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Am J Physiol Heart Circ Physiol 283: H2276-H2281, 2002. First published September 12, 2002; doi:10.1152/ajpheart.00635.2002
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Vol. 283, Issue 6, H2276-H2281, December 2002

SPECIAL TOPICS
Interaction of myogenic mechanisms and hypoxic dilation in rat middle cerebral arteries

Yanping Liu, David R. Harder, and Julian H. Lombard

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The goal of this study was to determine how myogenic responses and vascular responses to reduced PO2 interact to determine vascular smooth muscle (VSM) transmembrane potential and active tone in isolated middle cerebral arteries from Sprague-Dawley rats. Stepwise elevation of transmural pressure led to depolarization of the VSM cells and myogenic constriction, and reduction of the O2 concentration of the perfusion and superfusion reservoirs from 21% O2 to 0% O2 caused vasodilation and VSM hyperpolarization. Myogenic constriction and VSM depolarization in response to transmural pressure elevation still occurred at reduced PO2. Arterial dilation in response to reduced PO2 was not impaired by pressure elevation but was significantly reduced at the lowest transmural pressure (60 mmHg). However, the magnitude of VSM hyperpolarization was unaffected by transmural pressure elevation. This study demonstrates that myogenic activation in response to transmural pressure elevation does not override hypoxic relaxation of middle cerebral arteries and that myogenic responses and hypoxic relaxation can independently regulate vessel diameter despite substantial changes in the other variable.

myogenic response; vascular relaxation; oxygen; hypoxia; vascular smooth muscle; vasodilation


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE MYOGENIC RESPONSE (changes in vessel tone in response to changes in transmural pressure in the vessel) and hypoxic dilation of resistance arteries in response to reduced O2 availability both play an important role in regulating blood flow in the cerebral circulation and other vascular beds. However, these two regulatory mechanisms can be thrown into opposition under some conditions encountered physiologically or in pathophysiological conditions such as hypertension.

Several previous studies (8, 10, 26, 29) have investigated the interaction between myogenic responses and changes in O2 availability in isolated resistance arteries and in situ arterioles of different vascular beds. However, the mechanisms by which changes in PO2 can affect myogenic responses in resistance arteries are incompletely understood, and very little is known regarding any modulating effect of transmural pressure elevation on vasodilator responses to reduced O2 availability in arterioles and resistance arteries. In this respect, a detailed knowledge of the interaction between transmural pressure and the response of resistance arteries to reduced PO2 is essential to gain a complete understanding of the local regulation of vascular resistance in the peripheral circulation.

Changes in the transmembrane potential (Em) of vascular smooth muscle (VSM) cells play a crucial role in regulating vascular tone during both myogenic activation (14, 15, 26) and hypoxic dilation (25) of resistance arteries. Myogenic activation of resistance arteries is associated with a substantial depolarization of the arterial smooth muscle cells (3, 14, 15, 26) and the entry of extracellular Ca2+ into the cells (3, 4, 14, 22, 28, 32). In contrast, hypoxic dilation of middle cerebral artery (MCA) is mediated via hyperpolarization of the arterial smooth muscle cells due either to the opening of Ca2+-activated K+ (KCa) channels or ATP-sensitive K+ (KATP) channels in the VSM cell membrane (9, 12, 25), which causes vascular relaxation by decreasing Ca2+ influx through voltage-gated Ca2+ channels in the cell membrane.

There is a very steep relationship between VSM Em and active tone in blood vessels, such that very small changes in VSM Em lead to substantial changes in contractile force in the arterial smooth muscle cells (20). Therefore, the changes in VSM Em that occur in resistance arteries during changes in transmural pressure or exposure to reduced PO2 could play a major role in determining how these regulatory stimuli interact to regulate blood flow in the in vivo microcirculation. For example, depolarization of the VSM cells in response to transmural pressure elevation could affect the sensitivity of the vessels to vasodilator stimuli such as hypoxia, which exert their relaxing effect by changing the Em of the VSM cells. Conversely, hyperpolarization of the VSM cell membrane in response to hypoxia could affect myogenic activation of the vessels. Therefore, a crucial question to consider in evaluating the interactions between transmural pressure and vascular O2 levels in resistance arteries is how hypoxia and changes in transmural pressure affect the final value of VSM Em and how this, in turn, may affect active tone in the vessel. The present study employed isolated, cannulated MCAs of Sprague-Dawley rats to address two major questions. First, can hypoxic dilation override myogenic constriction and VSM depolarization in the vessel, and, second, can elevated transmural pressure override hypoxic dilation and VSM hyperpolarization in the MCA?


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

General procedures. Male Sprague-Dawley rats (Sasco-King; Madison, WI) were anesthetized with pentobarbital sodium (60 mg/kg ip), and the MCA (100-300 µm inner diameter) was carefully removed and placed in warmed physiological salt solution (PSS) bubbled with 21% O2-7% CO2-balance N2. The constituents of the PSS used in these experiments were (in mM) 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.6 CaCl2, 1.18 NaH2PO4, 24 NaHCO3, 0.026 EDTA, and 5.5 glucose.

After isolation, the arteries were placed in a heated (37°C) superfusion/perfusion chamber and cannulated with tapered glass micropipettes (100-200 µm diameter). The inflow pipette was connected to a reservoir system, which allowed the intraluminal pressure and gas concentrations of the luminal perfusate to be controlled. The vessels were secured with 10-0 nylon suture (22 µm diameter, Look; Norwell, MA) and all side branches were tied off with a single strand teased from 2-0 silk suture (Ethicon; Somerville, NJ). After being mounted, the artery was stretched to approximate its in situ length and intraluminal pressure was set at 80 mmHg. The vessel was allowed to equilibrate for 30 min with continuous superfusion and perfusion of the vessel lumen with PSS equilibrated with 21% O2.

Reactivity of the arteries was assessed by verifying the ability of the vessel to contract in response to a brief exposure to 0.1 µM serotonin. Endothelial function was verified by demonstrating that the serotonin-contracted vessels dilated in response to 1 µM acetylcholine. Any vessel that was unresponsive to serotonin and acetylcholine or did not exhibit a large dilation in response to Ca2+-free relaxing solution (see below) was not used in the study. Vessel diameters were measured by television microscopy and VSM Em were measured with a high-impedance amplifier and glass microelectrodes (40-80 MOmega impedance) filled with 3 M KCl, as previously described (24, 25). The criteria for a successful impalement included an abrupt drop to a steady level of Em for a minimum of 5 s and an abrupt return to baseline on exit of the electrode from the cell. Five measurements were made under each condition, and the results were averaged to obtain the final value of Em for that vessel under each experimental condition, i.e., each observation made for statistical purposes was the average of the five individual measurements. One vessel was used per animal.

After the initial equilibration period at 21% O2, vessel diameters or VSM Em were measured under control conditions, and the measurements were then repeated during hypoxic conditions produced by simultaneous reductions of the O2 concentration of the PSS in the tissue bath (superfusate) and inflow reservoir (luminal perfusate). Superfusate PO2 was reduced by bubbling the PSS with a 0% O2 gas mixture via air stones in the supply reservoir and vessel chamber and by covering the vessel chamber with glass microscope slides except during diameter or VSM Em measurements. PO2 in the perfusate was reduced by bubbling the PSS in the perfusion reservoir with the same gas mixtures and by using gas impermeable delivery lines. This results in a reduction of both luminal and superfusate PO2 to ~40-45 mmHg (8). After the PO2 reduction protocol, the perfusate and superfusate were reequilibrated with 21% O2 to verify that vessel responses to reduced PO2 were reversible. In time control experiments, diameters of MCAs did not change during continuous exposure to 21% O2 solution, demonstrating that the baseline did not drift with time.

Effects of reduced PO2 on responses of MCAs to transmural pressure elevation. In one series of experiments, we tested the effect of reduced PO2 on myogenic activation of the arteries in response to increases in transmural pressure. In these experiments, the arteries were maintained at a transmural pressure of 80 mmHg during a 30-min equilibration period with 21% O2 PSS. At the end of the equilibration period, the perfusion was stopped by clamping the outflow tubing to prevent any flow-dependent changes in vascular tone from affecting the myogenic response. Transmural pressure was lowered to 0 mmHg, and arterial diameters were measured during successive 10-mmHg increments in transmural pressure over the range of 0-160 mmHg. Intraluminal pressure was maintained at each pressure level for 5 min and vessel diameter was measured at the new steady-state value. After the initial myogenic response was determined in 21% O2 solution, transmural pressure was returned to 80 mmHg, perfusion was reestablished, and the superfusion and perfusion solutions were equilibrated with 0% O2. Thirty minutes later, the myogenic response to transmural pressure elevation was tested again during exposure to the reduced PO2 solution. At the conclusion of the experiment, arterial diameters were measured as transmural pressure was elevated during exposure to Ca2+-free relaxing solution, and the magnitude of the dilation occurring in response to the Ca2+-free solution was used as an index of the level of active tone in the vessel at each pressure. In another series of experiments, VSM Em was measured as transmural pressure was elevated in 20-mmHg increments from 40 to 160 mmHg during normoxic (21% O2 perfusion/superfusion) and hypoxic (0% O2 perfusion/superfusion) conditions. In the latter experiments, individual levels of transmural pressure were maintained for 10-20 min, due to the longer time required to obtain measurements of VSM Em compared with measurements of vessel diameter.

Effect of transmural pressure elevation on electrical and mechanical response of MCAs to reduced O2 availability. This part of the study determined whether myogenic activation in response to transmural pressure elevation overrides the dilation of MCAs in response to reduced PO2. After the initial equilibration period, transmural pressure in the artery was set at 60, 80, 100, 140, and 160 mmHg, respectively, and the vessel was equilibrated for 10 min at each pressure. In a series of companion experiments, VSM Em was measured at different transmural pressures. After the control equilibration period with 21% O2 perfusion/superfusion, arterial diameter or VSM Em were measured after a 20-min reduction of the O2 concentration of the PSS in the tissue bath (superfusate) and the inflow reservoir (luminal perfusate) by equilibrating the supply reservoirs with 0% O2 gas mixture as described above. In these experiments, control measurements (21% O2) were obtained during a brief interruption of vessel perfusion, and then the vessels were perfused with the reduced PO2 solution for 20 min. After equilibration with the reduced PO2 solution, flow through the vessel was temporarily interrupted by clamping the outflow tubing to prevent flow-dependent mechanisms from affecting vessel responses. After PO2 reduction, flow was restored and the perfusate and superfusate were reequilibrated with 21% O2 to verify that vessel responses to reduced PO2 were reversible. After the normoxic recovery period, the artery was equilibrated at the next pressure level, and the response to reduced PO2 was tested again. At the conclusion of each experiment, arterial diameter was measured during maximal relaxation produced by perfusion and superfusion with Ca2+-free PSS containing 20 mM MgCl2 and 2.0 mM EGTA as an indication of the level of active tone in the vessels.

Statistical analysis. In these experiments, data were summarized as means ± SE. Differences between multiple means were assessed using analysis of variance with a subsequent Newman-Keuls test. Differences between two means were evaluated by a Student's t-test and slopes of myogenic depolarization were determined using linear regression. Differences between individual means were judged to be statistically significant at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Response to transmural pressure elevation at reduced PO2. The effect of reduced PO2 on myogenic activation of MCAs in response to transmural pressure elevation is summarized in Fig. 1. During 21% O2 perfusion/superfusion, the MCAs maintained their diameter or constricted in response to transmural pressure elevation. Perfusion and superfusion of the vessels with PSS equilibrated with 0% O2 caused the vessels to dilate significantly from their resting diameter during 21% O2 perfusion/superfusion control. At the control equilibration pressure of 80 mmHg, vessel diameter increased from 138 ± 5.8 µm during 21% O2 perfusion/superfusion to 170 ± 7.8 µm during 0% O2 perfusion/superfusion (P < 0.05). During myogenic activation of the artery, vessel diameters were significantly larger during hypoxia than during 21% O2 perfusion/superfusion over the transmural pressure range of 10-90 mmHg and were not significantly different from the 21% O2 values over the remainder of the transmural pressure range used in the experiments (100-160 mmHg).


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  		Fig. 1.   Myogenic response of isolated middle cerebral arteries from different rats (n = 6 vessels/rats) to transmural pressure elevation during perfusion/superfusion with 21% O2 and 0% O2 physiological salt solution (PSS). Arteries dilated during perfusion and superfusion with 0% O2 PSS, but myogenic activation of the vessels still occurred, starting from a larger diameter. Ca2+-free PSS eliminated active tone and myogenic response in the vessels. See text for details.

Although the arteries dilated from their control diameter during 21% O2 perfusion/superfusion, myogenic activation of the arteries was still present, because the vessels were able to maintain their diameter or constrict as in transmural pressure was elevated during exposure to reduced PO2 solution. As expected, Ca2+-free solution caused a large increase in the diameter of the MCA and eliminated the myogenic activation of the vessels.

Figure 2 shows myogenic depolarization of VSM cells in the rat MCA under normoxic control conditions and during hypoxia produced by simultaneous reduction of perfusate and superfusate PO2 to ~40-45 mmHg. Transmural pressure elevation caused a significant depolarization of the VSM during both normoxic and hypoxic conditions, demonstrating that myogenic depolarization is not overridden by reduced PO2. There was no significant difference in the slope of the myogenic depolarization during normoxic (-0.1661 ± 0.01 mV/mmHg) and hypoxic (-0.1755 ± 0.02 mV/mmHg) conditions, but myogenic depolarization was shifted to more negative values of Em during hypoxia, as indicated by a significant shift in the y-intercept during hypoxia (-65.9 ± 1.84 mV) compared with normoxic control conditions (-59.8 ± 1.26 mV, P < 0.05). The latter observation is consistent with the diameter measurements and suggests that myogenic responses can still regulate vessel diameter, but at a higher value than exists during normoxic conditions.


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  		Fig. 2.   Myogenic depolarization of vascular smooth muscle (VSM) cells in rat middle cerebral artery during perfusion/superfusion with 21% O2 and 0% O2 PSS. Vessels hyperpolarized during exposure to hypoxia, but myogenic depolarization of the smooth muscle cells was unaffected by reduced PO2. Membrane potential (Em) data were obtained from six rats and represent 7-10 measurements at each pressure, with a minimum of five impalements per measurement.

Effect of transmural pressure elevation on arterial dilation and VSM hyperpolarization in response to reduced PO2. The dilation of MCAs in response to reduced PO2 at the different transmural pressures is summarized in Fig. 3. In these experiments, transmural pressure elevation did not inhibit dilation in response to reduced O2 availability. Instead, vasodilator responses to reduced PO2 were significantly smaller at the lowest transmural pressure (60 mmHg) than at the higher transmural pressures, where the responses to reduced PO2 were not different from each other.


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  		Fig. 3.   Dilation of rat middle cerebral artery in response to reduced PO2 at different levels of transmural pressure; n = 5-14 animals at each pressure. * P < 0.05, significant reduction of the dilator response to hypoxia compared with the other pressures.

The effect of transmural pressure elevation on the magnitude of VSM hyperpolarization in response to hypoxia is summarized in Fig. 4. Hyperpolarization of the arterial smooth muscle cells in response to hypoxia was unaffected by transmural pressure elevation, demonstrating that hypoxia-induced hyperpolarization of the VSM is not overridden by elevated transmural pressure. However, the resting Em of the smooth muscle cells before hypoxia was more negative at lower transmural pressures than at higher pressures. Control Em in 21% O2 perfusion/superfusion was -51 ± 2 mV (n = 7) at 60-75 mmHg; -47 ± 1.2 mV (n = 7) at 80-99 mmHg; -46 ± 2.2 mV (n = 6) mV at 100-125 mmHg; and -44 ± 0.7 (n = 6) mV at 140-160 mmHg (P < 0.05; 60-75 vs. 140-160 mmHg).


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  		Fig. 4.   Hyperpolarization of VSM cells in isolated rat middle cerebral arteries exposed to reduced PO2 at various transmural pressures; n = 6-7 animals in each group, with a minimum of five impalements at each pressure. There were no significant differences in the magnitude of the VSM hyperpolarization in response to hypoxia at any of the pressures. See text for details.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Earlier studies of the rat caudal artery (20) demonstrated that contractile force and VSM Em are closely coupled over a range of Em that are likely to exist at normal intravascular pressures in vivo and that small changes in Em within the range of close electromechanical coupling can cause substantial changes of contractile force in the smooth muscle. As mentioned earlier, changes in VSM Em play an important role in mediating both myogenic activation (3, 14, 15, 26) and hypoxic dilation (25) of resistance arteries. Given the dependence of both myogenic responses and hypoxic dilation on changes in VSM Em, it is important to determine how the combined action of myogenic mechanisms and vessel responses to reduced PO2 may affect the VSM Em, to understand how these mechanisms may interact to control the level of active tone in the vessel.

Many studies (1, 2, 5-7, 19, 27, 33-35) have investigated the effects of reduced PO2 on agonist-induced contractions of large blood vessels. However, there have been very few studies of the combined effect of reduced PO2 and myogenic responses on VSM Em in resistance arteries. In the present experiments, myogenic activation of the vessels in response to transmural pressure elevation was unaffected by reduced PO2, indicating that the mechanisms underlying myogenic activation are not specifically inhibited by decreased O2 availability. The preservation of myogenic activation in the face of reduced PO2 is consistent with our earlier studies of skeletal muscle resistance arteries (8), which suggest that myogenic responses are preserved during exposure to reduced PO2, but contrasts to some extent with our earlier observation that myogenic depolarization and VSM contraction in response to transmural pressure elevation were partially inhibited by reduced PO2 in cat MCA.

The reasons for the inhibitory effect of reduced PO2 on myogenic responses in the cat MCA, but not in the rat MCA, are not clear. However, it is possible that this difference in the ability of reduced PO2 to inhibit myogenic responses of MCAs from these different sources could be related to different mechanisms of hypoxic dilation in the two vessels. Myogenic activation of resistance arteries is generally considered to be mediated via the effects of pressure or stretch on the VSM cells themselves and to be independent of the endothelium (3). There is evidence that myogenic activation of small arteries from a variety of different vascular beds (13, 17, 18, 21), including the rat MCA (13), depends on inhibition of KCa channels by 20-HETE liberated in response to pressure elevation. Other studies suggest that hypoxic relaxation of some resistance arteries is mediated in part by decreased formation of 20-HETE (11). In the cat MCA, hypoxic dilation depends on activation of KCa channels in the VSM cell membrane (12). Therefore, in this vessel, activation of KCa channels in response to hypoxia (possibly due to reduced 20-HETE formation by the smooth muscle cells) could override the myogenic constriction and depolarization of VSM cells, because the latter responses are normally mediated by KCa channel closure in response to 20-HETE liberated in response to transmural pressure elevation. In the rat MCA, hypoxic dilation is mediated by activation of glibenclamide-sensitive K+ channels by endothelium-derived prostacyclin released in response to reduced PO2 (25). In this vessel, opening of KATP channels would not counteract any 20-HETE-dependent inhibition of KCa channels that would lead to pressure-induced depolarization of the VSM cells and myogenic activation of the vessel. Therefore, myogenic depolarization and contraction should still occur when transmural pressure is elevated, despite the presence of an initial dilation of the vessel in response to reduced PO2. However, this hypothesis remains to be tested.

The observation that myogenic responses are preserved despite VSM hyperpolarization and relaxation in response to reduced PO2 indicates that myogenic mechanisms can operate to protect the downstream microcirculation from sudden pressure increases, despite a reduction in O2 availability. This conclusion is consistent with the results of studies by Meininger et al. (29), who demonstrated that in situ arterioles of the rat cremaster muscle exhibit a sustained myogenic constriction in response to transmural pressure elevation, despite a reduction in blood flow and periarteriolar PO2. The most likely explanation for the ability of myogenic responses to regulate vessel diameter despite a reduction in O2 availability is that myogenic mechanisms are mediated via the direct effects of pressure or stretch on the VSM cells, whereas hypoxia itself has no direct inhibitory effect on the VSM cells, at least in the rat MCA (25). Regardless of its underlying mechanism(s), the preservation of myogenic activation during exposure to reduced PO2 may be important in allowing organs to regulate overall blood flow in response to changes in O2 availability while maintaining their ability to buffer the effects of acute changes in perfusion pressure.

Another crucially important question regarding the integrated control of blood flow in the peripheral circulation is whether or not myogenic activation of resistance arteries will override the dilation of the vessels in response to hypoxia, or whether the arteries retain their ability to respond to reduced PO2 when they are myogenically activated in response to elevated pressure in the vessel. This could be particularly important in hypertension because inhibition of hypoxic dilation by higher levels of arterial pressure could, in theory, explain the impaired vasodilator responses to reduced PO2 and arterial hypoxemia that have been reported in hypertension (23, 36).

To date, studies of the interaction of transmural pressure and vascular responses to vasoactive stimuli or altered PO2 have focused on the interaction of transmural pressure and vasoconstrictor stimuli. For example, Meininger and Trzeciakowski reported that perfusion pressure is an important determinant of the vasoconstrictor response to angiotensin II and phenylephrine in the hindquarters (31) and splanchnic (30) vascular beds of rats and that arterial pressure and vasoconstrictor responses interact to ultimately determine the resistance to blood flow in these vascular beds during intravenous infusion of these agonists. Transmural pressure elevation also enhances the sensitivity of small renal arteries to norepinephrine (24) and MCAs to serotonin (16). This increase in vasoconstrictor sensitivity with elevated transmural pressure appears to be mediated by depolarization of the arterial smooth muscle cells, bringing the Em closer to the threshold for mechanical activation (24). In contrast, elevation of transmural pressure via the pressurized box method does not lead to an enhanced constriction of arterioles in response to elevated PO2 or angiotensin II in the in situ microcirculation of the cremaster muscle (10).

In the present study, the dilation of the vessels in response to hypoxia was not impaired by elevated pressure inside the vessel but instead was significantly reduced at the lowest transmural pressure (60 mmHg). The reduced dilation at lower transmural pressure may be due, in part, to a reduction in the distending pressure in the artery. However, it is likely that a substantial component of this impaired relaxation at low pressure is due to the hyperpolarized Em that exist in the VSM cells before hypoxia, as a result of the low distending pressure in the vessel. Under these conditions, it is likely that the change in VSM Em that occurs in response to hypoxia at the lowest level of transmural pressure falls outside of the steep portion of the Em force curve (20), which would minimize the overall dilation of the vessel at the lowest levels of transmural pressure. However, an equivalent hyperpolarization at a higher level of transmural pressure would have a much greater effect on vessel diameter, because VSM Em before hypoxia would be within the steep portion of the VSM Em-force relationship.

In summary, reduced PO2 does not inhibit myogenic activation of rat MCAs. However, the slope of the myogenic depolarization of the vessel in response to elevated transmural pressure is shifted to more negative values during hypoxia, and the vessel exhibits myogenic activation starting from a larger diameter. In addition, transmural pressure elevation does not inhibit VSM hyperpolarization or override the dilation of rat MCA in response to reduced PO2. Taken together, these findings suggest that hypoxic relaxation in response to reduced PO2 and myogenic activation in response to transmural pressure elevation are both capable of regulating the diameter of cerebral arteries independently, despite substantial changes in the magnitude of the other variable.


    ACKNOWLEDGEMENTS

The authors thank Donna Bizub and Tianjian Huang for outstanding technical assistance in these studies.


    FOOTNOTES

This study was supported by National Institutes of Health Grants HL-37374, HL-29587, HL-65289, and NS-32321.

Address for reprint requests and other correspondence: J. H. Lombard, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jlombard{at}mcw.edu).

 This article belongs to a collection of papers accepted in response to the Editor's special call for papers entitled "Mechanisms of vascular myogenic tone."

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.

10.1152/ajpheart.00635.2002

Received 22 July 2002; accepted in final form 19 August 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 283(6):H2276-H2281
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