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Functional and structural adaptation of common carotid artery could be one of the important causes of postflight orthostatic intolerance after microgravity exposure, the mechanisms of which remain unclear. Recent evidence indicates that long- term spaceflight increases carotid artery stiffness, which might present a high risk to astronaut health and postflight working ability. Studies have suggested that vascular calcification is a common pathological change in cardiovascular diseases that is mainly manifested as an increase in vascular stiffness. Therefore, this study investigated whether simulated microgravity induces calcification of common carotid artery and to elucidate the underlying mechanisms. Four-week-old hindlimb-unweighted (HU) rats were used to simulate the deconditioning effects of microgravity on cardiovascular system. We found that simulated microgravity induced vascular smooth muscle cell (VSMC) osteogenic differentiation and medial calcification, increased receptor activator of nuclear factor [kappa]B (NF-[kappa]B) ligand (RANKL) and RANK expression, and enhanced NF-[kappa]B activation in rat common carotid artery. In vitro activation of the RANK pathway with exogenous RANKL, a RANK ligand, increased RANK and osteoprotegerin (OPG) expression in HU rats. Moreover, the expression of osteogenic markers and activation of NF-[kappa]B in HU rats were further enhanced by exogenous RANKL but suppressed by the RANK inhibitor osteoprotegerin fusion protein (OPG-Fc). These results indicated that the OPG/RANKL/RANK system modulates VSMC osteogenic differentiation and medial calcification of common carotid artery in simulated microgravity rats by regulating the NF- [kappa]B pathway. Key words: simulated microgravity, common carotid artery, vascular calcification, receptor activator of nuclear factor [kappa]B, osteoprotegerin. L'adaptation fonctionnelle et structurelle de l'artere carotide commune pourrait l'une des causes importantes d'intolerance orthostatique apres envol a la suite d'une exposition a la microgravite, mais les modes d'action demeurent a clarifier. Des donnees probantes recentes montrent que le voyage spatial de longue duree entraine une augmentation de la rigidite des arteres carotides, ce qui pourrait exposer l'astronaute a un risque accru pour sa sante de meme que pour sa capacite fonctionnelle apres un envol. Des etudes ont laisse entrevoir que les calcifications vasculaires constituent une observation pathologique frequente dans les maladies cardiovasculaires, lesquelles se manifestent surtout par une augmentation de la rigidite vasculaire. Par consequent, cette etude portait sur la possibilite que la microgravite entraine une calcification de l'artere carotide, ainsi que sur les modes d'action sous-jacents. A l'aide du soulagement de la charge portee par les pattes posterieures chez le rat (rats HU pour << hindlimb-unweighted >>) pendant quatre semaines, nous avons simule les effets de deconditionnement du systeme cardiovasculaire par la microgravite. Nous avons observe que la simulation de la microgravite entrainait une differenciation osteogenique des cellules musculaires lisses vasculaires (CMLV) et une calcification de la media, une augmentation de l'expression du ligand du facteur nucleaire (FN) [kappa]B (ou RANKL pour << receptor activator of nuclear factor [kappa]B >>) et de RANK, avec une augmentation de l'activation du FN- [kappa]B dans l'artere carotide commune chez le rat. L'activation in vitro de la voie de signalisation de RANK avec du RANKL exogene, un ligand de RANK, entrainait une augmentation de l'expression de RANK et de l'osteoprotegerine (OPG) chez les rats HU. En outre, l'expression de marqueurs de l'osteogenese et'activation du FN-[kappa]B chez les rats HU augmentait encore davantage avec l'administration de RANKL exogene, mais etait inhibee avec l'OPG-Fc, un inhibiteur de RANK. Ces resultats montraient que le systeme OPG/RANKL/RANK participe a la modulation de la differentiation osteogenique des CMLV et a la calcification de la media de l'artere carotide commune avec la microgravite simulee chez le rat, et ce, par l'intermediaire de la regulation de la voie de signalisation du FN-[kappa]B. [Traduit par la Redaction] Mots-cles : microgravite simulee, artere carotide commune, calcification vasculaire, activateur des recepteurs du facteur nucleaire [kappa]B, osteoprotegerine., 1. Introduction Exposure to microgravity during spaceflight has been shown to induce physiological adaptations of the heart and vessels, leading to the occurrence of postflight cardiovascular deconditioning, including orthostatic intolerance [...]

Recent studies have suggested that microgravity-induced arterial remodelling contributes to post-flight orthostatic intolerance and that multiple mechanisms are involved in arterial remodelling. However, the initial mechanism by which haemodynamic changes induce arterial remodelling is unknown. Focal adhesions (FAs) are dynamic protein complexes that have mechanotransduction properties. This study aimed to investigate the role of FAs in simulated-microgravity-induced basilar and femoral arterial remodelling. A 4-week hindlimb-unweighted (HU) rat model was used to simulate the effects of microgravity, and daily 1-hour intermittent artificial gravity (IAG) was used to prevent arterial remodelling. After 4-week HU, wall thickness, volume of smooth muscle cells (SMCs) and collagen content were increased in basilar artery but decreased in femoral artery (P < 0.05). Additionally, the expression of p-FAK Y397 and p-Src Y418 was increased and reduced in SMCs of basilar and femoral arteries, respectively, by HU (P < 0.05). The number of FAs was increased in basilar artery and reduced in femoral artery by HU (P < 0.05). Furthermore, daily 1-hour IAG prevented HU-induced differential structural adaptations and changes in FAs of basilar and femoral arteries. These results suggest that FAs may act as mechanosensors in arterial remodelling by initiating intracellular signal transduction in response to altered mechanical stress induced by microgravity. Key words: arterial remodelling, focal adhesions, intermittent artificial gravity, mechanical stress, simulated microgravity. Des etudes recentes ont laisse entendre que le remodelage arteriel provoque par la microgravite participerait a l'intolerance orthostatique apres le vol et que de nombreux modes d'action joueraient un role dans le remodelage arteriel. Cependant, on ne connait pas le mode d'action par lequel commencent les variations hemodynamiques qui engendrent le remodelage. Les adhesions focales (AF) sont des complexes proteiques dynamiques dotes de proprietes de mecanotransduction. Ces travaux visaient a etudier le role des AF dans le remodelage des arteres basilaires et femorales engendre par la microgravite simule. Nous avons utilise un modele de decharge des membres posterieurs (DMP) sur 4 semaines chez le rat en vue de simuler les effets de la microgravite, et la gravite artificielle intermittente (GAI) sur 1 heure en vue de prevenir le remodelage arteriel. Nous avons observe qu'apres une DMP de 4 semaines, l'epaisseur de la paroi, le volume de cellules musculaires lisses (CML) et le contenu en collagene augmentaient pour l'artere basilaire, mais diminuaient pour l'artere femorale (P < 0,05). De plus, la DMP entrainait une augmentation et une diminution de l'expression de p-FAK Y397 et de p-Src Y418 dans les CML des arteres basilaires et femorales, respectivement (P < 0,05). La DMP entrainait une augmentation et une diminution du nombre d'AF dans les arteres basilaires et femorales, respectivement (P < 0,05). De plus, la GAI sur 1 heure permettait de prevenir les adaptations structurelles et variations des AF provoquees par la DMP de maniere differentielle dans les arteres basilaires et femorales. Ces resultats laissent entendre que les AF pourraient agir en tant que capteurs mecaniques dans le remodelage arteriel en amorcant la transduction du signal intracellulaire en reaction aux modifications du stress mecanique provoquees par la microgravite. [Traduit par la Redaction] Mots-cles: remodelage arteriel, adhesions focales, gravite artificielle intermittente, stress mecanique, microgravite simulee., Introduction Exposure to microgravity during space flight leads to post-flight cardiovascular deconditioning manifested as orthostatic intolerance and decreased exercise capacity, which threaten flight safety and the health of astronauts (Buckey [...]

Cerebral arterial remodeling is one of the critical factors in the occurrence of postspaceflight orthostatic intolerance. We hypothesize that large-conductance calcium-activated [K.sup.+] ([BK.sub.Ca]) channels in vascular smooth muscle cells (VSMCs) may play an important role in regulating cerebrovascular adaptation during microgravity exposure. The aim of this work was to investigate whether activation of [BK.sub.Ca] channels is involved in regulation of apoptotic remodeling of cerebral arteries in simulated microgravity rats. In animal studies, Sprague-Dawley rats were subjected to 1-wk hindlimb unweighting to simulate microgravity. Alterations of [BK.sub.Ca] channels in cerebral VSMCs were investigated by patch clamp and Western blotting; apoptosis was assessed by electron microscopy and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling (TUNEL). To evaluate the correlation of [BK.sub.Ca] channel and apoptosis, channel protein and cell nucleus were double-stained. In cell studies, hSlo[alpha]+[beta]1 channel was coexpressed into human embryonic kidney 293 (HEK293) cells to observe the effects of [BK.sub.Ca] channels on apoptosis. In rats, enhanced activities and expression of [BK.sub.Ca] channels were found to be correlated with increased apoptosis in cerebral VSMCs after simulated microgravity. In transfected HEK293 cells, activation of cloned [BK.sub.Ca] channel induced apoptosis, whereas inhibition of cloned [BK.sub.Ca] channel decreased apoptosis. In conclusion, activation of [BK.sub.Ca] channels is associated with increased apoptosis in cerebral VSMCs of simulated microgravity rats. hindlimb unweighting; cerebral artery; human embryonic kidney 293 cells; cardiovascular remodeling doi: 10.1152/ajpcell.00474.2009.

Objectives: Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms. Materials and Methods: Sprague Dawley rats were subjected to 28‐day hindlimb‐unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T‐type CaV3.1 channel was revealed by assessing its blocking effects. MiR‐137 was identified as the upstream of CaV3.1 channel by luciferase assay and investigated by gain/loss‐of‐function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of CaV3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation. Results: Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T‐type CaV3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR‐137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T‐type CaV3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively. Conclusions: The present work demonstrated that miR‐137 and its target T‐type CaV3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway. [ABSTRACT FROM AUTHOR]

The large conductance Ca2+-activated K+ (BKCa) channels are highly expressed in vascular smooth muscle cells (VSMCs) and play an essential role in the regulation of various physiological functions. Besides its electrophysiological function in vascular relaxation, BKCa has also been reported to be implicated in nitric oxide (NO)-induced apoptosis of VSMCs. However, the molecular mechanism is not clear and has not been determined on cloned channels. The present study was designed to clarify whether activation of cloned BKCa channel was involved in NO-induced apoptosis in human embryonic kidney 293 (HEK293) cell. The cDNA encoding the α-subunit of BKCa channel, hSloα, was transiently transfected into HEK293 cells. The apoptotic death in HEK- hSloα cells was detected using immunocytochemistry, analysis of fragmented DNA by agarose gel electrophoresis, MTT test, and flow cytometry assays. Whole-cell and single-channel characteristics of HEK- hSloα cells exhibited functional features similar to native BKCa channel in VSMCs. Exposuring of HEK- hSloα cells to S-nitroso- N-acetyl-penicillamine increased the hSloα channel activities of whole-cell and single-channel, and then increased percentage of cells undergoing apoptosis. However, blocking hSloα channels with 1 mM tetraethylammonia or 100 nM iberiotoxin significantly decreased the NO-induced apoptosis, whereas 30 μM NS1619, the specific agonist of BKCa, independently increased hSloα currents and induced apoptosis. These results indicated that activation of cloned BKCa channel was involved in NO-induced apoptosis of HEK293 cells. [ABSTRACT FROM AUTHOR]

Objectives: Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms., Materials and Methods: Sprague Dawley rats were subjected to 28-day hindlimb-unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T-type Ca V 3.1 channel was revealed by assessing its blocking effects. MiR-137 was identified as the upstream of Ca V 3.1 channel by luciferase assay and investigated by gain/loss-of-function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of Ca V 3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation., Results: Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T-type Ca V 3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR-137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T-type Ca V 3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively., Conclusions: The present work demonstrated that miR-137 and its target T-type Ca V 3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway., (© 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut's cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of Ca V 1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca 2+ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of Ca V 1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/Ca V 1.2 signal pathway.

The aim of the present study was to evaluate the active and passive mechanical properties and wall collagen and elastin contents of mesenteric small arteries (MSAs) isolated from rats of 28-day simulated microgravity (SUS), countermeasure [S + D: SUS plus 1 h/d -G(x) to simulate intermittent artificial gravity (IAG)] and control (CON) groups. Three mechanical parameters were calculated: the overall stiffness (β), circumferential stress (σ(θ))-strain (ε(θ)) relationship and pressure-dependent incremental elastic modulus (E(inc,p)). Vessel wall collagen and elastin percentage were quantified by electron microscopy. The results demonstrate that the active mechanical behavior of MSAs differs noticeably among the three groups: the active stress-strain curve of SUS vessels is very close to the passive curve, whereas the active σ(θ)-ε(θ) curves of CON and S + D vessels are shifted leftward and display a parabolic shape, indicating that for MSAs isolated from S + D, but not those from SUS rats, the pressure-induced myogenic constriction can effectively stiffen the vessel wall as the CON vessels. The passive mechanical behavior of MSAs does not show significant differences among the three groups. However, the percentage of collagen is decreased in the wall of SUS and S + D compared with CON vessels in the following order: SUS < S + D < CON. Thus, the relationship between passive mechanical behavior and compositional changes may be complex and yet depends on factors other than the quantity of collagen and elastin. These findings have provided biomechanical data for the understanding of the mechanism of postflight orthostatic intolerance and its gravity-based countermeasure.

The present study was designed to test the hypothesis that a medium-term simulated microgravity can induce region-specific remodeling in large elastic arteries with their innermost smooth muscle (SM) layers being most profoundly affected. The second purpose was to examine whether these changes can be prevented by a simulated intermittent artificial gravity (IAG). The third purpose was to elucidate whether vascular local renin-angiotensin system (L-RAS) plays an important role in the regional vascular remodeling and its prevention by the gravity-based countermeasure. This study consisted of two interconnected series of in-vivo and ex-vivo experiments. In the in-vivo experiments, the tail-suspended, hindlimb unloaded rat model was used to simulate microgravity-induced cardiovascular deconditioning for 28 days (SUS group); and during the simulation period, another group was subjected to daily 1-hour dorso-ventral (-G(x)) gravitation provided by restoring to normal standing posture (S + D group). The activity of vascular L-RAS was evaluated by examining the gene and protein expression of angiotensinogen (Ao) and angiotensin II receptor type 1 (AT1R) in the arterial wall tissue. The results showed that SUS induced an increase in the media thickness of the common carotid artery due to hypertrophy of the four SM layers and a decrease in the total cross-sectional area of the nine SM layers of the abdominal aorta without significant change in its media thickness. And for both arteries, the most prominent changes were in the innermost SM layers. Immunohistochemistry and in situ hybridization revealed that SUS induced an up- and down-regulation of Ao and AT1R expression in the vessel wall of common carotid artery and abdominal aorta, respectively, which was further confirmed by Western blot analysis and real time PCR analysis. Daily 1-hour restoring to normal standing posture over 28 days fully prevented these remodeling and L-RAS changes in the large elastic arteries that might occur due to SUS alone. In the ex-vivo experiments, to elucidate the important role of transmural pressure in vascular regional remodeling and differential regulation of L-RAS activity, we established an organ culture system in which rat common carotid artery, held at in-vivo length, can be perfused and pressurized at varied flow and pressure for 7 days. In arteries perfused at a flow rate of 7.9 mL/min and pressurized at 150 mmHg, but not at 0 or 80 mmHg, for 3 days led to an augmentation of c-fibronectin (c-FN) expression, which was also more markedly expressed in the innermost SM layers, and an increase in Ang II production detected in the perfusion fluid. However, the enhanced c-FN expression and increased Ang II production that might occur due to a sustained high perfusion pressure alone were fully prevented by daily restoration to 0 or 80 mmHg for a short duration. These findings from in-vivo and ex-vivo experiments have provided evidence supporting our hypothesis that redistribution of transmural pressures might be the primary factor that initiates region-specific remodeling of arteries during microgravity and the mechanism of IAG is associated with an intermittent restoration of the transmural pressures to their normal distribution. And they also provide support to the hypothesis that L-RAS plays an important role in vascular adaptation to microgravity and its prevention by the IAG countermeasure.

Parkinson's disease is a progressive neurodegenerative disorder characterized clinically by rigidity, akinesia, resting tremor and postural instability. It has recently been suggested that low frequency stimulation of the pedunculopontine nucleus (PPN) has a role in the therapy for Parkinsonism, particularly in gait disorder and postural instability. However, there is limited information about the mechanism of low frequency stimulation of the PPN on Parkinson's disease. The present study was to investigate the effect and mechanism of low frequency stimulation of the PPN on the firing rate of the ventrolateral thalamic nucleus (VL) in a rat model with unilateral 6-hydroxydopamine lesioning of the substantia nigra pars compacta. In vivo extracellular recording and microiontophoresis were adopted. The results showed that the firing rate of 60.71% VL neurons in normal rats and 59.57% VL neurons in 6-hydroxydopamine lesioned rats increased with low frequency stimulation of the PPN. Using microiontophoresis to VL neurons, we found the firing rate in VL neurons responded with either an increase or decrease in application of acetylcholine (ACh) in normal rats, whereas with a predominant decrease in M receptor antagonist atropine. Furthermore, the VL neurons were mainly inhibited by application of γ-aminobutyric acid (GABA) and excited by GABA(A) receptor antagonist bicuculline. Importantly, the VL neurons responding to ACh were also inhibited by application of GABA. We also found that the excitatory response of the VL neurons to the low frequency stimulation of the PPN was significantly reversed by microiontophoresis of atropine. These results demonstrate that cholinergic and GABAergic afferent nerve fibers may converge on the same VL neurons and they are involved in the effects of low frequency stimulation of the PPN, with ACh combining M(2) receptors on the presynaptic membrane of GABAergic afferents, which will inhibit the release of GABA in the VL and then improve the symptoms of Parkinson's disease.

The aim of the present study was to further elucidate the mechanisms of vascular adaptation to microgravity and its gravity-based countermeasure by a biomechanical approach. Active (the dissected vessel segment was superfused with PPS) and passive (while it was superfused with Ca(2+)-free PPS) biomechanical properties of mesenteric third-order small arteries and middle cerebral arteries isolated from 3-day simulated microgravity (SUS), countermeasure (STD, daily 1 h of -G(x) gravitation), and control (CON) groups of rats were studied. The following mechanical parameters were calculated: the overall stiffness parameter of passive vessels (beta), circumferential stress (sigma(theta))-strain (epsilon(theta)) relationship, and pressure-dependent incremental elastic modulus (E(inc,p)) of both active and passive vessels, and vascular smooth muscle (VSM) activity-dependent incremental modulus (E(inc,a)). Results from the analysis of active biomechanical properties revealed the contribution of vascular smooth muscle (VSM) tone during the early adaptation to microgravity: (1) For mesenteric small arteries, active circumferential sigma(theta) -epsilon(theta) curve of SUS group was comparable with that of the passive vessels, indicating that the function of VSM to restore the normal stress distribution is compromised; however, this mal-adaptation was fully prevented by the countermeasure of daily 1 h of -G(x) gravitation; (2) For the middle cerebral arteries, active circumferential sigma(theta) -epsilon(theta) relation of SUS group was shifted to the left side of the passive curve and epsilon(theta) was kept at a nearly constant level with the corresponding sigma(theta) being at its normal range; furthermore, the enhanced myogenic tone responsiveness was not prevented by daily short-duration -G(x). Analysis of the passive biomechanical properties has suggested remodeling changes in matrix components of different types of vessels, which might be significant if the exposure duration was further prolonged. In brief, studies of vascular biomechanics are of particular importance in elucidating the mechanisms underlying vascular adaptation to microgravity and its gravity-based countermeasure.

This study was designed to test the hypothesis that postsuspension cardiovascular manifestation in conscious rats after a medium-term (28-day) tail suspension (SUS) is hypertensive and tachycardiac and can be prevented by a countermeasure of daily 1-h dorsoventral (-G(x)) gravitation provided by standing (STD). To assess associated changes in cardiovascular regulation, blood pressure (BP) and heart rate (HR) variability were analyzed by spectral analysis computed by parametric autoregressive (AR) method and by nonlinear recurrence quantification analysis (RQA) and approximate entropy (ApEn) measure. The results showed that conscious SUS rats manifested hypertensive and tachycardiac response before and after being released from suspension compared with the controls, and the countermeasure of 1 h/day -G(x) prevented the hypertensive response. Auto- and cross-spectral analysis and transfer function analysis did not show significant changes in cardiovascular variability. However, SUS decreased the three RQA indexes [recurrence percentage (RC%), determinism percentage (DT%), and the longest diagonal line (L(max))] of systolic BP, whereas STD alleviated these changes. ApEn values of HR data sets were significantly higher in the SUS and SUS + STD groups compared with those of the control group before and after release from suspension. The present study has demonstrated that daily -G(x) for as short as 1 h is sufficient to prevent postsuspension cardiovascular alteration in conscious rats after a medium-term SUS. Nonlinear measures, but not spectral analysis, might provide promising data to estimate the overall changes in cardiovascular autonomic regulation due to microgravity exposure.

The aim of the present study was to examine whether there are changes in systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) and their spectral indices in conscious free-moving rats after tail-suspension for 28 d. The tail-suspended hindlimb-unloaded (HU) rat model was used to simulate the cardiovascular effect of microgravity and the post-spaceflight cardiovascular dysfunction. The auto- and cross-spectral analysis of SBP variability (SBPV) and HR variability (HRV) were performed by the method based on the autoregressive model (AR), and the auto-spectral results was compared with the results from the classical periodogram method. The baroreceptor-heart rate reflex sensitivity (BRS) was estimated using transfer function analysis from SBP to HR. The results indicated that auto-spectral results based on the two methods were comparable, while smoother power spectral curves with distinguished peaks were trained by the AR method. The means of SBP, DBP, and HR, the main spectral indices of SBPV and HRV, and the mean average gain of transfer functions computed at low- and high-frequency ranges (0.25-0.8 Hz and 0.8-2.4 Hz) did not show significant changes before and after release from suspension. Furthermore, the main spectral indices of SBPV and HRV at different time points did not show significant differences between the control and suspension groups. However, the means of SBP, DBP, and HR at different time points were significantly higher in simulated weightless rats than those in the control rats. The findings of the present study suggest that a mid-term simulated microgravity might induce hypertension and tachycardia upon removal from the suspension which reflects a general sympathetic hyperactivity. We speculated that the sympathetic hyperactivity might be a compensatory mechanism activated in the intact animal to counteract HU-induced hypo-responsiveness of resistance vessels. In addition, lack of clear and distinct changes in HRV and BRS have also been reported in some recent space and ground-based human studies.

Aim: To investigate the effects of simulated microgravity on dilatory responsiveness and NOS expression of abdominal aorta in rats., Methods: Twenty male healthy SD rats, which body weight ranged from 300 g to 330 g, were divided into control group and simulated microgravity group randomly. After 4 weeks, using isolated arterial rings from rats, arterial dilatory responsiveness of abdominal aorta were examined in vitro. And the expression of nitric oxide synthase (NOS), including endothelial NOS (eNOS) and inducible NOS (iNOS), were observed by Western blot., Results: Dilatory responses of arterial rings to L-Arginine (10(-8)-10(-3) mol/L), and Acetylcholine mol/L) were decreased in simulated microgravity rats compared with that of controls; but dilatory responses of isolated aortic rings to sodium nitroprusside (mol/L) and 8-bromo-cGMP(mol/L) were similar in both simulated microgravity rats and control rats. The expression of both eNOS and iNOS had not showed significant differences between two groups., Conclusion: The data indicate that endothelium dependent vasorelaxation in abdominal aortic rings are decreased by 4-week simulated microgravity, and this change may be result from altered NOS activity in endothelium.

The aim of the present study was to clarify whether simulated microgravity-induced post-suspension cardiovascular deconditioning in rats could be prevented by daily short-duration standing (STD). Three groups of rats were used as subjects to perform the experiments. Compared to a control group of male Sprague-Dawley rats (CON), a group of rats with tail-suspension (SUS) for 28 d was used to simulate cardiovascular deconditioning due to microgravity. Another group of tailed-suspended rats with daily STD for 1 h was used to provide -GX (dorso-ventral) gravitational loading as countermeasure. In addition to hemodynamic changes to head-up tilt, blood pressure variability (BPV) signals were also analyzed by spectral and nonlinear analysis. The results showed 1) Blood pressure immediately decreased after head-up tilt in all three groups. After several minutes, blood pressure could restore to the initial condition in both CON and SUS+STD group, but the recovery process was slower in the latter group. In contrast, the recovery process was the slowest in the SUS group and could not restore to the initial level completely. 2) In frequency domain, power spectra has similar pattern in CON and SUS+STD group. However, they are quite different in the SUS group in that spectra peak is obvious increased in very low frequency and spectra is narrower and higher in high frequency.

Objective: To evaluate the inhibiting effect of niflumic acid (NFA), an inhibitor of calcium-activated chloride channel (ClCa) on airway epithelium, on the airway hyperresponsiveness in asthmatic mice., Methods: BALB/c mice were randomly divided into an asthma group (A group), a NFA prevention asthmatic group (B group) and a sham-challenged group (C group). The airway pressure time index (APTI) and the content of ET-1 and NO in bronchoalveolar lavage fluid (BALF) in all groups were measured. With the isolated tracheal rings with integral epithelium or epithelium removed from the asthma group (A(1) group and A(2) group) and the sham-challenged group (C(1) group and C(2) group), the contractile responsiveness of various rings to methacholine (mACh) was examined, and its change was observed when the rings were exposed to NFA beforehand., Results: Compared with A group (1.62 +/- 0.14), the APTI in B group (1.21 +/- 0.07) was reduced remarkably (P < 0.01), and the contents of ET-1 [(103 +/- 9) ng/L] and NO [(48.5 +/- 3.2) micromol/L] in BALF of A group were significantly higher than those in B group, [(53 +/- 5) ng/L, (23.7 +/- 2.5) micromol/L (P < 0.01), respectively]. The ratios of maximum contractility in A(1), A(2), C(1) and C(2) groups were (3.79 +/- 0.44), (2.15 +/- 0.21), (1.26 +/- 0.14) and (2.06 +/- 0.18), respectively. The contractility of A(1) group was highest among all groups (all P < 0.01), but could be effectively decreased by NFA., Conclusions: By inhibiting the special ClCa on the airway epithelium, NFA can inhibit the production of ET-1 and NO by epithelium and thus exert preventive effect on airway hyperresponsiveness in asthma.

To assess the potential value of intermittent artificial gravity as an efficient countermeasure, our previous studies have showed that daily 4-h standing (STD) is sufficient in counteracting muscle atrophy but not bone atrophy induced by simulated microgravity. The aim of the present study was to determine whether intermittent gravitational loading by daily 2-h or 4-h, +45 degrees head-up tilt (HUT) is more effective than STD in counteracting muscle and, particularly, bone atrophy due to simulated microgravity. Sprague-Dawley male rats weighing 290-300 g were subjected to a 28-d tail-suspension to simulate microgravity deconditioning. Daily HUT for 2, or 4 h was used to provide intermittent gravitational loading in foot-ward and tail-ward directions. The results showed that 4 h/d HUT was sufficient, and 2 h/d was less effective, in preventing adverse changes in muscle weights, fiber types, and cross-sectional areas (CSA) of muscles due to a 28-d simulated microgravity. The % protections by 4 h/d HUT in maintaining the CSAs of type I fibers in soleus, medial and lateral gastrocnemius and extensor digitorum longus muscles were 103%, 82%, 102%, and 83%, respectively. However, according to changes in physical and mechanical properties of femur, daily 4-h HUT was ineffective in attenuating the adverse changes in bone due to a 28-d simulated microgravity. Reductions in wet, dry, and ash weights and decreases in mechanical strength of femur did not show significant improvement by daily 2-h or 4-h HUT. Taken together, the findings indicate that the countermeasure effectiveness of daily 2-h or 4-h HUT for muscles is comparable with that by daily STD with the same durations. Daily 4-h HUT, as 4-h STD, is also ineffective in attenuating adverse changes in bone mass, but seems partially effective in preventing declines in mechanical properties due to simulated microgravity.

Objective. To observe the dynamic changes in tetanic tension in 4-week tail-suspended rat soleus (SOL) and extensor digitorum longus muscle (EDL) and to elucidate its underlying mechanisms. Method. After 4 weeks of tail suspension SOL and EDL of the rats were isolated and perfused. Their isometric twitch and tetanic tensions were recorded. Result. Atrophy occurred in the SOL, but not in the EDL. The maximum twitch tension (Pt) decreased significantly and was more dependent on stimulation voltage in SOL of tail-suspended rat. Time to maximum twitch tension (TPT) and time from maximum twitch tension to half relaxation (TR50) were reduced in the SOL. Pt also decreased in the EDL, but TPT and TR50 did not change in the EDL. The maximum tetanic tension reduced in SOL and EDL of tail-suspended rats. The decline rate of tetanic tension in SOL was faster than the control. The profile of tetanic contraction curve in atrophic SOL approached that in EDL. Conclusion. The above results suggested that the underlying mechanisms of reduced maximum twitch and tetanic tension in 4-week tail-suspended rat SOL may involve the reduction in number of cross-bridge per cross-section area or force produced per cross-bridge. The rapid decline rate in atrophic SOL may be related to the shift in myosin heavy chain and troponin I isoforms or to decrease in excitability.