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Department of Pharmacology, College of Medicine, University of California, Irvine, California 92697-4625
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Adaptation of the cerebral circulation to microgravity was investigated in rat middle cerebral arteries after 20 days of hindlimb unweighting (HU). Myogenic responses were measured in isolated, pressurized arteries from HU and control animals. Maximal passive lumen diameters, obtained in the absence of extracellular Ca2+ plus EDTA, were not significantly different between groups (249 vs. 258 µm). In physiological salt solution, arteries from both HU and control animals maintained a constant lumen diameter when subjected to incremental increases in transmural pressure (20-80 mmHg). However, the diameter of arteries from HU animals was significantly smaller than that of arteries from control animals at all pressures; this difference could be eliminated by exposure to the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. After HU treatment, transient distensibility of the artery wall in response to pressure was also significantly decreased, whereas the frequency and amplitude of vasomotion were increased. The latter changes were not affected by NG-nitro-L-arginine methyl ester. Thus simulated microgravity increases cerebral artery myogenic tone through both nitric oxide synthase-dependent and -independent mechanisms.
nitric oxide; hindlimb unweighting
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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MICROGRAVITY RESULTS IN A LOSS of the normal blood pressure gradient between cerebral and peripheral circulations when individuals are in a standing posture (20). In humans, exposure to weightlessness shifts the mean arterial pressure of the head from 70 mmHg in the upright posture on Earth to ~100 mmHg in space (21). This microgravitational-induced change in cerebral perfusion pressure results in elevated middle cerebral artery flow velocity, increased capillary blood flow and pressure, and elevated intracranial pressure (20). Adaptations to chronic blood and fluid pressure alterations resulting from weightlessness undoubtedly contribute to postflight orthostatic intolerance (21). These observations suggest that microgravity influences cerebral blood flow; however, little is known about the effect of simulated microgravity on function of resistance-sized cerebral arteries.
Cerebral circulation is controlled by autoregulatory mechanisms that maintain a constant cerebral blood flow despite changes in arterial perfusion pressure (13, 22). Three mechanisms, myogenic, metabolic, and neural, have been recognized as potential contributors to cerebral autoregulation (22). The rapidity of cerebral autoregulatory responses, initiated within a few seconds after change in transmural pressure and largely complete within 60 s, supports the existence of an active myogenic mechanism in the cerebral circulation (23).
The vascular myogenic mechanism involves active constriction or dilation in response to an increase or decrease, respectively, in the transmural pressure gradient (3, 9). Cerebral arteries are known to be especially responsive to changes in transmural pressure (14, 24, 27). The mechanisms by which an active contractile response is initiated by application of force to the vascular wall are not well understood, although changes in membrane potential and Ca2+ and K+ conductances appear to be involved (7). In addition, endothelial dilatory factors, such as nitric oxide (NO), have been shown to modulate myogenic reactivity (9).
One possible effect of the microgravity-induced increase in cranial blood pressure is an alteration of the myogenic reactivity of cerebral blood vessels. A heightened level of myogenic reactivity in small cerebral arteries and arterioles would be important to protect capillaries from elevated perfusion pressure in the microgravitational environment (5). Additionally, postflight orthostatic intolerance may result from microgravity-induced adaptation in myogenic responsiveness that slowly resolves after return to Earth (6). Interestingly, cardiovascular effects similar to microgravity have been shown to occur in rats after hindlimb unweighting (HU) (12, 29, 32). For example, reduced sensitivity to contractile agonists, hypovolemia, increased heart rate, and changes in vascular resistance were associated with both spaceflight and HU.
Therefore, to test the effect of HU on myogenic response of the cerebral circulation, we compared arteries isolated from control and HU rats, and we measured lumen diameter after multiple step changes in transmural pressure. In addition, the contribution of NO to the modulation of myogenic reactivity was determined by inhibiting NO synthase (NOS) with NG-nitro-L-arginine methyl ester (L-NAME). Finally, the passive response of each isolated artery to step changes in transmural pressure was determined after Ca2+ removal.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals. Animal procedures were approved by the Animal the Care and Use Committee of the University of California, Irvine. Male Wistar rats weighing between 200 and 250 g were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed under a 12:12-h light-dark cycle with food and water available ad libitum. Two groups of rats were used in the present study: untreated (control; n = 5) and HU (n = 5). HU treatment was applied for 20 days. Although the time course of changes in vascular function due to HU is unknown, changes in vascular function are apparent at 14 days (10). In addition, skeletal muscle changes occur over the first 18 days of HU and approach a steady state thereafter. Furthermore, significant changes in peripheral vascular function have been shown after 20 days of HU treatment (30). HU was achieved by use of a tail harness to suspend the hindlimbs above the floor of the cage according to the method of Thomason et al. (33). Briefly, the rat was suspended by a swivel harness from a hook above the suspension cage, allowing free 360° rotation. The height of the hook was adjusted so that only the front limbs were in contact with the floor. The hindlimbs, when fully extended, were elevated ~0.5 cm above the floor, which tilted the body of the rat ~35° from horizontal.
Tissue preparation. After 20 days of HU treatment, rats were euthanized by exposure to 100% CO2 for 90 s. Brains were rapidly removed from the cranial cavity and placed in a dissecting dish with cold oxygenated physiological salt solution (PSS) containing the following (in mM): 118 NaCl, 4.8 KCl, 1.6 CaCl2, 1.2 KH2PO4, 25 NaHCO3, 1.2 MgSO4, 0.3 ascorbic acid, and 11.5 glucose. A 1- to 2-mm segment of the middle cerebral artery, taken ~2 mm from the circle of Willis, was carefully dissected and mounted in an arteriograph (Living Systems, Burlington, VT). Micropipettes were inserted into each end of the artery and secured in place with nylon ties. The proximal cannula was connected through a pressure transducer and windkessel to a reservoir of PSS equilibrated with 95% O2-5% CO2. The distal cannula was connected to a Luer-lok that was open during the initial equilibration to gently flush the luminal contents. After the equilibration period, the Luer-lok remained closed so all experiments were conducted under no-flow conditions. A constant-flow peristaltic pump continuously superfused (30 ml/min) the artery with PSS. During a 60-min equilibration period, a pressure servo system maintained transmural pressure at 40 mmHg. The artery was viewed with an inverted microscope equipped with a video camera and monitor. A video-electronic dimension analyzer was used to continuously measure luminal diameter. Changes in transmural pressure and lumen diameter were digitized by a MacLab analog-to-digital converter and recorded on a Macintosh computer. All drugs, individually or in combination, were administered via the superfusate in their final concentration.
Experimental protocols. In all protocols, the changes in artery diameter in response to increased transmural pressure (no luminal flow) were measured. All vessels developed spontaneous tone. After the 60-min equilibration period, pressure was reduced to 20 mmHg. Pressure was then increased to 80 mmHg with a single 60-mmHg pressure step (<1 s), maintained for 10 min, and then returned to 20 mmHg. Three such cycles were performed on each vessel to remove mechanical hysteresis. After the three initial cycling periods, three separate series of pressure steps (each from 20 to 80 mmHg in 10-mmHg steps) were performed. The first series of pressure steps was in PSS, the second in the presence of L-NAME (1 µM), and the third in 0 Ca2+ + EDTA (1 mM). As presented in RESULTS, we have found that ACh-induced vasodilation of myogenically reactive rat middle cerebral arteries is inhibited during exposure to 1 µM L-NAME. All drugs were perfused for 20 min before the first pressure step, and each pressure step was maintained for 5-10 min to allow the vessel to reach a stable condition before diameter was measured. Control arteries showed consistent responses to the three series of pressure steps.
Myogenic tone was determined by subtracting the steady-state diameter at any given pressure in PSS from the passive diameter (0 Ca2+ + 1 mM EDTA) at that same pressure. Constriction to L-NAME was determined by subtracting steady-state diameter at any given pressure in the presence of L-NAME from the steady-state diameter in PSS at that same pressure. When vasomotion was present, the steady-state, mean diameter was calculated during the last 3 min before the next pressure-step increase. Distensibility of the arterial wall (in µm) was determined by measuring the transient change in diameter that occurred immediately after a 10-mmHg step increase in pressure. To quantify vasomotion, both the magnitude (amplitude in µm) and frequency (cycles/min) of the diameter change were measured at 20 and 80 mmHg in PSS and during L-NAME exposure. All drugs were purchased from Sigma Chemical (St. Louis, MO). Data are expressed as means ± SE. Statistical significance was determined by using either an unpaired Student's t-test (vasomotion) or ANOVA with Scheffé's test. Acceptable level of significance was defined as P < 0.05. Specific statistical tests used in each case are specified in RESULTS or in the legends of Figs. 1-6, as appropriate.| |
RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Artery response to pressure changes. Diameters of endothelium-intact cerebral arteries from untreated (control) and HU animals responded passively to step changes in transmural pressure after Ca2+ removal from the PSS with 1 mM EDTA present (Figs. 1 and 2). There were no differences in passive diameters at any pressure between arteries from control and HU animals. Maximum passive diameters (80 mmHg) were 249 ± 5 µm in arteries from control animals and 258 ± 5 µm in arteries from HU animals and were not significantly different (Fig. 2).
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Artery response to pressure changes during NOS inhibition.
To determine the degree to which NO modulates pressure-induced
myogenic tone, we used
L-NAME, a NOS
inhibitor. We have repeatedly found that ACh-induced vasodilation of
myogenically reactive rat middle cerebral arteries is inhibited during
exposure to 1 µM L-NAME
[1 µM ACh vasodilation, 19 ± 4 µm; 1 µM ACh + 1 µM L-NAME, 
5 ± 4 µm]. In the presence of
L-NAME, artery diameters from
both control and HU groups were significantly smaller at each pressure compared with their diameters at that pressure in PSS
(P < 0.05, ANOVA; Figs. 1 and
2). Furthermore, the original diameter differences between
arteries from control and HU animals were abolished after NOS
inhibition. For example, at 20 mmHg the control artery diameter was 173 ± 16 µm compared with 143 ± 18 µm in HU arteries (Fig. 2).
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Distensibility. The transient change in vessel diameter occurring immediately after each pressure step was determined in arteries from both control and HU animals in the presence of either PSS or L-NAME (Fig. 5). Arteries from control animals were significantly more distensible immediately after each pressure step than were arteries from HU animals (P < 0.005, ANOVA). In addition, although arteries from HU animals did demonstrate measurable diameter changes at the lowest pressure steps (20-40 mmHg), at higher pressures initial artery diameters did not change after step increases in pressure. In the presence of L-NAME, the distensibility of arteries from control animals tended to decrease, although this was not significantly different (P > 0.05, ANOVA) from their distensibility in PSS. For example, at 20 and 80 mmHg in the presence of L-NAME, distensibility of arteries from control animals decreased 50 ± 17 and 31 ± 20%, respectively, compared with that of arteries from control animals in PSS. Arteries from HU animals did not possess any measurable distensibility in the presence of L-NAME. Interestingly, in the presence of L-NAME, arteries from control animals were still significantly more distensible than were arteries from HU animals at pressures between 20 and 60 mmHg (P < 0.05, ANOVA).
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Vasomotion. Diameters of arteries from control and HU animals also showed different frequencies and amplitude of vasomotion (Fig. 1). In the presence of PSS, arteries from HU animals had significantly greater frequency and amplitude of vasomotion compared with that of arteries from control animals (P < 0.01, unpaired t-test; Fig. 6, A and C). During NOS inhibition at 20 mmHg, vasomotion frequency and amplitude in arteries from HU animals remained significantly greater compared with arteries from control animals at the same pressure (P < 0.01, unpaired t-test). However, in the presence of L-NAME at 80 mmHg, both the amplitude and frequency of vasomotion in arteries from control animals increased such that they were no longer significantly different from that of arteries from HU animals.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The major findings of this study are as follows: 1) HU resulted in an increase in the myogenic tone of resistance-sized cerebral arteries; 2) passive diameters of arteries from control and HU animals were not significantly different; 3) after NOS inhibition, myogenic tone of arteries from both control and HU animals increased significantly; 4) differences in myogenic tone observed in PSS were abolished after NOS inhibition; and 5) arteries from HU-treated animals were less distensible and showed greater frequency and amplitude of vasomotion. These data suggest that both NO-dependent- and -independent mechanisms modulate myogenic reactivity of cerebral arteries from HU animals. A heightened myogenic tone may serve to protect capillaries from excessive perfusion pressures in the microgravitational environment.
Exposure to microgravity removes the normal blood pressure gradients associated with upright posture on Earth (21). For example, in humans, microgravity increases mean arterial pressure within the head from near 70 mmHg in the standing position on Earth to ~100 mmHg in microgravity. Autoregulatory mechanisms of the cerebral circulation function to compensate for this increase in pressure to maintain capillary pressure and prevent edema (13, 20, 22). The stability of cerebral hemodynamics under microgravity conditions has recently been demonstrated by direct cerebral blood flow measurements in both real and simulated microgravitational environments (1). Therefore, the mechanisms that autoregulate cerebral blood flow are intact and functional in microgravity, although adaptations of the responsible effector mechanisms to make these adjustments possible are as yet unknown.
In the normal gravitational environment, cerebral circulation is regulated by a combination of neural, metabolic, and myogenic mechanisms (13, 22). As mentioned previously, in spaceflight, autoregulatory mechanisms responsible for controlling capillary pressures are unknown. However, after exposure to microgravity, changes in peripheral neural control of blood pressure have been extensively associated with the pathophysiology of postflight orthostatic hypotension (8). Although neural mechanisms can contribute to cerebral autoregulation under certain conditions (hypertension) (31), the effect of neural factors in flight would seem to be minimal because resistance-sized cerebral blood vessels are relatively devoid of sympathetic innervation (4). Mechanisms intrinsic to the vascular smooth muscle may be more responsible for autoregulation of cerebral blood flow during exposure to microgravity.
Cardiovascular effects of microgravity have been simulated in rats after HU (12, 26, 29, 32). These changes include reduced sensitivity to contractile agonists, hypovolemia, increased heart rate, and changes in vascular resistance. In addition, HU treatment has been recently shown to reduce the contractile effects of K+ and norepinephrine on rat aorta (10) and carotid and femoral arteries (30). These findings suggest that HU alters vascular reactivity. However, the effects of HU and microgravity on the cerebral circulation have not previously been studied.
Changes in vascular reactivity after HU treatment appear to be hemodynamic consequence of the head-down tilt and not a result of chronic stress. Measurements of adrenal weights and plasma corticosterone indicate a transient increase in stress at the onset of HU, but the animals appear to adapt to this condition (26, 32). Additionally, the absence of significant cardiac hypertrophy suggests that the cardiovascular system was not overly stressed by HU (33). Combined, these data suggest that vascular reactivity changes induced by HU are most likely to be the consequence of simulated microgravity on the cardiovascular system and not effects of chronic stress on the animal. However, additional studies would be necessary to further confirm this point.
In the present study, we have shown that myogenic tone was significantly greater in arteries from HU animals compared with arteries from control animals; however, maximum passive diameters were not significantly different between groups. Together, these findings suggest that simulated microgravity heightens the myogenic responsiveness of the cerebral arteries without altering the structural composition of the arterial wall (27, 28, 34). This conclusion is reinforced by calculations of transient distensibility, which demonstrate a decrease in distensibility in arteries from HU- treated rats, reflecting an increase in myogenic tone.
How does HU treatment result in an alteration of cerebrovascular myogenic tone? Myogenic tone is the intrinsic ability of vascular smooth muscle to alter its state of contractile activation in response to changes in transmural pressure (9). Although the precise mechanisms responsible for the initiation and maintenance of myogenic tone are as yet unknown, changes in membrane potential and intracellular Ca2+ are critically important (9). The release of NO from the vascular endothelium also regulates myogenic tone, although the role of NO and the endothelium is clearly one of modulation rather than initiation or maintenance (9). Finally, K+ channels, located in the smooth muscle cell membrane, operate as a negative-feedback mechanism, controlling the magnitude of tone caused by elevated transmural pressure (7).
Because NO modulates myogenic reactivity, HU could alter either the synthesis or effect of NO on the vascular smooth muscle. If a primary effect of HU is to influence NO-dependent modulation of myogenic tone, then myogenic tone differences between arteries from control and HU animals should be abolished when NOS is inhibited. We found that inhibition of NOS significantly increased myogenic tone in arteries from both control and HU animals, demonstrating that, in both groups of animals, production of NO due to activity of NOS significantly modulates the development of myogenic tone. However, after inhibition of NOS, myogenic tone differences between arteries from control and HU animals were not present. These data imply that HU treatment caused a downregulation of NO-dependent vasodilatory mechanisms, allowing a greater expression of myogenic tone in arteries from HU animals compared with arteries from control animals. Thus, when NO was not being produced, diameters of arteries from control and HU animals were similar.
Besides having an effect on modulation of NO, it also appears that HU treatment influences additional mechanisms, intrinsic to the smooth muscle, which are involved in myogenic regulation. We analyzed the smooth muscle activation state by determining passive diameters, distensibility, and vasomotion. These three physical characteristics of arterial smooth muscle are known to be dependent on both ionic and structural properties of the vessel wall (2, 17-19, 27, 28). Passive diameters of arteries from control and HU animals were not significantly different at any pressure studied. These data suggest that HU does not cause any gross structural changes to the blood vessel wall (27, 28, 34). Distensibility is the transient expansion of the artery wall after step increases in pressure (15, 35). Vasomotion, on the other hand, is the spontaneous and cyclic variation of vessel diameter (2, 17, 18). In the present study, arteries from HU animals were significantly less distensible both before and during inhibition of NOS compared with arteries from control animals. Furthermore, the frequency and amplitude of vasomotion at two different pressures were significantly greater in arteries from HU animals with functional NOS. After inhibition of NOS, frequency and amplitude of vasomotion of HU arteries were still significantly greater than those of control arteries at the lower pressures. Therefore, it appears that HU alters intrinsic smooth muscle control mechanisms, independent of the activity of NOS, and these intrinsic mechanisms are responsible for both the generation and maintenance of rhythmical activity and myogenic tone.
The intrinsic smooth muscle control mechanisms that regulate myogenic tone, distensibility, and vasomotion are similar (2, 9, 18, 19). These control mechanisms operate through dynamic changes to the smooth muscle membrane potential, Ca2+ and K+ conductances, and membrane electrogenic pump activity (9, 28). Therefore, the enhanced myogenic tone, decreased distensibility, and greater vasomotion in arteries from HU animals may all arise from pressure-dependent changes to these mechanisms that regulate membrane excitability.
Cerebrovascular resistance must increase to compensate for the acute elevation of perfusion pressure in microgravity. Alterations in arterial distensibility and vasomotion are two possible mechanisms that the vascular network could utilize during microgravity to autoregulate capillary pressure and flow (15, 16). For example, less-distensible vessels are stronger, hyperreactive, and able to withstand a wider pressure range (15). Vasomotion, on the other hand, modulates the magnitude of elevated vascular resistance to maintain capillary pressure (16). In combination, decreased distensibility and increased vasomotor function could modify vascular resistance and assist cerebral autoregulation during microgravity.
The cerebral and peripheral blood vessels appear to respond differently to HU. We have found that vascular reactivity to norepinephrine and membrane-depolarizing concentrations of K+ were reduced in wire-mounted carotid and femoral arteries from HU-treated animals (30). Our data are supported by previous findings that HU treatment depressed the maximal contractile response of the rat aorta to vasoconstrictor stimuli (10). The precise mechanisms responsible for these disparate findings are unknown. However, the cephalad shift in mean arterial pressure that occurs during HU undoubtedly alters hemodynamic, myogenic, neurogenic, and metabolic regulatory mechanisms of the cardiovascular system.
Exposure to microgravity increases mean cerebral perfusion pressure. Although these changes are acute and reversible (1), they mimic some of the cardiovascular and cerebrovascular effects of chronic hypertension (13). Interestingly, isolated cerebral arteries from genetically hypertensive rats possess greater myogenic tone, reduced distensibility, greater vasomotion, and reduced basal formation of NO compared with normotensive arteries (11, 28). Therefore, the acute cerebrovascular adaptations required during brief exposure to microgravity may be similar to chronic changes in the cerebral vasculature that occur during maintained hypertension.
In conclusion, the present study has shown that HU increases myogenic tone in resistance-sized cerebral arteries. Although a portion of these myogenic tone differences appear to be NO dependent, regulatory mechanisms intrinsic to the vascular smooth muscle also appear to change after HU. The physiological implications of greater myogenic tone in microgravity are unknown. However, capillary protection against an elevated cerebral perfusion pressure induced by microgravity would maintain normal cerebral autoregulation and prevent edema and possibly stroke. Thus the present findings begin to explain physiological adaptations of cerebral blood vessels during exposure to microgravity.
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ACKNOWLEDGEMENTS |
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The authors thank D. Sara for invaluable technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-50775 and National Aeronautics and Space Administration Grant NAGW-4415.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: G. G. Geary, Dept. of Pharmacology, College of Medicine, Univ. of California, Irvine, CA 92697-4625 (E-mail: gggeary{at}uci.edu).
Received 23 February 1998; accepted in final form 19 June 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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) in
transmural pressure. After initial series of pressure steps in PSS,
L-NAME (1 µM) was superfused
for 20 min before and during the next series of pressure steps. Values
are means ± SE; n = 5 animals.
* P < 0.05, compared with
control (ANOVA).
