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Am J Physiol Heart Circ Physiol 281: H1170-H1177, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 3, H1170-H1177, September 2001

Hindlimb unweighting affects rat vascular capacitance function

Stacey L. Dunbar1, Laleh Tamhidi1, Dan E. Berkowitz1,2, and Artin A. Shoukas1

1 Department of Biomedical Engineering and 2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Microgravity is associated with an impaired stroke volume and, therefore, cardiac output response to orthostatic stress. We hypothesized that a decreased venous filling pressure due to increased venous compliance may be an important contributing factor in this response. We used a constant flow, constant right atrial pressure cardiopulmonary bypass procedure to measure total systemic vascular compliance (CT), arterial compliance (CA), and venous compliance (CV) in seven control and seven 21-day hindlimb unweighted (HLU) rats. These compliance values were calculated under baseline conditions and during an infusion of 0.2 µg · kg-1 · min-1 norepinephrine (NE). The change in reservoir volume, which reflects changes in unstressed vascular volume (Delta V0) that occurred upon infusion of NE, was also measured. CT and CV were larger in HLU rats both at baseline and during the NE infusion (P < 0.05). Infusion of NE decreased CT and CV by ~20% in both HLU and control rats (P < 0.01). CA was also significantly decreased in both groups of rats by NE (P < 0.01), but values of CA were similar between HLU and control rats both at baseline and during the NE infusion. Additionally, the NE-induced Delta V0 was attenuated by 53% in HLU rats compared with control rats (P < 0.05). The larger CV and attenuated Delta V0 in HLU rats could contribute to a decreased filling pressure during orthostasis and thus may partially underlie the mechanism leading to the exaggerated fall in stroke volume and cardiac output seen in astronauts during an orthostatic stress after exposure to microgravity.

microgravity; compliance; vein; sympathetic nervous system; orthostatic intolerance


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ORTHOSTATIC INTOLERANCE is common in astronauts after prolonged spaceflight. This microgravity-induced orthostatic intolerance appears to be due, in part, to a greater postural decrease in stroke volume and cardiac output (2). Changes in cardiac output can occur for two reasons: via the Frank-Starling mechanism through changes in venous filling pressure or through altered heart rate and/or contractility of the heart. The observed changes in cardiac output after exposure to microgravity cannot be fully explained by changes in contractility or heart rate alone because orthostatic heart rate tends to be higher postflight (2). This increase in postflight heart rate is presumably not enough to limit cardiac output by encroaching on filling time, however. Therefore, we hypothesized that changes in filling pressure regulated by systemic venous capacitance function may be an important determinant of cardiac output after exposure to microgravity.

Evidence from several rodent studies suggests that vascular capacitance could be altered by exposure to microgravity. In a recent study from our laboratory (8), mesenteric veins from rats that had undergone 21 days of hindlimb unweighting (HLU) were found to have larger unstressed vascular volumes than vessels from control rats. Furthermore, the veins from HLU rats did not exhibit a decrease in unstressed vascular volume upon exposure to equimolar concentrations of norepinephrine (NE) compared with control rats. Additionally, studies (7, 17) have shown that simulated microgravity in rodents decreases the arterial contractile response to sympathomimetics such as NE. A diminished sensitivity of the rat vena cava to NE was also reported after HLU by Sayet et al. (20).

The purpose of this study was to determine the effects of simulated microgravity on vascular capacitance. Changes in vascular capacitance were evidenced through changes in compliance as well as the unstressed vascular volume (18). We used rat HLU as a model for microgravity because it has been shown to mimic the effects of spaceflight on the cardiovascular system (15). With the use of a constant flow cardiopulmonary bypass procedure, we measured total (CT), arterial (CA), and venous compliances (CV) in control as well as HLU rats before and after stimulation with NE. The change in unstressed vascular volume (Delta V0) was estimated from the change in reservoir volume (Delta VRES) upon the infusion of NE. We hypothesized that CT would be altered in the HLU rats and that the change in capacitance elicited by NE would be attenuated.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. This protocol was approved by the Institutional Animal Care and Use Committee of Johns Hopkins University School of Medicine. Seven control male Sprague-Dawley rats were maintained in normal cage environment, whereas seven male Sprague-Dawley rats underwent HLU for 21 days. The HLU procedure was similar to that previously described (8). The HLU rats were maintained at a suspension angle of ~30°. Briefly, the suspension entailed placing the animals in a jacket that was connected to a short length of Tygon tubing. The tail was then attached to the tubing via an adhesive material. The tubing was then affixed to a crossbar and swivel apparatus across the top of the cage. Rats had full mobility in the cage using their forelimbs with ad libitum access to normal rat chow and water. After the 21-day treatment period, rats were anesthetized with 120 mg/kg ketamine hydrochloride (100 g/ml) and 2 mg/kg acepromazine maleate (10 mg/ml). Body temperature was maintained at 37°C by placing animals on a heated tray in preparation for surgery and cardiopulmonary bypass.

Surgical preparation. Heat cauterization was used for every incision to minimize blood loss. The right femoral artery and vein were cannulated with polyethylene (PE)-50 tubing (Intramedic) for monitoring of arterial (PA) and venous pressures (PV), respectively. A tracheotomy was performed through a midline incision from the base of the neck to the sternal notch, and a catheter (PE-205, Intramedic) was inserted and secured with a 3-0 silk suture. Immediately before sternotomy, the rat was ventilated through the catheter with 95% O2-5% CO2 (respirator model SAR-830, CWE).

A longitudinal sternotomy from the Xiphoid process to the sternal notch was performed to open the chest. The chest was retracted using sutures (3-0 silk) at four sites, and a 3-0 silk suture was placed around the aorta. Two sutures (6-0 silk) were then longitudinally placed ~1 cm apart through the right atrial appendage. A loop of suture (3-0 silk) was placed above the right atrium and under the aforementioned right atrial sutures. A purse string (5-0 silk) was then placed around the left ventricle. A stainless steel cannula [inner diameter (ID), 2.3 mm; outer diameter (OD), 3.0 mm] was inserted into the right atrium and secured using the previously mentioned right atrial suture (3-0 silk). The right atrial pressure (PRA) was monitored via a catheter (OD, 0.93 mm; Silastic 602-135, Dow Corning) that was advanced past the tip of the stainless steel cannula inserted in the right atrium. The aorta was then cannulated using a stainless steel cannula (ID, 1.8 mm; OD, 2.2 mm), which was inserted through the apex of the left ventricle and then advanced to the tip of the ascending aorta. The suture around the aorta was tied, thereby securing the cannula in place. The right atrial and aortic cannulas were connected to the bypass circuit as described in Cardiopulmonary bypass circuit.

Cardiopulmonary bypass circuit. Figure 1 illustrates the bypass circuit used for the experiment. The right atrial cannula emptied into an open venous reservoir made from a cylindrical plastic column (ID, 12.8 mm; total capacity, ~10 ml). At the base of the reservoir, a high-sensitivity transducer (model 8503-4M11, Beckman) was situated to monitor blood volume in the reservoir. Throughout the experiment, the open venous reservoir had to be refilled due to loss of fluid into the extravascular space and evaporation. This was typically done during the interval between each experimental run (see Protocol). At times, however, the reservoir had to be filled while the experiment was conducted. In such instances, a volume-adjustable closed reservoir (not shown in Fig. 1) within the bypass circuit was used. By adjusting the volume of the closed reservoir, the open reservoir volume was refilled with blood that was identical to the circulating blood. This was important due to the fact that noncirculating blood significantly disturbs the stability of measured variables. Roller pump 1 pumped the blood from the reservoir to the oxygenator (COBE). The blood was oxygenated with 95% O2-5% CO2. The perfusion used yielded an arterial PO2 of 550 ± 25 mmHg, a PCO2 of 44 ± 8 mmHg, and a pH of 7.2 ± 0.03. We used this very high level of PO2 to maintain the rats in good condition for the duration of the experiment. Once the blood was oxygenated, a heat exchanger maintained the blood and body temperatures of the rat at 37°C. Roller pump 2 supplied the rat with the oxygenated blood. The arterial blood flow rate was measured before entry in the rat via an ultrasonic transit time flow probe (model 2N, Transonic System).


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  		Fig. 1.   Schematic diagram of cardiopulmonary bypass circuit. See text for detailed explanation of surgery. SVC, superior vena cava; IVC, inferior vena cava; RA, right atrium.

Blood preparation. The entire perfusion circuit was primed with triple-washed porcine red blood cells reconstituted in Plasma-Lyte (Abbott Labs; Abbott, IL) solution with 5% albumin to obtain a hematocrit of ~40%. Appropriate doses of sodium bicarbonate were added to the prepared blood to adjust the pH to 7.4. Heparin (750 U/100 ml) was finally added to prevent any clotting. The priming volume of the system was ~100 ml.

Calibration. PA, PV, and PRA were measured with pressure transducers (P23 db, P23 bc, and P23 bb, respectively). Zero pressures were referenced to the level of the right atrium/vena cava. Changes in the blood volume were measured from the hydrostatic changes at the bottom of the venous reservoir of the cardiopulmonary bypass circuit. The reservoir itself was calibrated by changing the blood volume present in the reservoir by known amounts and recording subsequent pressure changes. All pressure and flow signals were recorded on an ink recorder (model 2800, Gould) and digitized (Biopac Data Acquisition, Biopac Systems) and stored on a Dell Dimension XPS D300 (Dell Computer).

Protocol. The total flow rate (Qc) was adjusted to ~200 ml · min-1 · kg-1 based on the reading from the arterial flow probe. This flow rate was typical of that found in intact rats, under ketamine anesthesia, using a chronically implanted aortic flow probe. Minimal bleeding, which occurred almost exclusively within the chest cavity, was continuously drained back into the venous reservoir. The surgical table was tilted ~30° to the rat's left to relieve the compression of the inferior vena cava by the abdominal organs. The height of the venous reservoir outlet was adjusted so that the PRA was 2 mmHg. After all pressures and VRES reached a steady state, measurement of CT and CA began as previously described (23).

Figure 2 shows a schematic of the experimental protocol and Fig. 3 shows a recording from part of an experiment on one control rat. CT was determined by adjusting the height of the venous outflow tube, thus altering PRA and PV. This resulted in Delta VRES, which reached a new steady state after ~1 min. The change in the steady-state VRES divided by the steady-state PRA resulted in the measurement of CT. PRA was raised in 2-mmHg increments from the initial steady-state level of 2 mmHg to 6 mmHg and then stepped back down to the initial control level, thus giving four values of CT. There were no differences between these four values, and thus they were pooled for the subsequent analysis.


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  		Fig. 2.   Experimental protocol. Total vascular compliance (CT) was calculated when the right atrial pressure was raised and lowered in a stepwise fashion. Similarly, arterial compliance (CA) was measured when arterial pressure was changed in a stepwise fashion. These variables were measured both during baseline conditions and during an infusion of 0.2 µg · kg-1 · min-1 norepinephrine. Venous compliance (CV) was calculated as the difference between CT and CA. The change in unstressed vascular volume (Delta V0) was calculated upon infusion of norepinephrine.



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  		Fig. 3.   Sample recording from an experiment on one control rat. On this trace, the protocol for determining CT began at 27 min and ended at 31 min. When right atrial pressure increases, the volume in the reservoir decreases and vice versa. The protocol for determining CA began at 32 min and ended at 37 min. When arterial pressure is increased, there is a concomitant decrease in reservoir volume and vice versa.

To measure CA, mean arterial pressure (MAP) was adjusted by ~5-15 mmHg by altering pump flow while keeping PRA constant at 2 mmHg. Pump flow was sequentially stepped up and down by ~40 ml · min-1 · kg-1 increments from the initial flow of 200 ml · min-1 · kg-1 (to a maximum of 235 ml · min-1 · kg-1 and minimum of 155 ml · min-1 · kg-1). Steady-state Delta VRES values due to changes in flow were recorded, and CA was calculated from Delta VRES/Delta PA (23). This resulted in four values of CA. There were no differences between these four values, and thus they were pooled for the subsequent analysis. This method of determining CA slightly overestimates the true CA (22). Because flow through the systemic vascular bed was changed, there would be pressure changes in small veins despite the constancy of PRA. Therefore, some venous volume is included in the volume change used to measure CA.

As can be seen in Fig. 2, increasing PV or PA sometimes caused VRES to slowly decrease for the entire time that pressure is increased. This is probably due to increased capillary filtration. When this occurred, the slope of the slow decrease was calculated. This allowed extrapolation back to the instantaneous volume response that occurred upon raising the pressure.

Total peripheral resistance (TPR) was calculated from the difference between MAP and PRA divided by flow at steady state as seen below
TPR<IT>=</IT>(MAP<IT>−</IT>P<SUB>RA</SUB>)<IT>/</IT>Q<SUB>C</SUB> (1)
Following this protocol, we determined the effects of NE on vascular capacitance. NE was administered at a constant rate of 0.2 µg · kg-1 · min-1, causing an increase in PA. Preliminary experiments showed that this dose of NE caused a significant increase in PA without causing excessive bleeding and edema during the protocol. Once the PA and VRES reached a steady state, the above protocols for determining CA and CT were repeated.

Delta V0 was calculated from the algebraic summation of Delta VRES and CA times Delta PA as shown below (21)
&Dgr;V<SUB>0</SUB><IT>=</IT>−(<IT>&Dgr;</IT>V<SUB>RES</SUB><IT>+</IT>C<SUB>A</SUB><IT>×&Dgr;</IT>P<SUB>A</SUB>) (2)
The CA that was used was the respective mean value obtained before and after the administration of NE.

With the use of this two-capacitor, single resistance model, we calculated CV by subtracting CA from CT.

Data analysis. All data were normalized to individual body weights to allow comparison among all rats. All data are reported as means ± SE. A two-way repeated-measures analysis of variance was performed to determine the effects of HLU and NE on the calculated variables. Post hoc comparisons were performed when necessary with the Bonferroni method. Significance levels were set at P < 0.05 for all analyses.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

There was no difference between the body weights of the control and HLU rats at the time of experimentation (441 ± 15 vs. 412 ± 12 g, respectively, P = 0.16). Table 1 shows the values for Qc, PA, and TPR measured during the experiment. There were no differences between the groups for any of these variables either at baseline or after infusion of NE. As expected, infusion of NE significantly increased PA (P < 0.05) via increases in TPR (P < 0.05) in both groups of rats.

                              
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  		Table 1.   Hemodynamic parameters

Compliance. Figure 4 shows CT in both groups of rats at baseline and during the NE infusion. CT was ~18% larger in HLU rats than in control rats both at baseline and during the NE infusion (main effect of group, P < 0.05). Infusion of NE caused a significant decrease in CT in both groups of rats (main effect of NE, P < 0.01). The magnitude of this decrease was ~20% in both groups of rats (interaction effect of group × NE, P = 0.63).


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  		Fig. 4.   CT in control and hindlimb unweighted (HLU) rats at baseline and during infusion of 0.2 µg · kg-1 · min-1 norepinephrine. CT was larger in the HLU rats both at baseline and during norepinephrine infusion (*P < 0.05). Infusion of norepinephrine decreased CT in both groups of rats (#P < 0.01).

CA in control and HLU rats at baseline and during the NE infusion is shown in Fig. 5. HLU and control rats had similar values for CA at baseline and during the NE infusion (main effect of group, P = 0.86). Infusion of 0.2 µg · kg-1 · min-1 NE significantly decreased CA in both groups of rats by ~22% (main effect of NE, P < 0.05), but there was no difference between the groups in the magnitude of that decrease (interaction effect of group × NE, P = 0.71).


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  		Fig. 5.   CA in control and HLU rats at baseline and during infusion of 0.2 µg · kg-1 · min-1 norepinephrine. CA was not different between the control and HLU rats. Infusion of norepinephrine decreased CA in both groups of rats (#P < 0.01).

Figure 6 shows CV. This variable followed a pattern similar to that of CT, that is, CV was 19% larger in HLU rats than in control rats both at baseline and during the NE infusion (main effect of group, P < 0.05). Infusion of NE caused a significant 20% decrease in CV in both groups of rats (main effect of NE, P < 0.01), and there was no difference between the groups in the magnitude of that decrease (interaction effect of group × NE, P = 0.64).


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  		Fig. 6.   CV in control and HLU rats at baseline and during infusion of 0.2 µg · kg-1 · min-1 norepinephrine. CV was larger in the HLU rats both at baseline and during norepinephrine infusion (*P < 0.05). Infusion of norepinephrine decreased CV in both groups of rats (#P < 0.01).

Unstressed vascular volume. We calculated Delta V0 after infusion of NE. Because the total systemic blood volume is constant, a decrease in V0 was given by the algebraic sum of the volume changes in the arterial compartment and the external reservoir measured when 0.2 µg · kg-1 · min-1 NE was infused. These data are shown in Fig. 7. Delta V0 was attenuated by 53% in the HLU rats compared with the control rats (P < 0.05).


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  		Fig. 7.   Delta V0 measured when 0.2 µg · kg-1 · min-1 norepinephrine was infused. Delta V0 was significantly attenuated in HLU rats compared with control rats (*P < 0.05).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Our study demonstrates that after 21 days of HLU, systemic venous capacitance function is altered in rats. This is evidenced by both an increased CV and an attenuated Delta V0 upon infusion of NE. Compliance and unstressed vascular volume are the two key factors regulating capacitance. Changes in vascular capacitance can contribute to changes in venous filling pressure and therefore stroke volume (23).

Our results have profound implications for the understanding of the pathophysiology of microgravity-induced orthostatic intolerance. Both the larger CV and the attenuated NE-induced Delta V0 would impair cardiac filling after exposure to microgravity, leading to the observed exaggerated fall in stroke volume and cardiac output during orthostasis.

In a recent study from our laboratory (8), HLU altered the capacitance function of isolated mesenteric veins. In this study, vessels from HLU rats failed to decrease unstressed diameter (which correlates with unstressed vascular volume) when exposed to NE, whereas vessels from control rats showed a significant NE-induced decrease in unstressed diameter. The results from the current study agree well with this previous data, as unstressed venous volume in the HLU rats decreased less during the NE infusion compared with control rats.

In addition to the attenuated NE-induced decrease in unstressed vascular volume, systemic CV was larger in the HLU rats. To our knowledge, this is the first animal study to show such results for the total systemic vascular bed. Several human studies (3-5) have shown increased leg compliance after exposure to simulated microgravity in the form of bed rest. In general, these investigators have concluded that the primary mechanism responsible for increased leg compliance is a decrease in skeletal muscle mass, that is, muscle atrophy may cause a decrease in mechanical resistance that allows the veins to expand. However, recent data (2) suggest that standing leg volumes are not significantly changed after spaceflight. Interestingly, segmental body impedance studies (2) performed after simulated microgravity suggest that abdominal venous pooling is both increased and progressive during orthostasis. In light of these data and those from our previous study in isolated mesenteric veins, it seems that increases in mesenteric venous capacitance could be largely responsible for the changes in total capacitance.

A potential mechanism explaining the increased CV in the HLU rats is a decreased basal release of catecholamines. Results of several human studies (6, 10) have shown a decreased basal rate of appearance of NE in plasma after a period of bed rest. Additionally, microgravity has been shown to decrease adrenal catecholamine content in rats (14). This "sympathoinhibition" could mean that basal venous tone is inhibited after exposure to simulated microgravity, leading to a larger basal CV. Direct measurement of efferent sympathetic nerve traffic would be useful for investigating this mechanism.

One problem with the sympathoinhibition theory is that it might be expected to cause denervation sensitivity. This would mean that the reduced endogenous release of NE would lead to enhanced responsiveness to exogenous NE. Our data indicate that this was not the case because NE affected compliance to the same extent in both groups.

Additionally, a decreased basal release of catecholamines cannot explain the attenuated NE-induced decrease in unstressed venous volume in the HLU rats compared with control rats. One possible mechanism underlying this result could relate to a decreased end-organ responsiveness to NE. Sayet et al. (20) studied the influence of HLU and spaceflight on the contractile responses of the rat vena cava. In this study, HLU and spaceflight decreased the responsiveness of the rat vena cava to NE. Because alpha 1B- and alpha 2-adrenoceptors have both been identified as playing important roles in modulating venous tone in the rat (12, 13, 16), a decreased expression of these receptors could lead to a defect in the venoconstriction response and could explain the diminished NE-induced decrease in unstressed venous volume.

We originally hypothesized that the decreased compliance caused by an infusion of NE would be attenuated in HLU rats compared with control rats. This, however, was not the case. NE caused an ~20% decrease in CT, CV, and CA in both groups of rats. The dose of NE we used may represent a saturating dose and may elicit a maximal response. A dose-response curve would be needed to characterize this response. Additionally, it is important to note that in this study we used exogenous NE to cause changes in capacitance. There could be major differences between changes in venous capacitance elicited in this way and those elicited via the baroreceptor reflex.

The fact that the NE-induced decrease in compliance did not differ between the two groups of rats, whereas the NE-induced decrease in unstressed volume was attenuated in the HLU rats, may seem contradictory because compliance and unstressed volume are both affected by venous smooth muscle tone. However, this finding is similar to that of the recent study from our laboratory (8) investigating capacitance in single veins. Unstressed volume can best be described as the diameter of a vessel, whereas compliance can best be thought of as the ability of the vessel to stretch. Thus it appears that HLU affects the ability of the vessels to change their size but does not alter their ability to stretch. While this description is highly oversimplified, it does help to clarify how the two components of capacitance differ and might be separately regulated.

While alpha -mediated vasoconstricting mechanisms are the primary regulators of vascular capacitance, local modulation by the endothelium also contributes to these responses. It is now known that nitric oxide plays a role in regulating venous tone in both humans and rats (1, 9) in addition to its well-characterized role in regulating CA. Sangha et al. (19) have shown that endothelial vasodilator mechanisms may be upregulated in the carotid artery of HLU rats. It has also recently been shown that, after head-down bed rest in humans, local nitric oxide levels no longer correlate with total peripheral resistance values (11). We plan to use specific nitric oxide inhibitors in our cardiopulmonary bypass preparation in the future to determine if nitric oxide may be playing a role in the observed microgravity-induced changes in venous capacitance.

We used HLU in this study to simulate the effects of microgravity because it has been shown to mimic the effects of spaceflight on the cardiovascular system. However, there are a few differences between microgravity and HLU. First, in HLU, there is some gravitational impedance to arterial flow to the hindlimbs. Additionally, there is some gravitational assistance to venous drainage from the hindlimbs. Consequently, HLU does not exactly mimic the effects of microgravity. These effects are probably very small, however.

We did not measure blood volume in this study. Because the initial compensation to HLU in the rats is probably activation of the cardiopulmonary volume reflexes, we cannot rule out the possibility that the HLU rats in this study had lower blood volumes than the control rats. In general, blood volume can affect compliance. However, in this study, we calculated compliance at the same PV in all of the rats. Thus blood volume would have no effect on our compliance measurements.

In conclusion, this study shows that HLU has pronounced effects on the vascular capacitance function of rats. HLU increases CV and attenuates the NE-induced decrease in unstressed vascular volume. Given the influence that venous capacitance has on cardiac filling pressure, these changes can partially explain the exaggerated orthostatic decrease in stroke volume and cardiac output after exposure to microgravity.


    ACKNOWLEDGEMENTS

We thank COBE Incorporated for donating the oxygenators for this study.


    FOOTNOTES

This work was supported by National Space and Biomedical Research Institute Grant M592-125-2015.

Address for reprint requests and other correspondence: A. A. Shoukas, Johns Hopkins Univ. School of Medicine, 720 Rutland Ave., 624 Traylor Bldg., Baltimore, MD 21205 (E-mail: ashoukas{at}bme.jhu.edu).

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.

Received 7 August 2000; accepted in final form 24 May 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 281(3):H1170-H1177
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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