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J Appl Physiol 100: 1793-1798, 2006. First published February 23, 2006; doi:10.1152/japplphysiol.01632.2005
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Vascular wall energetics in arterioles during nitric oxide-dependent and -independent vasodilation

Masahiro Shibata,1 Kairong Qin,1,2 Shigeru Ichioka,1 and Akira Kamiya1

1Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan and 2Institute for Mechanobiology and Medical Engineering, Shanghai Jiao Tong University, Shanghai, China

Submitted 28 December 2005 ; accepted in final form 20 February 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The objective of this study was to evaluate whether the nitric oxide (NO) released from vascular endothelial cells would decrease vessel wall oxygen consumption by decreasing the energy expenditure of mechanical work by vascular smooth muscle. The oxygen consumption rate of arteriolar walls in rat cremaster muscle was determined in vivo during NO-dependent and -independent vasodilation on the basis of the intra- and perivascular oxygen tension (PO2) measured by phosphorescence quenching laser microscopy. NO-dependent vasodilation was induced by increased NO production due to increased blood flow, whereas NO-independent vasodilation was induced by topical administration of papaverine. The energy efficiency of vessel walls was evaluated by the variable ratio of circumferential wall stress (amount of mechanical work) to vessel wall oxygen consumption rate (energy cost) in the arteriole between normal and vasodilated conditions. NO-dependent and -independent dilation increased arteriolar diameters by 13 and 17%, respectively, relative to the values under normal condition. Vessel wall oxygen consumption decreased significantly during both NO-dependent and -independent vasodilation compared with that under normal condition. However, vessel wall oxygen consumption during NO-independent vasodilation was significantly lower than that during NO-dependent vasodilation. On the other hand, there was no significant difference between the energy efficiency of vessel walls during NO-dependent and -independent vasodilation, suggesting the decrease in vessel wall oxygen consumption produced by NO to be related to reduced mechanical work of vascular smooth muscle.

energy efficiency; oxygen consumption; circumferential wall stress; vascular smooth muscle

NITRIC OXIDE (NO) synthesized by the endothelium of small vessels not only controls vascular tone but also regulates tissue oxygen consumption (28, 30). Inhibitory effects of NO on cell respiration have been reported in various in vitro and in vivo preparations. At the cellular level especially it has become widely accepted that NO reduces the activity of mitochondrial functions by modulating oxygen uptake via NO inhibition of mitochondrial cytochrome-c oxidase (1, 5, 6, 23). In vivo studies have also demonstrated that NO modulates tissue metabolism (4, 14, 15, 21, 24). However, despite many studies reporting that the inhibition of NO production or impairment of endothelial function increases whole body oxygen consumption, still other reports provide evidence against this contention (3, 6). Crystal et al. (6) stated that basally released endogenous NO had a tonic systemic vasodilator effect, but it had no influence on whole body oxygen consumption. However, they also suggested that it could not be ruled out that increases in oxygen consumption in some tissues were balanced by decreases in oxygen consumption in others. Thus the potential physiological relevance of NO-mediated control of tissue metabolism in vivo remains to be established.

Recently, high oxygen consumption by vessel walls in functional arterioles has been reported (13, 32). These studies were carried out utilizing the phosphorescence quenching technique, and vessel wall oxygen consumption was determined on the basis of a transmural PO2 gradient (26, 31). Furthermore, oxygen consumption by vessel walls depends on vascular tone. Vascular smooth muscle contraction significantly increases vessel wall oxygen consumption (9), whereas vascular smooth muscle relaxation decreases the oxygen tension (PO2) gradient across the arteriolar wall, suggesting a decrease in vessel wall oxygen consumption (12). In contrast to these findings, however, other statements claiming that the vessel wall oxygen consumption was similar in magnitude to that of other tissues have been proposed (19, 29, 33). Estimated values of the maximum oxygen consumption of vessel walls were one order lower than those values determined by a transmural PO2 gradient (33). As the fact still remains unclear, further insight using direct transmural PO2 measurements is required to resolve these discrepancies.

Our most recent study (27), concerning the role of endothelium NO in regulating oxygen consumption by vessel walls, demonstrated that inhibition of NO synthesis increases oxygen consumption of arteriolar walls, whereas enhancement of flow-induced NO release decreases it. It is well known that the inhibition of NO synthesis also induces vasoconstriction and that enhancement of NO release induces vasodilation in resistance arterioles. Consequently, NO regulation of vessel wall oxygen consumption is directly related to the level of vascular tone. This raises the question of whether NO modulation of oxygen consumption has a direct effect on cell respiration or is a result of change in the mechanical work of vessel walls. To answer the question, we carried out the present study to determine the energy efficiency of vessel walls in skeletal muscle arterioles in vivo during NO-dependent and -independent vasodilation. The energy efficiency of vessel walls was calculated by changes in circumferential wall stress (amount of mechanical work) and vessel wall oxygen consumption rates (energy cost) before and during vasodilation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental protocols.   Experiments were performed using male Wistar rats weighing 150–200 g. All animal procedures were approved by the University of Tokyo Animal Care and Use Committee. The complete animal preparation protocol was described in detail elsewhere (25), and it is only briefly outlined here. Animals were anesthetized with urethane (1 g/kg) intramuscularly, and a tracheotomy was performed to facilitate spontaneous breathing. A carotid artery was cannulated to measure arterial blood pressure and arterial blood gases, and a jugular vein was cannulated to facilitate injection of the intravascular phosphorescence probes and to administer drugs. The cremaster muscle was spread out in a bath chamber, and the muscle surface was suffused with a 37°C Krebs solution with 5% CO2 in 95% N2. After a 20-min equilibration period, suffusion was stopped, and finally the muscle surface was covered with Saran film to prevent dehydration and hyperoxia. During the experiment, a noncontact thermo-heater with thermo-controller was used to maintain the body and muscle temperature at 35–36°C. All animals with systemic arterial pressure <60 mmHg during the experiment were excluded.

Phosphorescence quenching laser microscopy.   General observations of the microcirculation and in vivo PO2 measurements were made with a modified Nikon microscope and the oxygen-dependent quenching of phosphorescence decay technique (25). Intra- and perivascular PO2 measurements were made at first order (1A) arterioles having a diameter of ~100 µm and located 300–500 µm past the branch from the central cremasteric artery. Pd-meso-tetra (4-carboxyphenyl) porphyrin (Pd-porphyrin, Porphyrin Products) bound to bovine serum albumin was used for phosphorescence probe. The intravascular PO2 measurements were made at the center of the vessel 20–30 min after intravenous injection of Pd-porphyrin solution (~25 mg/kg), and perivascular PO2 measurements were then performed immediately in the vicinity of the vessel walls of the same arterioles. The phosphorescent probe was excited by epi-illumination with an N2-dye pulse laser (LN120C, Laser Photonics) with a 535-nm line at 20 Hz through the objective lens (CF Plan x20/0.40 EPI ELWD, Nikon, Tokyo, Japan). The surface of the epi-illuminated tissue was 10 µm in diameter. The average optical power and pulse width of the laser were 1.2 mW and 300 ps, respectively, and the excitation pulse energy was estimated to be 60 µJ per pulse at the outlet of the laser. However, the energy is reduced by the time it travels to the tissue surface, because the laser beam is induced by fiber optics and is irradiated through an objective lens; thus it appears to have relatively little impact on the measurement. A quenching process of phosphorescent emissions was captured by a photomultiplier and was converted to 10-bit digital signals at intervals of 3 µs. Ten decay curves of phosphorescent emissions in total were averaged to obtain a mean phosphorescence decay curve. PO2 values were calculated from the time constant of the phosphorescence decay curve according to the Stern-Volmer relationship (11, 34).

Hemodynamic changes.   After intra- and perivascular PO2 measurements of 1A arterioles under normal conditions, the PO2 measurements during NO dependent or -independent vasodilation were once again performed at the same sites. NO-dependent vasodilation was induced by the parallel arteriolar bifurcation occlusion method (18). The mechanical occlusion of one branch causes an increase in blood flow in the unoccluded branch, thus it enhances flow-induced NO release from vascular endothelial cells. NO-independent vasodilation was induced by topical administration of papaverine (10–4 mol/l) to the muscle surface. The changes in internal diameter of arterioles during vasodilation were analyzed off-line from video recorded images. To determine the mechanical work needed to maintain the vessel diameter against blood pressure under normal conditions, the difference in circumferential wall stress of the arteriole between vasodilated and normal conditions ({Delta}{sigma}, in dyn/cm2) was calculated by utilizing the Laplace law for a blood vessel, with wall thickness (w), as follows,

Formula 1(1)
where P is the mean blood pressure of arterioles, and Rinor and Ridil represent internal radii of arterioles under normal conditions and during vasodilation, respectively. Because blood pressure in arterioles with a diameter of ~100 µm would still be 75–95% of systemic arterial pressure in skeletal muscle (8), the P values used in this study were calculated from 85% of individual values of mean arterial pressure measured in each animal.

Estimation of vessel wall oxygen consumption rates.   Oxygen consumption rates of vessel walls were calculated by employing a modified Krogh capillary-tissue model (17) for an arteriolar wall with cylindrical geometry, as previously described (26). Assuming that the arteriole is cylindrical and has an outer radius and an internal radius of Ro and Ri, respectively, the oxygen consumption rate per unit tissue volume per unit of time in its wall (QO2, in mlO2·s–1·g–1) can be expressed as:

Formula 2(2)
where PO2peri and PO2in represent the PO2 values measured in the immediate vicinity of the outer surface of the arteriolar wall and within the arteriole, respectively. Dt and {alpha}t represent oxygen diffusivity and oxygen solubility, respectively, in the arteriolar wall, for which values of 1.5 x 10–5 cm2/s and 3.0 x 10–5 ml·g–1·Torr–1, respectively, were used (22). Therefore, the oxygen consumption rate of the vessel wall was determined by utilizing the measured intra- and perivascular PO2 values of the arteriole. Because of the uncertainty of the location of the outer boundary of the vessel wall, the wall thickness was assumed to be 20% of arteriolar internal radius under normal conditions.

Vessel wall energy efficiency.   Mechanical energy would be required to maintain the vessel diameter against blood pressure. Thus the energy efficiency of the vessel wall was determined from the total amount of mechanical work needed to change vessels from a vasodilated to a normal state and its energy cost. This value was defined as the variable ratio of circumferential wall stress to vessel wall oxygen consumption rate ({Delta}{sigma}/{Delta}QO2) in the arteriole between a normal and a vasodilated state (J·mlO2–1·s–1 or W/mlO2).

Data analysis.   All data are reported as means ± SD. Data within each group were analyzed by ANOVA for repeated measurements. Differences between groups were determined using a t-test with the Bonferroni correction. Differences with a P value of <0.05 were considered statistically significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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Nine rats were used to study the response to NO-dependent vasodilation and six rats to study NO-independent vasodilation. Systemic arterial PO2, PCO2, and pH were measured with a blood-analysis system (series 2000, Diametrics Medical, St. Paul, MN) in samples from the carotid arteries after performing the microvascular PO2 measurements. In the NO-dependent vasodilation study, arterial PO2 averaged 89.7 ± 6.0 Torr, and arterial PCO2 and pH averaged 48.8 ± 8.7 Torr and 7.33 ± 0.05, respectively. On the other hand, for the study of NO-independent vasodilation, the arterial PO2 was 97.8 ± 10.5 Torr, and the arterial PCO2 46.1 ± 8.2 Torr and pH 7.31 ± 0.05. Mean arterial blood pressure averaged 77.6 ± 7.1 mmHg, in which there was no significant difference between NO-dependent and -independent experiments.

Changes in vessel diameters during vasodilation.   The maximum values of internal diameter during the occlusion period (60 s) and after application of papaverine were defined as the diameter values during NO-dependent and -independent vasodilation. The individual internal diameter changes of arterioles for each preparation and mean percent changes before and during NO-dependent and -independent vasodilation are shown in Fig. 1. NO-dependent and -independent dilation increased diameters by 13 and 17%, respectively, relative to the values under normal conditions. The diameter values during NO-dependent and -independent dilation were both significantly higher than the values before dilation. On the basis of these vessel diameter data, the changes in circumferential wall stress in the arteriole under normal conditions and during vasodilation were calculated utilizing the Laplace law. Figure 2 shows the circumferential wall stress increment in the arteriole before and during NO-dependent or -independent vasodilation ({Delta}{sigma}). The {Delta}{sigma} during NO-independent vasodilation was greater than that during the NO-dependent vasodilation, because {Delta}{sigma} depends on changes in vessel diameter.


Figure 1
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  		Fig. 1. Individual changes in internal diameters of arterioles for each preparation before and during NO-dependent and -independent vasodilation (top and middle) and their mean relative changes (bottom). NO-dependent vasodilation was performed by the parallel bifurcation occlusion method (16), which causes an increase in blood flow in the unoccluded branch. NO-independent vasodilation was performed by topical administration of papaverine. Error bars indicate SD (NO dependent, n = 9 rats; NO independent, n = 7 rats).

 

Figure 2
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  		Fig. 2. Circumferential wall stress increment in the arteriole before and during NO-dependent and -independent vasodilation ({Delta}{sigma}, in dyn/cm2). {Delta}{sigma} values were calculated by use of the Laplace law on the basis of the vessel diameter data shown in Fig. 1. Error bars indicate SD (NO dependent, n = 9 rats; NO independent, n = 7 rats).

 
Intra- and perivascular PO2 and oxygen consumption rates.   The changes in the average values of intra- and perivascular PO2 in arterioles before and during NO-dependent and -independent vasodilation are shown in Fig. 3. Intravascular PO2 values of the arterioles under all conditions were significantly lower than the systemic arterial PO2 value. Perivascular PO2 values of the arterioles during NO-dependent and -independent vasodilation were significantly higher than control. The average values of vessel wall oxygen consumption rates in arterioles before and during NO-dependent and -independent vasodilation calculated from the individual intra- and perivascular PO2 data are shown in Fig. 4. The oxygen consumption rates of arteriolar walls during NO-dependent and -independent vasodilation were significantly lower than control; however, vessel wall oxygen consumption during NO-independent vasodilation was significantly lower than that during NO-dependent vasodilation. To evaluate the participation of NO in vessel wall oxygen consumption, the energy efficiencies of vessel walls during NO-dependent and -independent vasodilation were calculated (Fig. 5). There was no significant difference in vessel wall energy efficiency during NO-dependent vs. -independent vasodilation, suggesting that vessel wall oxygen consumption depends on the amount of mechanical work performed by vessel walls.


Figure 3
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  		Fig. 3. Changes in average intra- and perivascular PO2 values of arterioles before and during NO-dependent and -independent vasodilation. NO-dependent vasodilation was performed by the parallel bifurcation occlusion method, and NO-independent vasodilation was performed by topical papaverine administration. Error bars indicate SD. *Significant difference from the control group.

 

Figure 4
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  		Fig. 4. Average values of vessel wall oxygen consumption rates in arterioles before and during NO-dependent and -independent vasodilation calculated from the individual intra- and perivascular PO2 data. Error bars indicate SD. *Significant difference from the control group.

 

Figure 5
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  		Fig. 5. Vessel wall energy efficiencies during NO-dependent and -independent vasodilation. The energy efficiency was determined by the variable ratio of circumferential wall stress to vessel wall oxygen consumption rate in the arteriole between the control vs. vasodilation ({Delta}{sigma}/{Delta}QO2, in J·mlO2–1·s–1). Error bars indicate SD.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The principal finding of the present study is that the energy efficiencies of vessel walls in arterioles during NO-dependent and -independent vasodilation have no significant difference, and the decrease in vessel wall oxygen consumption produced by NO depends on the reduced mechanical work of vascular smooth muscle. In vivo microvascular studies have reported that oxygen consumption by arteriolar walls depends on the level of vessel tone. Vasoconstriction, which is induced by administering arginine vasopressin or inhibiting NO synthesis, increased the PO2 gradient across the arteriolar vessel wall, whereas intra- and perivascular PO2 levels decreased significantly (9). Conversely, vascular smooth muscle relaxation decreased the PO2 gradient across the arteriolar wall, suggesting a decrease in vessel wall oxygen consumption (12). However, despite these contentions, Crystal et al. (6) suggested that basally released endogenous NO had a tonic systemic vasodilator effect but had no influence on whole body oxygen consumption. Their findings appear to show the irrelevance of vessel wall oxygen consumption to the level of vessel tone. However, they suggested whole body oxygen consumption values to be an aggregate of the oxygen consumed by individual body tissues. Thus it could not be ruled out that increases in oxygen consumption in some tissues were balanced by decreases in others with different levels of vessel tone. The present study clarified the relationship between the amount of mechanical work of vessel walls and their oxygen consumption by employing the energy efficiency of vessel walls. The fact that there is no significant difference between NO-dependent and -independent vasodilation further clarifies that NO decreases vessel wall oxygen consumption by decreasing the total amount of mechanical work of vascular smooth muscle.

In this study, the amount of mechanical work done by the vessel wall, which is responsible for vasoconstriction dilated vessels to restore the normal condition against blood pressure, was determined from the difference in circumferential wall stress in the arteriole under normal conditions and during vasodilation. The precision of this determination is dependent on the accuracy of vessel diameter measurement and a number of assumptions. Especially, changes in vessel diameter are very sensitive transport parameters to calculate changes in circumferential wall stress by different forms of vasodilation. Simple comparison of vessel wall oxygen consumption between the two forms of vasodilation would be easy to understand; however, in the present study, changes in diameter induced by papaverine were significantly greater than those of flow-induced vasodilation, revealing a statistical difference in oxygen consumption between the two forms of vasodilation. Blood pressure in arterioles of interest used in this study were calculated from 85% of individual values of mean arterial pressure measured in each animal, because it has been reported that the blood pressure is 75–95% of systemic in skeletal muscle arterioles with a diameter of ~100 µm (8). The thickness of vessel walls, on the other hand, was assumed to be 20% of the internal radius under normal conditions. Consequently, the wall thickness and internal radius ratios (w/Ri) during NO-dependent and -independent vasodilation were 18 and 17%, respectively. The calculated values of circumferential wall stress ranged between 47 x 104 and 55 x 104 dyn/cm2, i.e., they were fairly consistent with previously reported values (20).

Vascular wall oxygen consumption rates obtained in this study were one to two orders of magnitude higher than reported values of vascular cells measured from isolated vascular segments (16). High oxygen consumption by functional arterioles has been demonstrated by Intaglietta's group (31, 32). These studies were carried out utilizing the phosphorescence quenching technique, and vessel wall oxygen consumption was determined on the basis of a transmural PO2 gradient in vivo. In contrast to these findings, other statements claiming that the vessel wall oxygen consumption was similar in magnitude to that of other tissues have been proposed (19, 29, 33). Vadapalli et al. (33) reported that estimated values of maximum oxygen consumption of vessel walls utilizing the mitochondrial content and its oxygen consumption were an order lower than those values determined by a transmural PO2 gradient. We cannot rule out the possibility of technical problems in our perivascular PO2 measurements, resulting from this technique, because the perivascular measurement site contained stationary fluid. In such cases, the photo-activation of the phosphor would consume oxygen, and the perivascular PO2 could be lowered by the measurement process itself (10), thereby increasing the transmural PO2 difference. Another possibility of these discrepancies may be explained by the differences of experimental environments. Because most tissue segment studies were conducted under static conditions, in the absence of physiological function, they were under low metabolic activity. In our previous study (26), to evaluate the appropriateness of our estimation of wall oxygen consumption rates, we calculated the downstream intravascular PO2 value utilizing the wall oxygen consumption rate and upstream intravascular PO2 values. The calculated downstream intravascular PO2 value was consistent with that of measured values. This evaluation improved the reliability of our wall oxygen consumption rate measurements, because this calculation was carried out without the perivascular PO2 value.

The oxygen consumption rate of arteriolar walls was calculated on the basis of the measured intra- and perivascular PO2 values before and during NO-dependent and -independent vasodilation. NO-dependent vasodilation was performed by the parallel arteriolar bifurcation occlusion method (18), in which increased NO release by vascular endothelial cells was induced by an increase in blood flow through an unoccluded arteriole. Intravascular pressure within an unoccluded arteriole may rise during occlusion, but the effect of the increase in pressure on vasodilation is negligible. Most of the vasodilation was induced by the increase in flow-dependent NO release, because arteriolar diameter increased only 2.5% during occlusion using nitro-L-arginine methyl ester (L-NAME) or L-NAME plus indomethacin (data not shown), whereas it increased 13% during occlusion. The 2.5% increase in diameter may have been caused by intravascular pressure changes. On the other hand, NO-independent vasodilation was induced by topical papaverine administration (10–4 mol/l) to the muscle surface. Papaverine is a nonspecific smooth muscle relaxant, and its effects are known to include 1) acting directly on the smooth muscle cell membrane and inhibiting the flow of extracellular Ca2+ into the cell and 2) inhibiting phosphodiesterase activity and increasing the intracellular cAMP content.

The changes in wall shear stress would be an important factor to compare the differences in energy efficiency between NO-dependent and -independent vasodilation. In this study, both the intra- and perivascular PO2 measurements during NO-dependent vasodilation were carried out under high shear stress conditions, because their measurements have been finished within a period of 60 s after mechanical occlusion of other branch. On the other hand, changes in wall shear stress during NO-independent, papaverine-induced vasodilation was uncertain, because the measurement was started after when arteriole has been completely dilated. It is well known that change in vessel diameter is a sensitive parameter for wall shear stress, which is inversely proportional to the third power of the vessel radius. With regard to the effect of shear stress on energy expenditure in the vessel wall, Cabrales et al. (2) investigated the oxygen release from arterioles in the intact tissue, both with and without blood flow. They reported that shear stress induced a significant oxidative metabolic activity in the endothelium, which required oxygen. High shear stress during NO-dependent vasodilation might have affected our results in that vascular wall energy efficiencies, during NO-dependent and -independent vasodilation, have no significant differences.

In conclusion, NO-dependent and -independent vasodilation both decreased vessel wall oxygen consumption in arterioles. There was no significant difference in energy efficiencies of vessel walls between during NO dependent vs. -independent vasodilation. It appears that NO decreases vessel wall oxygen consumption by decreasing vascular smooth muscle mechanical work.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This study was supported by a Grant-in-Aid for Scientific Research (17300143) from Japan Society for the Promotion of Science.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Shibata, Dept. of Biomedical Engineering, Graduate School of Medicine, Univ. of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan (e-mail: shibatam{at}m.u-tokyo.ac.jp)

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.


   REFERENCES
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 RESULTS
 DISCUSSION
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