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Am J Physiol Heart Circ Physiol 287: H1505-H1515, 2004. First published May 13, 2004; doi:10.1152/ajpheart.00143.2004
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Differential activation of potassium channels in cerebral and hindquarter arteries of rats during simulated microgravity

Zhao-Jun Fu, Man-Jiang Xie, Li-Fan Zhang, Hong-Wei Cheng, and Jin Ma

Department of Aerospace Physiology, The Fourth Military Medical University, Xi'an 710032, China

Submitted 17 February 2004 ; accepted in final form 4 May 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The purpose of this study was to test the hypothesis that differential autoregulation of cerebral and hindquarter arteries during simulated microgravity is mediated or modulated by differential activation of K+ channels in vascular smooth muscle cells (VSMCs) of arteries in different anatomic regions. Sprague-Dawley rats were subjected to 1- and 4-wk tail suspension to simulate the cardiovascular deconditioning effect due to short- and medium-term microgravity. K+ channel function of VSMCs was studied by pharmacological methods and patch-clamp techniques. Large-conductance Ca2+-activated K+ (BKCa) and voltage-gated K+ (Kv) currents were determined by subtracting the current recorded after applications of 1 mM tetraethylammonium (TEA) and 1 mM TEA + 3 mM 4-aminopyridine (4-AP), respectively, from that of before. For cerebral vessels, the normalized contractility of basilar arterial rings to TEA, a BKCa blocker, and 4-AP, a Kv blocker, was significantly decreased after 1- and 4-wk simulated microgravity, respectively. VSMCs isolated from the middle cerebral artery branches of suspended rats had a more depolarized membrane potential (Em) and a smaller K+ current density compared with those of control rats. Furthermore, the reduced total current density was due to smaller BKCa and smaller Kv current density in cerebral VSMCs after 1- and 4-wk tail suspension, respectively. For hindquarter vessels, VSMCs isolated from second- to sixth-order small mesenteric arteries of both 1- and 4-wk suspended rats had a more negative Em and larger K+ current densities for total, BKCa, and Kv currents. These results indicate that differential activation of K+ channels occur in cerebral and hindquarter VSMCs during short- and medium-term simulated microgravity. It is further suggested that different profiles of channel remodeling might occur in VSMCs as one of the important underlying cellular mechanisms to mediate and modulate differential vascular adaptation during microgravity.

hindlimb unloading; ion channels; vessels; voltage-dependent potassium channels; calcium-dependent potassium channels

FINDINGS from recent spaceflight human studies have indicated that the inability to adequately elevate the peripheral vascular resistance and the enhancement of cerebral vasoconstriction are important factors in postflight orthostatic intolerance (7, 18, 22, 54, 61, 63). Studies in rats have revealed that simulated microgravity differentially alters the function and structure of cerebral and hindquarter vessels: for hindquarter arteries, attenuated myogenic tone and vasoreactivity and atrophy; and for cerebral vessels, enhanced myogenic tone and vasoreactivity and hypertrophy have been demonstrated (12, 19, 33–35, 56, 57, 61, 64). These findings substantiate in general the hypothesis that the redistribution of transmural pressures and flows across and within the arterial vasculature due to the removal of gravity may well initiate differential adaptations of vessels in different body regions (12, 22, 54, 61). Vascular adaptations to microgravity have been speculated as among the most important mechanisms responsible for postflight cardiovascular function (12, 22, 54, 61, 63). However, the underlying cellular mechanisms need to be further elucidated. Among them, the channel mechanism of vascular smooth muscle cells (VSMCs) may play an important role.

The cytoplasmic Ca2+ concentration ([Ca2+]cyt) is the most important signal transduction element in maintaining myogenic tone and triggering cell contraction (24) and proliferation of VSMCs (1, 21, 47, 60). Membrane potential (Em) in VSMCs plays a critical role in regulating [Ca2+]cyt by governing the activity of voltage-dependent Ca2+ channels (VDCs) (25, 40) and by facilitating the production of inositol (1,4,5)-triphosphate [Ins(1,4,5)P3], which opens Ca2+-release channels in the sarcoplasmic reticulum and triggers Ca2+ release (17). K+ channels are dominant ion-conductive pathways in VSMCs and play a dominant role in the maintenance of resting Em (24, 40). Because of the existing electrochemical gradient for K+, opening of K+ channels leads to diffusion of K+ out of the cells and membrane hyperpolarization, whereas closure of K+ channels leads to depolarization. Membrane depolarization opens VDCs, whereas hyperpolarization closes them (24). The roles of voltage-activated K+ (Kv) channels and large-conductance Ca2+-activated K+ (BKCa) channels in maintaining and regulating Em and myogenic tone have been studied most widely (25, 40).

Acute increases in intravascular pressure produce depolarization and constriction of cerebral arteries in vitro (6, 20, 27) and in vivo (46). Several lines of evidence suggest that Kv and BKCa channels in VSMCs participate in the autoregulation of cerebral vascular tone during acute pressure increases. In hypertensive animals, a sustained elevation in blood pressure is associated with an upregulation of VDCs and/or loss of Kv channels and overexpression of BKCa channels in VSMCs (11). Overexpression of BKCa channels has been proposed to be a universal protective mechanism to buffer the increased vasoreactivity and limit active vasoconstriction during hypertension (6, 11, 24, 32, 40, 45, 46, 51). Kv channels are also involved in the process of vascular remodeling. For example, findings from recent studies on the pathogenesis of primary pulmonary hypertension have indicated that a defect in mRNA expression of Kv channels, which lead to a reduction of Kv current in pulmonary VSMCs, may be a unique mechanism involved in initiating and maintaining pulmonary vasoconstriction and inducing vascular remodeling (59, 60). However, activation of KCa and Kv channels, which leads to a loss of cytoplasmic [K+] and an apoptotic volume decrease, has been speculated to be involved in nitric oxide-induced pulmonary VSMC apoptosis (28).

During microgravity exposure, all gravitational blood pressure gradients disappear; therefore, blood vessels in dependent body regions are chronically exposed to a lower than normal 1-g upright blood pressure, whereas vessels above the heart level are exposed to a higher than normal 1-g blood pressure (22, 54, 61). In rats, it is estimated that the mean blood pressure in the basilar artery would be increased by ~17 mmHg during head-down tilt by tail suspension compared with standing (57). Interestingly, the increased myogenic tone (19) and enhanced vasoreactivity (64) and hypertrophic remodeling (35, 61) in cerebral vessels of simulated microgravity rats are quite similar to changes in hypertensive rats (23, 42–44, 58), suggesting that these changes are mainly triggered and maintained by sustained elevations in transmural pressure in cerebral vessels. Thus it is important to examine whether similar changes in activities of Kv and KCa channels occur in VSMCs isolated from cerebral arteries of rats subjected to simulated microgravity. It is also of importance to examine whether the changes in both Kv and KCa activities of hindquarter arterial VSMCs are just in an opposite direction, because decreased transmural pressures and flows in these vessels during simulated microgravity have been predicted and reported (22, 37, 49, 54, 61). Interestingly, our preliminary pharmacological studies using tetraethylammonium (TEA) and 4-aminopyridine (4-AP) to inhibit BKCa and Kv channels, respectively, indicated that the activities of BKCa and Kv channels in VSMCs of the rat femoral artery were significantly altered after simulated microgravity (16).

Therefore, we designed the present study to investigate changes in Kv and KCa currents and Em of VSMCs isolated from the middle cerebral artery and its branches and small mesenteric arteries and arterioles of 1- and 4-wk simulated microgravity rats compared with those of control rats. Small mesenteric arteries were chosen because it had been reported that after simulated microgravity, splanchnic vasoconstriction function is compromised (33, 61). In addition, the K+ channel function of cerebral vessels was also studied by the vasoreactivity changes after BKCa and Kv blockades. The goal of this study was to test the hypothesis that the upward and downward autoregulations of cerebral and hindquarter arteries and arterioles during a short- or medium-term simulated microgravity are mediated or modulated, respectively, by a decrease and an increase in the activation of K+ channels in VSMCs of these arteries. Part of the findings regarding hindlimb vessels have been presented as meeting proceedings (15).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animal Model and Experimental Design

Tail-suspended, hindlimb-unloaded rat model. The technique of tail suspension (38) with modification from our laboratory has been described in detail previously (64). The animals were maintained in an about –30° head-down tilt position with their hindlimbs unloaded. The animals received standard lab chow and water ad libitum and were caged individually in a room maintained at 23°C on a 12:12-h light-dark cycle.

Animals and experimental design. All the protocols and procedures described herein were reviewed and approved by the Animal Care and Use Committee of the Fourth Military Medical University. This study incorporated two sets of experiments.

Experiment 1 was performed to determine the regional specificity of changes in the function of Kv and BKCa channels of VSMCs of cerebral arteries and arterioles by both pharmacological and electrophysiological methods. Eighty male Sprague-Dawley rats weighing between 200 and 250 g were randomly assigned to four groups (n = 20 rats/group): 1-wk control (Con-1), 1-wk suspended (Sus-1), 4-wk control (Con-4), and 4-wk suspended (Sus-4). In each group, one-half of the animals was used for determining vasoreactivity changes of basilar arterial rings, and the other half was used for recording whole cell K+ currents of VSMCs from middle cerebral arteries and their branches.

Experiment 2 was performed to determine the changes in whole cell K+ current of VSMCs from small mesenteric arteries. Forty male Sprague-Dawley rats weighing between 200 and 250 g were randomly assigned to four groups (n = 10 rats/group): Con-1, Sus-1, Con-4, and Sus-4.

After a 1- or 4-wk suspension period, animals from the Con and Sus groups were anesthetized with pentobarbital sodium (40 mg/kg ip) and killed by exanguination via the abdominal aorta. Brains or mesenteries were rapidly removed from the cranial or abdominal cavity and placed in a dissecting dish with cold oxygenated Krebs solution.

Basilar Arterial Ring Preparation and Vasoreactivity Measurement

Basilar arterial ring preparation and vasoreactivity measurement were performed as previously described (2, 39, 64).

Vasoreactivity of basilar arterial rings was determined according to the procedure described previously (64). Briefly, the basilar artery was carefully isolated from the brain under a dissecting microscope. The vessel was freed of fat and connective tissues and cut into rings (2 mm in length) with the endothelium intact. Each vessel preparation was mounted by means of two specially made plastic holders in a 20-ml organ bath filled with Krebs solution, maintained at 37°C and bubbled with a gas mixture of 95% O2-5% CO2 (39, 64). The Krebs solution contained (in mM) 115 NaCl, 4.7 KCl, 25 NaHCO3, 1.2 MgCl2, 1.2 KH2PO4, 2.5 CaCl2, and 10 glucose; pH 7.4. One holder was fixed to a micrometer-controlled device to allow the vessel to be stretched by known increments. The other one was attached to a force-displacement transducer (TB-6541T) and via the amplifier (EF-601G) connected to a polygraph recorder (RM-6000, Nihon Kohden; Tokyo, Japan) for isometric tension recording. For each individual vessel ring, the proper length-tension relationship during repeated exposures to 100 mM KCl was determined by 40-mg increments until an optimal resting force around 200 mg was identified. All the subsequent pharmacological examinations were conducted at this initial resting force. The contractile response of each arterial ring to 60 mM KCl was measured at first. The concentration-response relationship to TEA (Sigma) or 4-AP (Sigma) was then determined by cumulative addition of each K+ channel blocker. The contractile responses to various concentrations of K+ channel blockers are expressed as a percentage of the maximum contraction induced by 60 mM KCl to exclude the differences in vascular contractile mechanisms due to suspension (2, 34, 61, 64).

Electrophysiological Measurement

Electrophysiological measurements were performed as previously described (25).

Cell preparation. The middle cerebral artery with its branches and the superior mesenteric artery with its branches in the mesentery were removed and placed in 4°C cold physiological salt solution (PSS). PSS contained (in mM) 137 NaCl, 5.6 KCl, 1 MgCl2, 0.42 Na2HPO4, 0.44 NaH2PO4, 4.2 NaHCO3, and 10 HEPES, bubbled with 95% O2-5% CO2; pH was adjusted to 7.4 with NaOH. The tissues were then placed in a petri dish with PSS containing 1 mg/ml BSA (Sigma) and 30 µM sodium nitroprusside (SNP). The middle cerebral artery with first- to third-order branches and second- to sixth-order small mesenteric arteries and arterioles (250.6 ± 45.7 µm in diameter, n = 16) were isolated, dissected free of connective and fat tissues, and then cut into 1- to 2-mm lengths. Segments from different vessels were digested in separate test tubes with 5 mg/ml papain (BIB), 2 mg/ml dithioerythritol (Amresco), and 1 mg/ml BSA in PSS at 37°C for 20 min. Tissue was then transferred to enzyme-free, BSA-containing PSS, stored for 10 min, and triturated with a flame-polished pipette to disperse VSMCs. The suspension was stored in Ca2+-free PSS at 4°C for use within 6 h.

Measurement of K+ currents and Em. Whole cell currents were recorded with an amplifier (CEZ-2300, Nihon Kohden) and a version interface (Axon Instruments) using patch-clamp techniques. Patch pipettes (tip resistance, 2–6 M{Omega}) were fabricated on a electrode puller (Narishige) with the use of borosilicate glass tube. The perfusion bath (extracellular) solution contained (in mM) 135 NaCl, 4 KCl, 1 MgCl2, 2 CaCl2,10 HEPES, and 10 glucose, bubbled with 95% O2-5% CO2; pH was adjusted to 7.4 with NaOH. The pipette solution contained (in mM) 143 KCl, 1 MgCl2, 0.5 EGTA, and 10 HEPES; pH was adjusted to 7.2 by KOH. Command-voltage protocols and data acquisition were performed using pCLAMP software (version 8.0, Axon Instruments). Step-pulse protocols and data acquisition were performed at room temperature (22–24°C). Currents were filtered at 0.5–1 kHz and digitized at 4–6 kHz.

For measurement of whole cell K+ currents, the VSMC was perforated by applying a negative suction to the surface of the cell placed onto the bottom of a 2-ml recording chamber. After a gigaohm seal, cell capacitance and access resistance were estimated from the capacitive current transient evoked by applying a 20-mV pulse for 40 ms from a holding potential of –60 to –40 mV. Em was defined in voltage-clamp experiments from current-voltage (I-V) plots as the holding potential that yielded the zero membrane current. I-V relationships were generated in voltage-clamped cells held at an Em of –70 mV and then stepped in 10-mV increments to +60 mV. Voltage steps were 2 s in duration and 10-s intervals were allowed between steps. Currents were filtered at 1 kHz and sampled at 4 kHz. Currents during the last 400 ms in each step of two or three voltage-clamp trials were sampled and averaged before analysis of the current amplitudes. Currents were also normalized to cell capacitance to obtain the current densities. To separate BKCa and Kv currents from total currents, the following protocol was adapted. First, whole cell currents were recorded in two trials separated by 2 min, and the currents were then recorded after 3, 5, and 10 min after the perfusion fluid was changed to contain 1 mM TEA or 1 mM TEA + 3 mM 4-AP. By subtracting the average currents after each perfusion changing from that of before, we obtained the BKCa and Kv currents in succession.

Statistical Analysis

Unless specified, composite data are expressed as means ± SE. One-way ANOVA was used to determine the overall differences in K+ current density and vasoreactivity to TEA or 4-AP between different groups. Student's t-test was used to determine the differences in body weight, soleus wet weight, vasoreactivity to KCl, membrance capacitance, and resting Em between different groups. The 0.05 level of probability was chosen as significant for all analysis.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Body and Soleus Muscle Weight

There were no significant differences in final body weight between each Sus group and its simultaneous Con group in both experiments 1 and 2 (Table 1). After the 1- and 4-wk tail suspensions, wet weights of soleus muscle were 40% and 70% less, respectively, than in the respective Con group (P < 0.01), which indicated the deconditioning effect of simulated microgravity.


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  		Table 1. Body weight and soleus weight of rats in experiments 1 and 2

 
Vasoconstrictor Responses of Basilar Arterial Rings to BKCa or Kv Channel Blockers

As shown in Fig. 1, compared with that of the respective Con group, simulated microgravity for 1 wk as well as 4 wk resulted in an enhancement of the contractile response of the basilar arterial ring to 60 mM KCl as reported previously (61, 64). Cumulative addition of TEA (a blocker of BKCa channels) or 4-AP (a blocker of Kv channels) elicited concentration-dependent contractile responses of basilar arteries rings in rats of all the four groups. To exclude the influence of the increment in the ability of the vascular smooth muscle contractile apparatus to generate force in cerebral arteries due to simulated microgravity (61, 64), the contractile responses to K+ channel blockers were normalized to the maximum contractions induced by 60 mM KCl on respective basilar arterial rings. Figure 2 depicts normalized results. After 1 wk of simulated microgravity, the normalized contractile response of the basilar arterial ring to TEA was significantly smaller (P < 0.05), whereas after 4 wk, it did not show a significant change compared with that of the respective Con group. In contrast to the effect of TEA, after 1 wk of simulated microgravity, the normalized contractile response of the basilar arterial ring to 4-AP did not show a significant change, whereas after 4 wk, it was significantly smaller (P < 0.05) compared with that of the respective Con group.



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  		Fig. 1. Effect of 1-wk (A) and 4-wk (B) simulated microgravity on contractile responses to 60 mM KCl, tetraethylammonium (TEA), and 4-aminopyridine (4-AP) of basilar arterial rings from control (Con) and suspended (Sus) rats. Values are means ± SE. +P < 0.05; *P < 0.05 between groups by ANOVA.

 


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  		Fig. 2. Concentration-response curves showing differential effects of TEA and 4-AP on the normalized contractile response of basilar arterial rings from 1- (A) and 4-wk (B) simulated microgravity rats. *P < 0.05; **P < 0.01 between groups by ANOVA.

 
Electrophysiological Characteristics of Single VSMCs Isolated from the Middle Cerebral Artery and Its Branches

Membrane capacitance and resting Em. After 1 wk of simulated microgravity, the mean resting Em of VSMCs isolated from the middle cerebral artery and its first- to third-order branches of Sus rats did not show significant change. However, after 4 wk of simulated microgravity, the resting Em of VSMCs isolated from the same kind of cerebral vessels of Sus rats was significantly more positive, i.e., more depolarized, than that of Con rats (P < 0.05; Table 2). After 1 wk as well as 4 wk of simulated microgravity, cell capacitance, an index of cell membrane area, did not show significant changes compared with respective Cont rats (Table 2).


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  		Table 2. Cm and RP of VSMCs isolated from cerebral and mesenteric small arteries

 
Whole cell K+ current. Figure 3 illustrates whole cell K+ currents of a VSMC isolated from a middle cerebral artery and its branches of a Con rat and the effects of K+ channel blockers. A family of voltage-dependent, outward K+ currents was elicited by depolarizing the cell from a holding potential of –70 mV to a series of command potentials ranging from –60 to +60 mV. Extracellar application of 1 mM TEA significantly reduced the amplitude of the K+ currents and diminished the current noise associated with higher positive command potentials, whereas Em was not altered. These properties suggest that the outward currents blocked by TEA were currents through BKCa channels (24, 40). Application of 3 mM 4-AP in the presence of 1 mM TEA further suppressed the currents almost completely, attenuated the current decaying, and depolarized the cell. These are the characteristics of Kv currents (24, 40) (Fig. 3, A–C). The mean I-V curves of total currents and those after BKCa and Kv blockades for the cell are shown in Fig. 3D.



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  		Fig. 3. K+ currents of a vascular smooth muscle cell (VSMC) isolated from a middle cerebral artery of a Con rat, showing blocking effects of TEA and 4-AP (A–C) and current-voltage (I-V) curves of K+ currents (D).

 
In Fig. 4, the I-V relationships were further expressed in terms of current density, calculated using the estimated membrane capacitance. Although the total current densities of the cerebral VSMCs from both 1- and 4-wk Sus cells were significantly smaller than their respective Con groups (P < 0.05), the two components of the outward currents altered differently in different phases. After 1 wk of simulated microgravity, only the BKCa current density decreased significantly (P < 0.05), whereas after 4 wk, only the Kv current density showed a significant reduction (P < 0.05), compared with their respective Con groups (Fig. 4). The current density data for cerebral VSMCs measured under the +20-mV command potential are further summarized in Fig. 6, top.



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  		Fig. 4. Effects of 1-wk (A) and 4-wk (B) simulated microgravity on K+ channel current densities of VSMCs isolated from middle cerebral arteries. BKCa channels, large-conductance Ca2+-activated K+ channels; Kv channels, voltage-gated K+ channels. Values are means ± SE. *P < 0.05 between groups by ANOVA.

 


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  		Fig. 6. Comparision of changes in K+ current between cerebral (A) and small mesenteric (B) VSMCs after simulated microgravity. Testing potential: +20 mV. Values are means ± SE. *P < 0.05 vs. Con.

 
Electrophysiological Characteristics of Single VSMCs Isolated from Small Mesenteric Arteries

Membrane capacity and resting Em. After both 1 and 4 wk of simulated microgravity, the mean resting Em of VSMCs isolated from the second- to sixth-order small mesenteric arteries of Sus rats was more negative, i.e., hyperpolarized, than that of their respective Con rats (P < 0.05; Table 2), whereas the cell capacitance did not show significant changes (Table 2).

Whole cell K+ current. After 1 wk as well as 4 wk of simulated microgravity, the total, BKCa, and Kv current densities of VSMCs from small mesenteric arteries were significantly larger than those from the respective Con rats (P < 0.05; Fig. 5). The current density data from small mesenteric arteries measured under the +20-mV command potential are further summarized in Fig. 6, bottom.



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  		Fig. 5. Effects of 1-wk (A) and 4-wk (B) simulated microgravity on K+ channel current densities of VSMCs isolated from small mesenteric arteries. Values are means ± SE. *P < 0.05 between groups by ANOVA.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major findings of the present study have demonstrated that the activities of K+ channels of VSMCs are significantly decreased and increased, respectively, in cerebral and mesenteric resistive arteries during both short- and medium-term simulated microgravity. For cerebral vessels, the normalized vasoreactivity of basilar arterial ring to TEA and 4-AP was significantly smaller, respectively, in 1- and 4-wk simulated microgravity groups. The whole cell total K+ current density of cerebral VSMCs was significantly smaller in both simulation groups; however, BKCa and Kv current densities showed significant decreases, respectively, only in 1- and 4-wk simulated microgravity groups. The mean resting Em of cerebral VSMCs of Sus rats was significantly more positive than that of the controls only after a 4-wk simulated microgravity, whereas the membrane capacitance did not show significant change in both simulation groups. For small mesenteric arteries, the changes in electrophysiological characteristics of VSMCs were opposite to that of cerebral arteries. The total, BKCa, and Kv current densities of VSMCs isolated from the second- to sixth-order small mesenteric arteries of 1-wk as well as 4-wk Sus rats were significantly larger than those of control rats. The mean resting Em of mesenteric VSMCs was more negative in two simulation groups, whereas the membrane capacitance did not show significant change. The patch-clamp results are also in accord with our previous pharmacological studies on K+ channel function of the femoral artery (16). To our knowledge, this is the first study to demonstrate differential changes in K+ channel activities of VSMCs in cerebral and hindquarter resistive vessels due to simulated microgravity.

Pivotal Role of the VSMC Channel Mechanism in Functional and Structural Autoregulation of Vessels

It has been postulated that differential adaptational changes of vessels in different anatomic regions to real/simulated microgravity are basically a problem of vascular autoregulation to locally sustained elevated or lowered transmural pressures in different vascular beds (12, 22, 54, 61, 63). Thus the significance of the present findings should be considered at first in the light of recent progress in elucidating the role of ion channels in the pathogenesis of vascular disease (2, 11, 24, 36, 59, 60).

Blood vessels are permanently subjected to mechanical forces in the form of stretch (tension stress) due to blood pressure and shear stress due to blood flow, and these factors are interdependent in the process of vascular remodeling (29, 30). The present work focused on the K+ channel function of VSMCs isolated from two kinds of arteries, because ex vivo studies with aortic organ culture have shown that a certain level of stretch due to transmural pressure appears to be essential in maintaining vascular smooth muscle components. These studies have demonstrated further that overstretching triggers adaptational processes, resulting in hypertrophy, whereas abnormally lowered transmural pressure results in atrophic changes (3, 5, 30). The presence of endothelium was not essential for the maintenance of VSMC marker proteins (30). These results also corroborate earlier experiments with cultured VSMCs under cyclic stretching (30). Given the complexity of the vascular adaptation as a whole, much further work is certainly needed to obtain an integrated view considering the interaction of shear factor, which is sensed principally by endothelial cells. In fact, endothelial dysfunction of rat basilar arteries due to simulated microgravity similar to that of spontaneously hypertensive rats (SHR) have been reported (64). Nevertheless, elucidating channel mechanisms involved in VSMCs is of prime importance, because VSMCs are the main effector cells and endothelium-derived vasoactive substances exert their effects in part through ion channels in VSMCs.

Small arteries exist in a partially contracted state. This state is also termed myogenic tone, because a significant portion of which is a stretch-induced response to prevailing transmural pressure and is independent of neural and humoral influences (4). From this state, small arteries and arterioles can constrict further or dilate depending on pressure changes and other demands in circulatory adjustments. At least, the triad of Kv, KCa, and VDC ion channels plays a pivotal role in pressure-induced excitation-contraction coupling of VSMCs (11, 24, 36, 40). Em is a key determinant that regulates Ca2+ influx through VDCs channels, and K+ channels are one of the primary determinants that maintain and regulate Em.

Because of the electrochemical gradient for K+, opening of K+ channels results in diffusion K+ out of cells, plasma membrane hyperpolarization, closure of VDCs, and a decrease in [Ca2+]cyt, which leads to vasodilation. Conversely, closure of K+ channels causes membrane depolarization and activates VDCs, enhances Ca2+ influx, and triggers vasoconstriction (11, 24, 40). Among the four types of K+ channels expressed in VSMCs, at least Kv and high-conductance voltage- and Ca2+-sensitive BKCa channels are highly implicated in the regulation of vascular tone (11, 40). Kv channels are important regulators of smooth muscle membrane potential. One important role is to dampen excitation by providing a mechanism of hyperpolarization in response to depolarizing stimuli. A second important role of the Kv channel is its contribution in the maintenance of resting Em. Blockade of Kv channels by 4-AP leads to depolarization and vasoconstiction (24, 36, 40). BKCa channels are activated by membrane depolarization and increases in [Ca2+]cyt, particularly focal increases of subsarcolemmal Ca2+ (i.e., calcium sparks). BKCa channels are thought to represent a negative feedback mechanism that limits active vasoconstriction to pressure increase and other vasoconstrictor stimuli (24, 32, 36, 40, 45, 46, 50, 51). Vasoconstriction responses of cerebral vessels to acute increases in blood pressure are augmented by KCa blockers, like TEA and iberiotoxin (46).

If blood pressure remains high, the myogenic response may amplify the initial rise in blood pressure by increasing vascular tone and may ultimately lead to structural remodeling of vessels (14, 39). In addition to its role in excitation-contraction coupling, [Ca2+]cyt also serves as a critical signal transduction element in the regulation of growth and proliferation of VSMCs (1, 11, 21, 60). For example, a rise in [Ca2+]cyt can increase nuclear [Ca2+], which can promote cell proliferation (1, 21). The expression of many transcription factors that promote the cell cycle and stimulate cell division is also Ca2+ dependent (21). The critical roles of reduced Kv current, depolarized Em, and elevated [Ca2+]cyt in stimulating proliferation of cultured VSMCs isolated from the pulmonary artery have been demonstrated (47, 48). Membrane depolarization is also associated with inhibition of cell apoptosis (13). In contrast, increased Kv current has been demonstrated to be one of the underlying mechanisms in nitric oxide-induced pulmonary VSMC apoptosis (28). When cultured pulmonary VSMCs were exposed to nitric oxide, K+ currents and K+ efflux increased. The resulting net K+ loss would lead to an apoptotic volume decrease (cell shrinkage), cytosolic caspase activation, and induce apoptosis. Blocking K+ channels with TEA, 4-AP, or iberiotoxin significantly inhibited the nitric oxide-induced apoptosis (28).

Arterial Ion Channel Remodeling in Hypertension

Ion channel alterations in hypertension have been studied in detail with SHR. Several lines of evidence has suggested that high blood pressure may result in an altered ion channel expression to further alter the excitable properties of VSMCs and to maintain membrane depolarization, Ca2+ influx, and vascular tone as reported in earlier studies (20, 26). Recently, a "disease-specific" profile of ion channels, known as "ion channel remodeling," has been proposed as an important mechanism in the pathogenesis of hypertension (11). Pressure-induced channel remodeling includes reciprocal upregulation of VDCs channels and/or loss of Kv channels and a compensatory overexpression of BKCa channels (11). Patch-clamp evidence has been obtained in VSMCs from mesenteric (9, 10, 41), renal (36), and cerebral (32, 45, 55) arteries. Upregulation of mRNA encoding Kv{alpha}1.2 and increases in Kv{alpha}1.3 and Kv{beta}1.1 transcript level were found in SHR systemic arteries (8). Increased expression of the BKCa {alpha}-subunit at the protein level, but not the transcript level, has been observed in systemic VSMCs of SHR (11). The ion channel remodeling has also been thought to be involved in pulmonary hypertension (60). The Kv currents in cultured pulmonary VSMCs were decreased within 2 to 3 days after exposure to hypoxic conditions. The reduction of Kv currents was associated with a decreased gene expression of several Kv{alpha} transcripts as well as decreased protein expression of Kv{alpha}1.1, Kv{alpha}1.5, and Kv{alpha}2.1 (48). The mRNA expression of Kv{alpha}1.4 and Kv{alpha}1.5 in pulmonary VSMCs from patients with primary pulmonary hypertension is significantly attenuated. This defect in K+ channel expression has been proposed as unique mechanism involved in the pathogenesis of primary pulmonary hypertension (60). Taken together, these findings suggest that pressure-induced depolarization may reciprocally downregulate Kv gene expression and upregulate the gene expression of {alpha}1C-b (subunit of VDCs) (11). A major question of whether the ion channel alterations in VSMCs is the cause or consequence of hypertension remains unsolved (2, 36, 51). Perhaps studies with the tail suspension rat model may provide a novel approach in answering the question.

Does arterial channel remodeling take place during vascular adaptation to microgravity? The findings of the present work support the hypothesis that different profiles of channel remodeling in VSMCs mediate and modulate differential adaptations of cerebral and mesenteric small arteries in rats subjected to simulated microgravity.

The present work showed that activities of Kv and BKCa channels from mesenteric VSMCs significantly increased after 1 wk and maintained at this level after 4 wk of simulated microgravity within the time frame of the present study. This is apparently due to a lowered local transmural pressure during simulated microgravity. Although direct measurement data are still lacking, a lowered transmural pressure in the mesenteric vascular bed could be speculated from decreased blood flows by ~23% through the abdominal aorta (37, 49). The activity of VDCs of mesenteric VSMCs showed a trend of decrease and a significant decrease, respectively, at the end of the first and fourth week of simulated microgravity (Fu et al., unpublished observations). These results suggest that channel remodeling characterized by reciprocal up- and downregulations of K+ channels and VDCs takes place in hindquarter small arteries during simulated microgravity. Compared with the time courses of structural and functional change in hindquarter vessels (34, 35, 61), the increase in activities of K+ channels appears to be an immediate, early response and remains at this elevated level till the end of the simulation period. Thus we can speculate that changes in membrane properties that may lead to hyperpolarization and closure of VDCs take place rapidly in VSMCs of hindquarter resistance arteries at the beginning of, and are maintained throughout, the period of simulated microgravity. Rapid turnover of endogenous Kv channels is supported by recent studies on nonvascular tissues. For example, in pituitary cells, the half-lives of downregulation of subunit Kv{alpha} mRNA and protein levels are 0.5 and 4 h, respectively (31, 53). As discussed in the previous section, activation of K+ channels results in a decrease in [Ca2+]cyt, which is a shared signal element in excitation-contraction coupling and cell growth regulation (1, 11, 21, 30, 60). Enhanced K+ efflux through opened K+ channels also facilitates apoptosis (28, 60), which is expected to be involved in the development of atrophic changes in hindquarter arteries during microgravity exposure.

In contrast, evidence from both pharmacological and patch-clamp studies demonstrated that activities of K+ channels in cerebral small arteries significantly decreased at the end of the first week and maintained at this level till the end of the fourth week of simulated microgravity in the time frame of the present study. This is speculated to be due to local tissue stress changes causally related to a sustained elevation of transmural pressure across cerebral vessels. It has been estimated that the mean blood pressure in the basilar artery would be increased by ~17 mmHg (57) or by ~10 mmHg (56) during tail suspension compared with standing. It has been shown that blood flows to most brain regions decreased and cerebral vascular resistance increased in the early stage and tended to return toward their control levels later during tail suspension (56). The decrease in activities K+ channels in cerebral VSMCs also appears to be an immediate, early response ahead of the functional and structural upregulations of cerebral vessels, which reached their peaks at the end of the fourth week of simulated microgravity (35, 61). Decreases in the function of K+ channels cause changes in membrane properties leading to depolarization, opening of VDCs, and [Ca2+]cyt increase, thereby promoting cell proliferation (1, 47, 48, 60) in cerebral arteries during simulated microgravity. The upward regulation in structure and function of cerebral vessels in rats due to simulated microgravity (19, 35, 56, 57, 61, 64) are quite similar in certain respect to that in hypertension (20, 23, 39, 42–44). In both conditions, adaptational changes in cerebral vessels have been proposed to play a role in preventing pressure-induced damage to the microvasculature, particularly cerebral congestion, edema, and possibly stroke (52, 56, 57, 61, 64). Although altered functions of K+ channels are associated with both conditions, differences exist between these two conditions. In SHR, activity and expression of Kv and BKCa channels of cerebral as well as systemic arteries are decreased and increased, respectively (10, 11, 27, 32, 36, 50). In contrast, during simulated microgravity, the present results suggest that the initial decrease in K+ channel activities is due to a downregulation of BKCa channels, which is later replaced by a downregulation of Kv channels, maintaining the lowered activity of K+ channel function of cerebral VSMCs. Throughout the simulation period, the activities of BKCa channels in cerebral VSMCs did not increase within the time frame of the present study. The reasons for these discrepancies remain unclear. One point that should not be overlooked is that ion channel remodeling in cerebral VSMCs during simulated microgravity is the autoregulatory consequence to local sustained high blood pressure in nonhypertensive Sprague-Dawley rats, whereas in SHR, the altered K+ channel function and expression are supposed to be genetically regulated (2). Irrespective of these differences, ion channel remodeling in cerebral VSMCs to sustained elevation of local transmural pressure during microgravity, particularly during prolonged existence in microgravity, would be expected to have a possible adverse effect on cerebral vasculature. This may be further aggravated by a possible increase in the activities of the cerebral vascular renin-angiotensin system (36, 62). It seems that this potential risk factor should not be overlooked, because an Earth-like distribution of transmural pressure cannot be restored and maintained by current exercise-based countermeasures (22, 54, 61, 62). In this regard, the genetic aspect of astronauts for hypertension perhaps also merits attention, because lessons from SHR have provided insight into the problem of genetic link of vascular ion channel remodeling.

Although the data are encouraging, we emphasize that there are preliminary results limited at least by the channel blockers used. The above conclusions are based on that the half-block concentrations (Ki) of TEA for BKCa and Kv channels are 0.2 and 10 mM, respectively, and 4-AP is perhaps the most selective known inhibition of Kv channels in VSMCs with a Ki at 0.2–1.1 mM (40). Futher work using a high selective blocker for BKCa, like iberiotoxin, in whole cell and single channel recordings would provide a deeper insight into the channel mechanisms in vascular adaptation to microgravity. In summary, K+ channels in cerebral and hindquarter VSMCs are differentially activated during both short-term (1 wk) and medium-term (4 wk) simulated microgravity. In cerebral VSMCs, inhibited K+ channel function and membrane depolarization have been shown. However, the reduced total current density is initially due to a smaller BKCa current density and later on a diminished Kv current density during short- and medium-term simulated microgravity, respectively. In contrast, for hindquarter VSMCs, increased total, BKCa, and Kv current densities and membrane hyperpolarization have been observed during both stages of simulated microgravity. These data suggest that differential vascular adaptation to microgravity is mediated or modulated by different profiles of channel remodeling in different VSMCs.


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This study was supported by National Natural Science Foundation of China Grants 30170355 and 30200090.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L.-F. Zhang, Dept. of Aerospace Physiology, The Fourth Military Medical Univ., Xi'an 710032, China (E-mail: zhanglf{at}fmmu.edu.cn)

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. Section 1734 solely to indicate this fact.


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