differences in gene expression by using microarray and RT-qPCR experiments. The transcript for transient receptor potential cation channel subfamily V member 4 ( Trpv4) was found to be upregulated in SHR NTS in females compared with that in males. The channel was expressed in neurons and glial cells within NTS. The TRPV4 agonist 4-alpha-phorbol-12,13-didecanoate (4α-PDD) decreased blood pressure when injected into NTS of rats. These findings suggest that altered TRPV4 expression might be involved in the sex differences in blood pressure regulation.

Bidirectional cardiovascular responses evoked by microstimulation of the amygdala in rats.

Although the amygdala is known as a negative emotion center for coordinating defensive behaviors, its functions in autonomic control remain unclear. To resolve this issue, we examined effects on cardiovascular responses induced by stimulation and lesions of the amygdala in anesthetized and free-moving rats. Electrical microstimulation of the central nucleus of the amygdala (CeA) induced a gradual increase in arterial pressure (AP) and heart rate (HR), whereas stimulation of adjacent nuclei evoked a phasic AP decrease. The gain of the baroreceptor reflex was not altered by CeA stimulation, suggesting that CeA activity increases both AP and HR by resetting baroreceptor reflex function. Disinhibition of GABAergic input by amygdalar microinjection of the GABAA receptor antagonist induced robust increases in AP and HR. Furthermore, bilateral electrolytic lesions of CeA evoked consistent AP increases over the light/dark cycle. These results suggest that the amygdala exerts 'bidirectional' autonomic control over the cardiovascular system.

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.

Combined long-term caffeine intake and exercise inhibits the development of diabetic nephropathy in OLETF rats.

This study was performed to examine the effects of long-term caffeine-intake, with and without exercise, on the progression of diabetic nephropathy (DN) in an obese diabetic rat model. Thirty-two male Otsuka Long-Evans Tokushima fatty (OLETF) rats were assigned to sedentary (OLETF-Sed), exercise (OLETF-Ex), caffeine-intake (OLETF-Caf), and combined (OLETF-Caf + Ex) groups. Caffeine-intake groups were fed rat chow containing caffeine (90.7 ± 4.7 mg/kg/day). The OLETF-Ex and OLETF-Caf + Ex groups were able to run voluntarily at any time using a rotatory wheel. Body weight (BW) and blood pressure (BP) were measured weekly from 24 to 29 wk of age. Pre- and posttreatment serum glucose, insulin, and creatinine concentrations were measured, and a 24 h urine sample was collected for measurement of creatinine clearance (Ccr) and albumin excretion (UEAlb). After treatment, the kidneys were removed for morphological analysis. The OLETF-Caf and OLETF-Caf + Ex groups exhibited no BP increase during the study. Both the caffeine-intake groups exhibited a significant increase in urine volume (UV), electrolyte excretion, and Ccr, and decreased UEAlb, following treatment. Furthermore, no structural damage was observed in the kidneys of rats from either caffeine-intake group, whereas the OLETF-Sed and OLETF-Ex groups exhibited DN progression. This study demonstrates that caffeine-intake alone and/or combined with exercise significantly decreases BW and improves glucose intolerance, without the progression of DN. Further research should be performed to examine whether the quantities of caffeine contained in a normal human daily intake also have a protective effect against kidney damage.NEW & NOTEWORTHY The present study showed that caffeine administration alone and/or combined with exercise results in an improvement of diabetic nephropathy (DN), including an increase in creatinine clearance and urinary Na excretion, a decrease in urinary protein excretion, and in renal morphological findings. To our knowledge, there are no other studies showing that caffeine administration inhibits DN progression.

Systemic leukotriene B4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat.

KEY POINTS: Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB4 receptor 1 (BLT1) receptors were blocked with CP-105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. ABSTRACT: Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB4 -mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB4 receptor 1 (BLT1) receptor with CP-105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension.

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.

Spaceflight affects postnatal development of the aortic wall in rats.

We investigated effect of microgravity environment during spaceflight on postnatal development of the rheological properties of the aorta in rats. The neonate rats were randomly divided at 7 days of age into the spaceflight, asynchronous ground control, and vivarium control groups (8 pups for one dam). The spaceflight group rats at 9 days of age were exposed to microgravity environment for 16 days. A longitudinal wall strip of the proximal descending thoracic aorta was subjected to stress-strain and stress-relaxation tests. Wall tensile force was significantly smaller in the spaceflight group than in the two control groups, whereas there were no significant differences in wall stress or incremental elastic modulus at each strain among the three groups. Wall thickness and number of smooth muscle fibers were significantly smaller in the spaceflight group than in the two control groups, but there were no significant differences in amounts of either the elastin or collagen fibers among the three groups. The decreased thickness was mainly caused by the decreased number of smooth muscle cells. Plastic deformation was observed only in the spaceflight group in the stress-strain test. A microgravity environment during spaceflight could affect postnatal development of the morphological and rheological properties of the aorta.

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.

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.

Excessive leukotriene B4 in nucleus tractus solitarii is prohypertensive in spontaneously hypertensive rats.

Inflammation within the brain stem microvasculature has been associated with chronic cardiovascular diseases. We found that the expression of several enzymes involved in arachidonic acid-leukotriene B4 (LTB4) production was altered in nucleus tractus solitarii (NTS) of spontaneously hypertensive rat (SHR). LTB4 produced from arachidonic acid by 5-lipoxygenase is a potent chemoattractant of leukocytes. Leukotriene B4-12-hydroxydehydrogenase (LTB4-12-HD), which degrades LTB4, was downregulated in SHR rats compared with that in Wistar-Kyoto rats. Quantitative real-time PCR revealed that LTB4-12-HD was reduced by 63% and 58% in the NTS of adult SHR and prehypertensive SHR, respectively, compared with that in age-matched Wistar-Kyoto rats (n=6). 5-lipoxygenase gene expression was upregulated in the NTS of SHR (≈50%; n=6). LTB4 levels were increased in the NTS of the SHR, (17%; n=10, P<0.05). LTB4 receptors BLT1 (but not BLT2) were expressed on astroglia in the NTS but not neurons or vessels. Microinjection of LTB4 into the NTS of Wistar-Kyoto rats increased both leukocyte adherence and arterial pressure for over 4 days (peak: +15 mm Hg; P<0.01). In contrast, blockade of NTS BLT1 receptors lowered blood pressure in the SHR (peak: -13 mm Hg; P<0.05) but not in Wistar-Kyoto rats. Thus, excessive amounts of LTB4 in NTS of SHR, possibly as a result of upregulation of 5-lipoxygenase and downregulation of LTB4-12-HD, can induce inflammation. Because blockade of NTS BLT1 receptors lowered arterial pressure in the SHR, their endogenous activity may contribute to the hypertensive state of this rodent model. Thus, inflammatory reactions in the brain stem are causally associated with neurogenic hypertension.