The relative stability of cerebral blood flow is maintained by the baroreflex and cerebral autoregulation (CA). We assessed the relationship between baroreflex sensitivity (BRS) and CA in patients with atherosclerotic carotid stenosis or occlusion.
A chronic increase in blood flow in resistance arteries is associated with increased lumen diameter (outward remodeling) and improved endothelium (NO)-mediated relaxation. Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases. Nevertheless, it is impaired in 12 to 24-month old rats and in young Zucker Diabetic Fatty (ZDF) rats due to advanced glycation end products (AGEs) and oxidative stress. As type 2 diabetes occurs preferentially in older subjects we investigated flow-mediated remodeling and the effect of the AGEs breaker ALT-711 associated or not to the antioxidant TEMPOL in one-year old lean (LZ) and ZDF rats.
Heart rate spontaneously fluctuates despite homeostatic regulatory mechanisms to stabilize it. Harmonic and fractal fluctuations have been described. Non-harmonic non-fractal fluctuation has not been studied because it is usually thought that it is caused by apparatus noise. We hypothesized that this fluctuation looking like apparatus noise (that we call "noisy fluctuation") is linked to challenged blood pressure stabilization and not to apparatus noise. We assessed noisy fluctuation by quantifying the small and fastest beat-to-beat fluctuation of RR-interval by means of spectral analysis (Nyquist power of heart rate variability: nyHRV) after filtering out its fractal component. We observed nyHRV in healthy supine subjects and in patients with vasovagal symptoms. We challenged stabilization of blood pressure by upright posture (by means of a head-up tilt table test). Head-up position on the tilt table dramatically decreased nyHRV (0.128 ± 0.063 vs. 0.004 ± 0.002, p < 0.01) in healthy subjects (n = 12). Head-up position also decreased nyHRV in patients without vasovagal symptoms (n = 24; 0.220 ± 0.058 vs. 0.034 ± 0.015, p < 0.05), but not in patients with vasovagal symptoms during a head-up tilt table test (age and sex paired, 0.103 ± 0.041 vs. 0.122 ± 0.069, not significant). Heart rate variability includes a physiological non-harmonic non-fractal noisy fluctuation. This noisy fluctuation indicates low engagement of regulatory mechanisms because it disappears when the cardiovascular system is challenged (upright posture). It also indicates cardiovascular instability because it does not disappear in upright patients before vasovagal syncope, a transient failure of cardiovascular regulation.
Whole body vibration with resistive exercise is a promising countermeasure against some weightlessness-induced dysfunctions. Our objective was to study whether the combination of low-magnitude whole body vibration with a resistive exercise can prevent the cardiovascular deconditioning induced by a nonstrict 60-day head-down bed rest (Earth Star International Bed Rest Experiment Project). Fourteen healthy men participated in this study. We recorded electrocardiograms and blood pressure waves by means of a noninvasive beat-by-beat measurement system (Cardiospace, integrated by Centre National dEtudes Spatiales and Astronaut Center of China) during an orthostatic test (20 min of 75-degree head-up tilt test) before and immediately after bed rest. We estimated heart rate, blood pressure, cardiac output, stroke volume, total peripheral resistance, baroreflex sensitivity, and heart rate variability. Low-magnitude whole body vibration with resistive exercise prevented an increase of the sympathetic index (reflecting the sympathovagal balance of cardiac autonomic control) and limited the decrease of the spontaneous baroreflex sensitivity induced by 60 days of head-down bed rest. However, this countermeasure had very little effect on cardiac hemodynamics and did not improve the orthostatic tolerance. This combined countermeasure did not efficiently prevent orthostatic intolerance but prevents changes in the autonomic nervous system associated with cardiovascular deconditioning. The underlying mechanisms remain hypothetical but might involve cutaneous and muscular mechanoreceptors.
Immersion is a useful tool for studying fluid-volume homeostasis. Natriuretic peptides play a vital role in renal, humoral, and cardiovascular regulation under changing environmental conditions. We hypothesized that dry immersion would rapidly induce a new steady state for water and sodium metabolism, and that serum NT-proBNP levels, a proxy measure for brain natriuretic peptide (BNP), would decrease during long-term dry immersion and increase during recovery. Eight healthy young men were studied before, during, and after 7 days of dry immersion. Body weight, water balance, and plasma volume changes were evaluated. Plasma and serum samples were analyzed for active renin, NT-proBNP, aldosterone, electrolytes, osmolality, total protein, and creatinine. Urine samples were analyzed to determine levels of electrolytes, osmolality, creatinine, and free cortisol. A stand test was performed before and after dry immersion to evaluate cardiovascular deconditioning. Long-term dry immersion induced acute changes in water and sodium homeostasis on day 1, followed by a new steady state. Plasma volume decreased significantly during dry immersion. The serum levels of NT-proBNP increased significantly in recovery (10 ± 3 ng/L before dry immersion vs. 26 ± 5 ng/L on the fourth recovery day). Heart rate in the standing position was significantly greater after immersion. Results suggest that chronic dry immersion rapidly induced a new level of water-electrolyte homeostasis. The increase in NT-proBNP levels during the recovery period may be related to greater cardiac work and might reflect the degree of cardiovascular deconditioning.
Dry immersion, which is a ground-based model of prolonged conditions of microgravity, is widely used in Russia but is less well known elsewhere. Dry immersion involves immersing the subject in thermoneutral water covered with an elastic waterproof fabric. As a result, the immersed subject, who is freely suspended in the water mass, remains dry. For a relatively short duration, the model can faithfully reproduce most physiological effects of actual microgravity, including centralization of body fluids, support unloading, and hypokinesia. Unlike bed rest, dry immersion provides a unique opportunity to study the physiological effects of the lack of a supporting structure for the body (a phenomenon we call supportlessness). In this review, we attempt to provide a detailed description of dry immersion. The main sections of the paper discuss the changes induced by long-term dry immersion in the neuromuscular and sensorimotor systems, fluid-electrolyte regulation, the cardiovascular system, metabolism, blood and immunity, respiration, and thermoregulation. The long-term effects of dry immersion are compared with those of bed rest and actual space flight. The actual and potential uses of dry immersion are discussed in the context of fundamental studies and applications for medical support during space flight and terrestrial health care.
Actual and simulated microgravity induces hypovolemia and cardiovascular deconditioning, associated with vascular dysfunction. We hypothesized that vasoconstriction of skin microcirculatory bed should be altered following 7 days of simulated microgravity in order to maintain cardiovascular homeostasis during active standing. Eight healthy men were studied before and after 7 days of simulated microgravity modeled by dry immersion (DI). Changes of plasma volume and orthostatic tolerance were evaluated. Calf skin blood flow (laser-Doppler flowmetry), ECG and blood pressure signal during a 10-min stand test were recorded, and skin vascular resistance, central hemodynamics, baroreflex sensitivity and heart rate variability were estimated. After DI we observed increased calf skin vascular resistance in the standing position (12.0 ± 1.0 AU-after- vs. 6.8 ± 1.4 AU-before), while supine it was unchanged. Cardiovascular deconditioning was confirmed by greater tachycardia on standing and by hypovolemia (-16 ± 3% at day 7 of DI). Total peripheral resistance and indices of cardiovascular autonomic control were not modified. In conclusion, unchanged autonomic control and total peripheral resistance suggest that increased skin vasoconstriction to standing involves rather local mechanisms-as venoarteriolar reflex-and might compensate insufficient vasoconstriction of other vascular beds.
Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders.
A sedentary lifestyle has adverse effects on the cardiovascular system, including impaired endothelial functions. Subjecting healthy men to 7 days of dry immersion (DI) presented a unique opportunity to analyze the specific effects of enhanced inactivity on the endothelium. We investigated endothelial properties before, during, and after 7 days of DI involving eight subjects. Microcirculatory functions were assessed with laser Doppler in the skin of the calf. We studied basal blood flow and endothelium-dependent and -independent vasodilation. We also measured plasma levels of microparticles, a sign of cellular dysfunction, and soluble endothelial factors, reflecting the endothelial state. Basal flow and endothelium-dependent vasodilation were reduced by DI (22 + or - 4 vs. 15 + or - 2 arbitrary units and 29 + or - 6% vs. 12 + or - 6%, respectively, P < 0.05), and this was accompanied by an increase in circulating endothelial microparticles (EMPs), which was significant on day 3 (42 + or - 8 vs. 65 + or - 10 EMPs/microl, P < 0.05), whereas microparticles from other cell origins remained unchanged. Plasma soluble VEGF decreased significantly during DI, whereas VEGF receptor 1 and soluble CD62E were unchanged, indicating that the increase in EMPs was associated with a change in antiapoptotic tone rather than endothelial activation. Our study showed that extreme physical inactivity in humans induced by 7 days of DI causes microvascular impairment with a disturbance of endothelial functions, associated with a selective increase in EMPs. Microcirculatory endothelial dysfunction might contribute to cardiovascular deconditioning as well as to hypodynamia-associated pathologies. In conclusion, the endothelium should be the focus of special care in situations of acute limitation of physical activity.
Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N(G)-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II.
The most accepted animal model for simulation of the physiological and morphological consequences of microgravity on the cardiovascular system is one of head-down hindlimb unloading. Experimental conditions surrounding this model include not only head-down tilting of rats, but also social and restraint stresses that have their own influences on cardiovascular system function. Here, we studied levels of spontaneous locomotor activity, blood pressure, and heart rate during 14 days under the following experimental conditions: cage control, social isolation in standard rat housing, social isolation in special cages for hindlimb unloading, horizontal attachment (restraint), and head-down hindlimb unloading. General activity and hemodynamic parameters were continuously monitored in conscious rats by telemetry. Heart rate and blood pressure were both evaluated during treadmill running to reveal cardiovascular deconditioning development as a result of unloading. The main findings of our work are that: social isolation and restraint induced persistent physical inactivity, while unloading in rats resulted in initial inactivity followed by normalization and increased locomotion after one week. Moreover, 14 days of hindlimb unloading showed significant elevation of blood pressure and slight elevation of heart rate. Hemodynamic changes in isolated and restrained rats largely reproduced the trends observed during unloading. Finally, we detected no augmentation of tachycardia during moderate exercise in rats after 14 days of unloading. Thus, we concluded that both social isolation and restraint, as an integral part of the model conditions, contribute essentially to cardiovascular reactions during head-down hindlimb unloading, compared to the little changes in the hydrostatic gradient.
We quantified the impact of 60-day head-down bed rest (HDBR) with countermeasures on arterial and venous response to tilt.
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