Flow-induced dilation of rat soleus feed arteries

Departments of Medical Physiology and Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri 65211

	ABSTRACT

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Flow-induced dilation is thought to contribute to dilation of skeletal muscle arteries and arterioles during exercise hyperemia. We sought to determine whether rat soleus feed arteries (SFA) exhibit flow-induced dilation and to evaluate the potential contribution of flow-induced dilation of SFA to exercise hyperemia. Rat SFA were isolated and cannulated to allow pressure and intraluminal flow to be independently controlled. Intraluminal pressure was maintained at 90 cmH₂O throughout the experiment. All SFA (n = 13) developed spontaneous tone and dilated in response to flow. Flow of 10 and 14 µl/min produced a 34 ± 14 and 56 ± 17 µm increase above basal diameter (135 ± 12 µm), respectively. Flows >14 µl/min produced little further dilation. Maximum flow-induced dilation was 86 ± 3% of passive diameter determined in calcium-free physiological saline solution. Calculated shear stress was maintained at 4-6 dyn/cm² at flows of 10-20 µl/min but increased at greater flows because SFA did not dilate further. To determine whether dilation in response to flows in this range may contribute to exercise hyperemia, we estimated in vivo SFA blood flows from previously published soleus blood flow data. Anesthetized rats are estimated to have flows of 10 µl/min per SFA, and conscious rats are estimated to have flows of 95 (nonexercising), 153 (walking), and 225 (running) µl/min per SFA. Corresponding shear stresses were estimated to be 26 (anesthetized), 47 (conscious, nonexercising), 75 (walking), and 111 (running) dyn/cm². Because estimated in vivo values for both flow and wall shear stress are far greater than the flow and/or shear stresses at which maximal flow-induced dilation occurs in vitro, we conclude that flow-induced dilation contributes little to dilation of SFA during locomotory exercise.

shear stress; blood flow

	INTRODUCTION

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FLOW-INDUCED DILATION is one of many factors thought to contribute to regulation of vascular tone. In particular, flow-induced dilation may contribute to exercise hyperemia in skeletal muscle (27). Arterioles from the cremaster (7, 11, 30) and gracilis muscles (10), as well as larger conduit arteries in skeletal muscle (4, 9), exhibit flow-induced dilation. Feed arteries, which lie external to the muscle and give rise to the arterioles within the muscle, provide a major portion of the resistance to flow through individual skeletal muscles (27) and play an important role in mediating increases in blood flow to contracting skeletal muscle (14, 33). Because feed arteries are located outside of the muscle, they are not exposed to the metabolic environment within the muscle; therefore, metabolic factors are not expected to contribute directly to dilation of feed arteries during exercise hyperemia. It has been proposed that flow-induced dilation contributes to the dilation of feed arteries during exercise (27).

The purposes of this study were twofold: 1) to test the hypothesis that feed arteries of the rat soleus muscle dilate in response to flow and/or shear stress and 2) to evaluate the potential contribution of flow-induced dilation of soleus feed arteries (SFA) to exercise hyperemia. SFA were selected for this study for two reasons. First, our laboratory has a long-standing interest in the determinants of blood flow to the rat soleus muscle (17). Second, Williams and Segal (32, 33) provided anatomic and functional data for the rat soleus muscle, including the number of feed arteries, pressures in these arteries, and their level of vascular tone.

	METHODS

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Animals. Male Sprague-Dawley rats (weight 416 ± 15 g) were obtained (Sasco) and housed two animals per cage in a room with controlled temperature (24°C) and light (12:12-h light-dark cycle) conditions. The rats were fed and watered ad libitum. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of Missouri.

Preparation of arteries. On the morning of an experiment, rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (50.0 mg/kg). An incision was made on the lateral surface of the lower leg, and the soleus muscle feed arteries were carefully isolated. SFA (average length 1.9 mm) were removed and transferred to a Lucite vessel chamber containing cold (4°C) 3-(N-morpholino)propanesulfonic acid (MOPS)-buffered physiological saline solution (PSS) [composed of (in mM) 145.0 NaCl, 4.7 KCl, 2.0 CaCl₂, 1.17 MgSO₄, 1.2 NaH₂PO₄, 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 MOPS (pH 7.4)]. Arteries were cannulated on one end with a glass micropipette filled with PSS-albumin (1 g/100 ml) solution. Ophthalmic suture (11-0) was used to securely tie the artery to the pipette. The artery was then flushed with the PSS-albumin solution, and the other end was cannulated and secured with suture. Electrical resistances (model LCR-740, LCR bridge circuit, Leader Electronics) of pipettes were 150-250 k, and the resistances of each pipette pair were matched (±0.5%). Pipette inner diameters were 70-90 µm, and outer diameters were 95-115 µm.

Bovine serum albumin (United States Biochemical) >98% pure was used in the PSS perfusate. NaCl, KCl, and glucose were obtained from Fischer Scientific. All other reagents were obtained from Sigma Chemical.

After cannulation of the SFA the isolated vessel chamber was transferred to the stage of an inverted microscope (Nikon Diaphot 200, ×20 or ×40 magnification; spatial resolution with either magnification is <1 µm) coupled with a video camera (Javelin Electronics, Los Angeles, CA), video monitor (Sony), video micrometer (Microcirculation Research Institute, Texas A&M University), and Macintosh/MacLab data acquisition system. Luminal diameter and pressure were continuously monitored (sampling frequency 20/min) throughout the experiment and recorded on the computer. The bath was gradually warmed and maintained at 37°C for the duration of the experiment. Luminal pressure was set at 60 cmH₂O initially and raised to 90 cmH₂O halfway through the 1-h equilibration period. This pressure was selected based on the in vivo rat SFA pressure measurements of Williams and Segal (32). Micropipettes were connected to independent reservoir systems, and pressure was measured through sidearms connected to low-volume displacement pressure transducers (Electromedics). Arteries were pressurized by elevating both reservoirs to the same level. The bath solution was replaced every 15 min during the equilibration period. All SFA developed spontaneous tone during the equilibration period.

Experimental protocol. After the equilibration period and the development of spontaneous tone, flow was initiated by elevating one reservoir while lowering the other reservoir an equal distance. This produces a pressure gradient across the artery that causes perfusate flow through the artery without changing intraluminal arterial pressure (12). The artery was given at least 3 min at each level of flow to achieve a stable diameter (usually not more than 4 min but in two SFA one of the flow steps required 9 min because diameter continued to increase slowly after the initial rise). At this time the next level of flow was initiated by again raising one reservoir while lowering the other an equal amount. Pressure gradients of 2, 4, 6, 8, 10, 15, 20, 30, and 40 cmH₂O were used. This corresponded to flow rates of 10, 14, 17, 19, 20, 30, 37, 52, and 65 µl/min. Perfusate flow was measured with a ball flowmeter (Omega Engineering), which was calibrated using a Razel perfusion pump (model A99). At the completion of the experimental protocol the artery was incubated in calcium-free PSS (CaCl₂ omitted) containing 2 mM EDTA for 1 h at 90 cmH₂O and 37°C to obtain the passive diameter.

Data analysis. Data are presented as means ± SE. One SFA per rat was used from each of 13 rats. Percent spontaneous tone developed is defined as (D_PD_T/D_P) × 100, where D_P is the calcium-free diameter and D_T is the diameter after development of spontaneous tone before any experimental intervention.

Shear stress () was calculated for each artery at each flow step using Eq. 1

(1)

where  is the perfusate viscosity [0.008 poise at 37°C (13)], is the perfusate flow, and r is the internal radius of the artery. The use of this equation requires that flow is laminar. To determine whether flow was laminar we calculated the Reynolds number (Re) and the entry length (L_e), the distance for laminar flow to be reestablished after entry of flow from the pipette into the artery. Values of Re <2,000 indicate that flow is laminar, whereas higher values indicate turbulent flow (31). Calculations with the different combinations of flow and diameter present in this study reveal Re values ranging between 1 and 9, clearly well below the value of 2,000 at which flow becomes turbulent. Calculations of L_e (8) reveal that at the flow levels at which all the diameter changes occur, entry length is <100 µm. Because artery length between the pipette tips averages 1,900 µm and diameter is measured near the middle of the segment, it appears safe to assume that flow is laminar for a large distance in either direction from our measurement site. In addition, on occasion red blood cells were observed flowing through the artery. These cells always moved through in a linear fashion. They have never been observed to move in any way that would indicate a turbulent flow pattern.

Data were analyzed by analysis of variance for repeated measures followed by Tukey's multiple comparisons post hoc test. Significance was set at P < 0.05.

	RESULTS

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The soleus muscles of the rats used in this study weighed 210 ± 11 mg. There were typically three SFA per soleus muscle. The internal diameter of SFA after development of spontaneous tone and before initiation of flow was 135 ± 12 µm. SFA passive diameter determined in calcium-free PSS with 2 mM EDTA was 234 ± 7 µm. The level of spontaneous tone developed was 42 ± 5% of passive diameter.

SFA luminal diameters at different levels of flow are shown in Fig. 1A. Diameter increased markedly (34 ± 14 µm) at the lowest level of flow (10 µl/min) and increased further (to 56 ± 17 µm above basal diameter) at the second flow step (14 µl/min). Despite further increases in flow up to 65 µl/min, diameter did not increase significantly in response to these further elevations in flow. The maximal diameter achieved in response to flow was 86 ± 3% of the calcium-free passive diameter. When flow was stopped and the artery was rinsed with fresh PSS, the diameter returned to baseline levels (136 ± 10 µm).

View larger version (14K): [in this window] [in a new window]   Fig. 1.   Relationship of flow to diameter (A) or to wall shear stress (B) in rat soleus feed arteries (SFA). Data are means ± SE. Near maximal flow-induced dilation occurs at flow 14 µl/min. Diameter before flow is 58 ± 5% of passive diameter and maximal flow-induced diameter is 86 ± 3% of passive diameter. * Significant difference from all other points (P < 0.05). All points under bracket are not different from each other. Near maximal flow-induced dilation occurs at shear stress of 6 dyn/cm2. Shear stress was calculated using Eq. 1. ns, not significant.

The relationship between flow and calculated shear stress is shown in Fig. 1B. Shear stress increased from 0 dyn/cm² as flow was initiated. Wall shear stress was maintained relatively constant between 4 and 6 dyn/cm² for the first five flow steps; shear stress then increased as a result of increased flow without further increases in diameter.

	DISCUSSION

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The results of this study demonstrate that rat SFA dilate in response to flow and the associated shear stress. The full dilatory response to flow occurs by flows of 14 µl/min, and flows greater than this elicit little further dilation (Fig. 1A). In addition, only very low levels of calculated shear stress are generated by these low flows through SFA (Fig. 1B). Thus very low levels of shear stress (<6 dyn/cm²) produce near maximal flow-induced dilation in rat SFA.

The levels of flow and shear stress at which SFA responded are similar to the results reported by other investigators in in vitro and cell culture experiments. Large arteries feeding skeletal muscle, such as rabbit iliac (4) or femoral arteries (9), first-order arterioles from rat cremaster (7, 11, 30), second-order arterioles from rat gracilis (10), and porcine coronary arterioles (12, 13), and small arteries (13) all dilate in response to flows and shear stresses similar to those we report. In addition, experiments performed on cultured endothelial cells show shear stress-induced responses over the range of 0 to 25 dyn/cm² (3). Thus the range of flows and shear stresses over which SFA dilated in the present study is similar to results previously reported in the literature for vessels from other vascular beds.

In vivo blood flow and shear stress. We wondered whether the range of flows and shear stresses tested in our in vitro experiments reflects the forces acting on those vessels in vivo and thus whether flow-induced dilation could be expected to play a continuous role in regulation of feed artery diameter, as suggested by Smiesko and Johnson (29), or contribute to hyperemic responses of the soleus muscle such as during locomotion (27). Because the number of feed arteries in the rat soleus muscle is known and because rat soleus blood flows have been measured in numerous studies, we used these data to estimate in vivo flow and wall shear stress levels in SFA.

The literature values for measured in vivo soleus muscle blood flows under different conditions and the calculated blood flow and shear stress values for SFA are shown in Table 1. As depicted in Fig. 2A, with the exception of flows in anesthetized rats, these estimates of blood flow per feed artery are well above the flow of 14 µl/min at which we observed maximal flow-induced dilation of SFA in the present study. These results suggest that the ability of SFA to dilate in response to flow is saturated already in the nonexercising rat simply maintaining posture.

View this table: [in this window] [in a new window]   Table 1.   Calculations of soleus feed artery blood flow and shear stress in vivo

View larger version (18K): [in this window] [in a new window]   Fig. 2.   Estimated blood flow (A) and wall shear stress (B) per SFA in rats under 4 different conditions: 1) anesthetized, 2) conscious, nonexercising, but maintaining posture, 3) walking (15 m/min), and 4) running. Estimates of flow rate and wall shear stress assume 3 feed arteries per soleus. Dotted line in each panel represents value at which SFA in vitro displayed maximal flow-induced dilation. Blood flows per feed artery were estimated from published literature values of in vivo soleus blood flows as described in Table 1. Wall shear stresses were calculated using these estimated blood flows. See discussion for details.

Because viscosity is one determinant of shear stress and blood is more viscous than the PSS used in the present study, we expected that in vivo shear stress values would also be greater than those produced in our experiments. As shown in Fig. 2B, in all cases the calculated values for wall shear stress in vivo are much greater than 6 dyn/cm², the shear stress at which SFA exhibit maximal flow-induced dilation in vitro. This comparison of shear stresses leads to the same conclusion as the flow comparison: that in the nonexercising rat, SFA blood flows produce wall shear stresses that are greater than the shear stress necessary to produce maximal flow-induced dilation in vitro. If, as this analysis indicates, SFA flows and wall shear stresses are greater than necessary to produce maximal flow-induced dilation in a resting conscious rat, then it is unlikely that flow-induced dilation contributes to the feed artery dilation associated with functional hyperemia.

Two factors offer additional support for the argument that in vivo shear stresses are higher than the operating range for flow-induced dilation. First, because of the pulsatile nature of flow in the arterial circulation, large transient increases and decreases in wall shear stress probably occur during the cardiac cycle (19). Thus feed arteries are most likely transiently exposed to even higher shear stresses than the mean values estimated above. Second, in our calculations we have used the most conservative estimates of feed artery diameter. That is, our estimates of wall shear stress (Table 1) were determined assuming maximal feed artery diameters for conscious rats and 42% tone for anesthetized rats. The literature suggests that SFA diameters in anesthetized (33) and conscious rats (27, 28) are less than our assumed values, which means that in vivo shear stresses may be even greater than our estimates.

Feed arteries are believed to play an important role in controlling resistance and blood flow to skeletal muscle (14, 27, 33). Because these arteries are located outside of the muscle, they are not exposed to the metabolic environment within the muscle and should not be under the influence of metabolites produced within the muscle during contraction. Flow-induced dilation has been proposed as one mechanism that may contribute to the dilation of feed arteries during exercise hyperemia (27). This is the first time, to our knowledge, that in vitro responses to flow and wall shear stress in the microcirculation have been compared with estimated in vivo blood flows and shear stresses from conscious animals. The results show that it is improbable that flow-induced dilation contributes to SFA dilation during exercise. However, flow-induced dilation may play an important role in setting basal vascular tone of SFA in rats at rest or during maintenance of posture. This notion is supported by the results summarized in Fig. 2 and by the fact that arginine analogs, which inhibit the production of nitric oxide (a mediator of flow-induced dilation), cause reduced muscle vascular conductance when administered systemically (23), indicating a tonic release of nitric oxide.

Although flow-induced dilation apparently does not contribute to dilation of SFA, at least two other mechanisms exist that may explain feed artery dilation during exercise. First, both vascular endothelium and smooth muscle are capable of conducting vasodilatory responses via gap junctions between cells (20, 34). These responses can be conducted upstream in the arterial circulation, and it has been proposed that conducted responses contribute to the dilation of upstream vessels during exercise (27). Second, there is evidence that endothelium-derived relaxing factors from veins can cause dilation of paired arteries (6, 26). Because SFA typically have a vein on each side, metabolites or other substances arising from the muscle during contraction may enter the veins leaving the soleus and thereby contribute to alterations in the diameter of the neighboring feed arteries.

The results of this study should not be extrapolated to other vessels or the vascular beds of other muscles or other organs. First, because the soleus muscle is used in maintenance of posture, nonexercising blood flows to the soleus in the conscious rat are higher than to most other muscles (16). These high blood flows may result in higher shear stresses in the SFA than in the vasculature supplying other muscles. Second, as numerous branches occur soon after the feed arteries enter the soleus (32), blood flow and shear stress per vessel may be different in other branch orders than at the feed artery level. Third, the soleus has a high percentage of slow-twitch muscle fibers (16). The fiber type of a muscle also influences its blood flow, with muscles composed primarily of highly oxidative fibers receiving more blood flow at rest than muscles composed primarily of highly glycolytic fibers (15).

Finally it is important to emphasize that the present data do not indicate that SFA are maximally dilated already before exercise begins. Flow-induced dilation is but one potential dilatory stimulus that may be present in vivo. Also, there are a number of potential constrictor stimuli that may be active in vivo. Unfortunately, there is no definitive way to know the level of tone in SFA of conscious animals. The conclusion that SFA are maximally dilated would be both counterintuitive and contrary to published results in anesthetized animals. Williams and Segal (33) have shown that SFA of anesthetized rats dilate in response to soleus muscle contraction, and calculations by Segal and Duling (28) and Segal (27) indicate that skeletal muscle feed artery dilation is necessary for muscle blood flows to increase to measured values. Thus it appears unlikely that SFA in vivo are fully dilated before exercise begins.

In conclusion, we tested the hypothesis that isolated SFA exhibit flow-induced vasodilation. Our results reveal that all SFA dilated in response to intraluminal flow. Maximal responses were observed at flows of 14 µl/min per feed artery producing shear stresses of <6 dyn/cm². We compared these results with estimates of blood flow and shear stress in SFA in vivo. Estimates of flow and shear stress in SFA of conscious animals were greater in every condition (nonexercising, walking, or running) than the flows and shear stresses that produced maximal flow-induced vasodilation in vitro. We conclude that while flow-induced vasodilation of SFA may contribute to hyperemic responses in the soleus of anesthetized rats, it probably does not contribute to the decreases in soleus vascular resistance associated with locomotion.

	ACKNOWLEDGEMENTS

We thank Pam K. Thorne and Tammy Strawn for invaluable technical assistance and Drs. R. M. McAllister and V. H. Huxley for critical review of the manuscript.

	FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-36088 and Missouri Affiliate of the American Heart Association predoctoral fellowship to J. L. Jasperse.

Address for reprint requests: M. H. Laughlin, E102 Veterinary Biomedical Sciences, Univ. of Missouri, Columbia, MO 65211.

Received 6 January 1997; accepted in final form 25 July 1997.

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