Exercise Training Augments Flow-Dependent Dilation in Rat Skeletal Muscle Arterioles
Role of Endothelial Nitric Oxide and Prostaglandins
Abstract We aimed to test the hypothesis that as a consequence of short-term daily exercise, flow (shear stress)–dependent dilation and its mediation by the endothelium are altered in skeletal muscle arterioles. After initial familiarization with the protocol, rats ran on a treadmill once a day (with gradually increasing intensity up to 40 minutes and 28 m/min) for ≈3 weeks (EX group); a control group remained sedentary (SED group). The active (internal) diameters of isolated gracilis muscle arterioles of SED and EX rats at 80 mm Hg were significantly different (55.2±2.1 and 49.3±2.0 μm, P<.05), and their passive diameters (in Ca2+-free solution) were 105.3±3.1 and 111.2±2.4 μm (not significantly different), respectively. Increases in flow of the perfusion solution from 0 to 12 μL/min elicited a significantly greater increase in diameter of EX arterioles (by 83.5% at maximum flow). This enhanced sensitivity maintained a lower shear stress in EX arterioles (15 to 20 dyne/cm2) compared with SED arterioles (25 to 35 dyne/cm2). In both SED and EX arterioles, flow-dependent dilation was eliminated after removal of the endothelium. Either Nω-nitro-l-arginine, a nitric oxide synthase inhibitor, or indomethacin, an inhibitor of prostaglandin synthesis, shifted the flow-diameter and calculated wall shear stress–diameter curves significantly to the right. Each of the inhibitors reduced flow-dependent dilation to a similar degree (≈40% to 45%); their combined administration nearly completely eliminated the dilation of arterioles of both SED and EX rats. Thus, we conclude that the sensitivity of gracilis muscle arterioles of rats to wall shear stress is upregulated after short-term daily exercise, resulting in an augmented dilator response that is due to an increased release of both endothelium-derived nitric oxide and prostaglandins.
Several studies have already established that daily exercise elicits significant adaptations of the cardiovascular system.1 2 Previous studies have demonstrated significant changes in the vasoactive function of large arteries3 4 and their endothelia5 6 in response to exercise training. In our previous study, we found that the dilation of skeletal muscle arterioles in response to acetylcholine and l-arginine was significantly enhanced in rats after a brief period of exercise training compared with sedentary rats.7 It is known that functions of the vascular endothelium are affected greatly by hemodynamic forces in various in vivo and in vitro conditions. In skeletal muscle arterioles,8 9 10 previous studies have demonstrated that acute increases in shear stress, induced by increases in blood or perfusate flow and/or viscosity, stimulate the synthesis of endothelial factors, among them nitric oxide and prostaglandins, eliciting vasodilation. In addition, repeated increases in flow or the chronic presence of high blood flow were shown to affect the function of vascular endothelium,11 and during treadmill exercise in rats, there is a significant increase in blood flow to working skeletal muscles.12 13 14 Taken together, these findings suggest that increases in blood flow in skeletal muscle during repeated bouts of daily exercise affect the synthesis of endothelial factors mediating flow (shear stress)–induced dilation. To test this hypothesis, arterioles of gracilis muscle of sedentary and exercised rats (SED and EX groups, respectively) were isolated and pressurized, and the changes in arteriolar diameter, as a function of perfusate flow (in the presence of a constant intravascular pressure), were assessed. The possible role of endothelial factors in the development and/or mediation of flow-induced dilation was assessed by the use of pharmacological agents affecting the synthesis of nitric oxide and/or prostaglandins.
Materials and Methods
Seven-week-old male Wistar rats (Charles River Laboratories, New York, NY) were randomly divided into SED and EX groups. Animals were exposed to a 12-hour light/dark cycle and received food and water ad libitum. Four to 5 days after arrival, they were adapted to the environment and were conditioned to walking and running on a treadmill (model 4215, Quinton Instrument Co) by a jet of air and a mild electrical stimulus to the tails of the rats that caused no injury. The exercise protocol was similar to that used in our previous study7 and was approved by the Animal Care Committee of New York Medical College. Exercise activity on the treadmill was carried out 5 days per week for an average of 3 weeks. The length of time on the treadmill was initially 5 minutes per day and was progressively increased to a maximum of 40 minutes per day by the end of the training period. The angle and the speed of the treadmill were increased from 0° grade and 11 m/min on day 1 to 2° and 28 m/min by the end of the training period. Similar activity on a treadmill was previously shown to elicit significant increases in blood flow to the thigh muscles of rats12 13 but was shown not to cause significant biochemical alterations (ie, cytochrome C or citrate synthase activity) in gracilis muscle.15 16 SED rats were also handled but were not made to run on the treadmill.
After the period of exercise training, arterioles from both groups of animals were studied. The rats were anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg). Second-generation arterioles of gracilis muscle were prepared for the experiments, as described previously.7 10 Briefly, the muscle was excised and then placed into a refrigerated dissecting dish containing a cold (0°C to 4°C) MOPS-buffered (pH 7.4) physiologic salt solution (PSS). The solution contained (mmol/L) NaCl 145, KCl 5, CaCl2 2, MgSO4 1, dextrose 5.0, pyruvate 2, EDTA 0.02, and MOPS 3.0. The muscle was splayed open as a flat sheet of tissue and pinned to the bottom of the silicone-lined base of the dissecting dish.
A segment (≈1 mm long) of a second-generation arteriole, branching off from the main arteriole supplying the muscle, was isolated from the gracilis muscle and surrounding tissue and cleared from the adhering tissue by microscissors. The arteriole was then transferred to the vessel chamber containing a Krebs’ bicarbonate-buffered PSS at room temperature. The proximal end of the arteriole was mounted to the inflow cannula, and the perfusion pressure was increased to 20 mm Hg with a pressure–servo syringe reservoir system (Living Systems, Inc), as described earlier.7 10 17 After the arteriole was cleared of clotted blood, its distal end was mounted to the outflow cannula.
The PSS, used to perfuse as well as to suffuse the arteriole in the vessel chamber, was a Krebs’ bicarbonate buffer solution equilibrated with 21% O2/5% CO2/74% nitrogen, with a pH of 7.4, at a temperature of 37°C. The solution contained (mmol/L) NaCl 110, KCl 5, CaCl2 2.5, MgSO4 1, KH2PO4 1, NaHCO3 24, dextrose 10, and EDTA 0.02. The suffusion system, reservoir, and the vessel chamber had a total volume of 100 mL. The PSS flow through the chamber was 40 mL/min. Initially, the vessel was perfused at 20 mm Hg pressure for several minutes to clear the arteriole and the cannula. The outflow cannula was then closed, and the intravascular pressure slowly increased to 80 mm Hg. The pressure-servo system was then placed in the manual mode, in which the stable pressure value indicated that there was no leak in the system. Then the pressure-servo system was set in the automatic mode, and pressure was maintained throughout the course of the experiment at 80 mm Hg.
As described previously,9 10 both inflow and outflow micropipettes were connected with silicone tubing to the pressure–servo syringe system. The system was arranged to have mirror symmetry; ie, both sides had equivalent resistances to flow.
In all protocols, only those vessels that developed spontaneous tone to pressure were used, since there was no vasoactive agent added to the PSS. Of the >50 vessels studied, only four did not develop spontaneous tone (two from the SED group and two from the EX group) and were for this reason discarded. After the equilibration period, flow-diameter relations were obtained in control conditions in arterioles of both SED and EX rats. Perfusate flow was increased from 0 to 12 μL/min in 2-μL/min steps. Flow was established at a constant intravascular pressure (80 mm Hg) by changing proximal and distal pressures to an equal degree, but in opposite directions, to keep midpoint lumenal pressure constant. The flow was measured by a ball flowmeter (Omega), which was calibrated by a Harvard perfusion pump in which flow rate was accurate in the range of 0 to 100 μL/min. Each flow step was maintained for ≈5 minutes to allow the vessels to reach steady state conditions before the diameter of the arterioles was measured. After obtaining the flow-diameter relation, flow was stopped; after ≈20 minutes, responses of arterioles to vasoactive agents were tested.
The vasoactive function of arteriolar smooth muscle and endothelium, before and after endothelial denudation, was assessed with the use of test concentrations of acetylcholine (10−8 mol/L) and sodium nitroprusside (10−7 mol/L), known to be endothelium-dependent and -independent dilator agents, respectively.18 19 As described previously in detail,19 perfusion of the arteriole with air results in complete removal of the endothelial cell layer. The vessel was untied from the primary pipette, and the endothelium was removed by injection of air into the lumen of the arteriole by using a 1-mL glass syringe. The arteriole was then reconnected to the primary pipette, filled with PSS, and cleared of debris by perfusing it for 10 minutes at 20 mm Hg. The outflow stopcock was then closed, and the pressure was raised to 80 mm Hg for ≈30 minutes, whereupon dilator responses to acetylcholine and sodium nitroprusside were retested.
The role of endothelium-derived relaxing factor/nitric oxide in flow-induced dilation was assessed by an analogue of l-arginine. After obtaining control flow-diameter curves, the vessels were subjected to Nω-nitro-l-arginine (L-NNA, 10−4 mol/L), an inhibitor of nitric oxide synthesis.20 21 22 Then, after an ≈15-minute period, changes in diameter in response to step increases in perfusate flow were reassessed. The efficacy and specificity of this inhibitor were assessed by arteriolar responses to acetylcholine (10−8 mol/L) and sodium nitroprusside (10−7 mol/L) before and after the vessels were exposed to L-NNA.
The role of prostaglandins in flow-induced arteriolar dilation was assessed by inhibition of cyclooxygenase. After control responses were obtained, to inhibit the synthesis of prostaglandins,9 18 indomethacin (INDO, 10−5 mol/L) was added to the suffusion solution. Thirty minutes later, flow-diameter relations were determined once more. To assess the efficacy and specificity of INDO, arteriolar responses to arachidonic acid (10−5 mol/L) and prostaglandin E2 (PGE2, 10−8 mol/L) were obtained before and after the vessels were exposed to the inhibitor. After obtaining responses in the presence of either L-NNA or INDO, the combined effect of the two inhibitors on the flow-diameter relation was determined. In approximately one half of the experiments, first L-NNA and then INDO was administered; in the rest of the experiments, the inhibitors were administered in reverse order.
Responses to vasoactive agents were tested at 80 mm Hg perfusion pressure and in no-flow conditions. All drugs were added to the reservoir connected to the vessel chamber, and final concentrations were reported. After the response to each drug subsided, the vessel chamber was flushed with PSS. To assess the active tone generated by the arterioles in response to intravascular pressure, at the conclusion of each experiment, the suffusion solution was changed to a Ca2+-free solution containing sodium nitroprusside (10−4 mol/L) and EGTA (1.0 mmol/L). The vessels were incubated for 10 minutes, and then the passive diameter of arterioles at 80 mm Hg perfusion pressure was obtained. In this condition, increases in perfusate flow did not affect the diameter of vessels. The internal diameters of vessels and peak responses, in various experimental conditions, were measured with an image-shearing monitor (model 907, IPM) and recorded on a chart recorder (Graphtec Multicorder MC6625 or Physiograph Six-B, Narco Biosystem Inc).
All salts and chemicals were obtained from J.T. Baker Chemical Co. Acetylcholine chloride and sodium nitroprusside were purchased from Sigma Chemical Co; INDO, arachidonic acid, and PGE2, from Nucheck; and L-NNA, from Aldrich Co. L-NNA was dissolved in PSS (pH 4 to 5) with sonication, and the pH was adjusted to 7.4. Vehicle solutions were tested and had no vasoactivity. The data are presented as mean±SEM. One or two vessels were studied from each animal. When two vessels were studied from one animal, their responses were averaged. In various experimental conditions, at each flow step, shear stress (τ) was calculated as follows: τ=4ηQ/πr3, where η is the viscosity of the perfusate (≈0.007 poise, at 37°C), Q is perfusate flow, and r is the vessel radius. Statistical significance was calculated by ANOVA for repeated measures, followed by the Tukey post hoc test, sigmoid curve–fitting analysis (slidewrite plus, Adanced Graphics Software, Inc), and paired and grouped Student’s t tests, as appropriate. The level of significance was taken at P<.05.
Spontaneous Arteriolar Tone
The active diameter of arterioles of SED and EX rats—obtained in the presence of constant intravascular pressure (80 mm Hg) and static flow conditions—was significantly different (55.2±2.1 and 49.3±2.0 μm, respectively; P<.05). After the conclusion of the experiments, in a Ca2+-free solution, the passive diameter of each arteriole was also obtained (see “Materials and Methods”). In these conditions, the mean passive diameters of SED and EX rats were not significantly different (105.3±3.1 and 111.2±2.4 μm, respectively). We also found that the active diameters, expressed as a percentage of the passive diameters, were significantly less in the EX arterioles (44.5%) compared with the SED arterioles (52.4%).
The arteriolar diameter, as a function of perfusate flow, was obtained in both SED and EX rats. Fig 1⇓ demonstrates that there was a significant difference between the diameters of SED and EX arterioles at the corresponding flow values, indicating that arterioles of EX rats have an augmented dilation to step increases in perfusate flow compared with arterioles of SED rats.
From these data, we calculated wall shear stress and plotted it against the changes in arteriolar diameter. Fig 2⇓ (upper panel) indicates that a given step increase in wall shear stress elicits a significantly greater increase in the diameters of EX arterioles compared with SED arterioles. This results in a significant leftward shift of the wall shear stress–diameter curve of EX arterioles. It is also apparent that the maintained shear stress values decreased from ≈25 to 35 to ≈15 to 20 dyne/cm2 in SED versus EX arterioles. In both groups, endothelium removal abolished the dilation to increases in flow (Fig 2⇓, lower panel). Hence, in this condition, calculated wall shear stress increased linearly, as a function of perfusate flow (Fig 2⇓, lower panel), as there were no increases in vessel diameter. The vessels lacking endothelial cells also did not respond to acetylcholine but still dilated to sodium nitroprusside, as in control conditions (Table⇓).
Next, we investigated the endothelial mechanism(s) responsible for the augmented flow-induced dilation of EX arterioles. The possible involvement of nitric oxide synthesis in the enhanced flow-induced response of EX arterioles was examined by the use of L-NNA, an inhibitor of nitric oxide synthase. As determined previously,7 we found that in control conditions, dilator responses of arterioles to acetylcholine were enhanced whereas those to sodium nitroprusside were not significantly different in EX compared with SED arterioles (Table⇑). In arterioles of both SED and EX rats, L-NNA elicited a significant suppression of the dilation to acetylcholine but not to sodium nitroprusside (Table⇑) and reduced the basal diameter of arterioles (by ≈19.5% and ≈13%, respectively). L-NNA significantly reduced flow-induced dilation in arterioles of both SED and EX rats (Fig 3⇓). In the presence of L-NNA, the flow-diameter curves were significantly different from control in both groups of arterioles (Fig 3⇓, upper and lower panels). This reduction in the response, in absolute numbers, was greater in EX than in SED arterioles. For example, at a flow of 12 μL/min, in the presence of L-NNA, the reduction in the dilator response of EX arterioles was 14.4 μm, whereas it was only 8.6 μm in SED arterioles. Percent reductions of the flow responses to L-NNA, however, were about the same in SED and EX arterioles (≈41% and ≈42%, respectively).
Next, we investigated the possible role of prostaglandins in the enhanced flow-induced dilation of EX vessels. We found that dilator responses of arterioles to arachidonic acid and PGE2 were not significantly different in vessels of EX compared with SED rats (Table⇑). The efficacy and specificity of the inhibition of cyclooxygenase by INDO is indicated by the elimination of the dilation to arachidonic acid in arterioles of both groups of rats, whereas the dilation to PGE2 was not affected (Table⇑). INDO reduced the basal diameter of arterioles of both SED and EX rats (11.7% and 8.8%, respectively) and also significantly reduced the dilation to increases in perfusate flow in arterioles of both groups (Fig 3⇑, upper and lower panels). In both EX and SED arterioles, the flow-diameter curves were significantly different in the presence of INDO compared with curves obtained in the control condition. Again, in absolute numbers but not in percentages, the effect of INDO was greater in EX than in SED arterioles.
In the presence of L-NNA, further administration of INDO (or further administration of L-NNA in the presence of INDO) elicited an additional significant reduction of flow-induced responses in both SED and EX vessels and practically eliminated the dilation to increases in perfusate flow (Fig 3⇑, upper and lower panels).
Calculated Wall Shear Stress Versus Diameter
Plotting calculated wall shear stress against change in vessel diameter indicated that use of a sole inhibitor (L-NNA or INDO) elicited an approximately similar rightward shift in the shear stress–diameter curve in both SED and EX groups; thus, shear stress was maintained at a higher range. Using inhibitors of nitric oxide synthase and cyclooxygenase simultaneously resulted in a further significant downward shift in the shear stress–diameter curve of both SED and EX arterioles (Fig 4⇓, upper and lower panels), indicating that there were practically no increases in diameter in response to increases in shear stress. Also, the effect of the inhibitors was independent of the sequence of their administration.
The salient finding of the present study is that short-term daily exercise activity augments the flow-dependent dilation of skeletal muscle arterioles of rats. This adaptation seems to be due to the increased sensitivity of arteriolar endothelium to wall shear stress, eliciting an augmented release of both nitric oxide and prostaglandins, which results in enhanced arteriolar dilation.
Recent studies indicate that in response to exercise training, an alteration in the function of vascular endothelial and smooth muscle cells occurs.3 4 5 6 Most of these studies investigated the effects of exercise training on the vasoactive function of large vessels. For example, studies involving ring preparations of rat aorta5 and coronary arteries6 of exercised animals demonstrated that responses to endothelium-dependent dilator agents were enhanced, whereas in most cases responses to endothelium-independent dilator agents remained unaltered. However, studies of the changes in the vasoactive function of arterioles (vessels that are intimately involved in the regulation of peripheral vascular tone in exercise) are few. Our recent findings suggest a possible role for the endothelium of skeletal muscle microvessels in the adaptation to exercise training that might be linked to changes in the synthesis of nitric oxide.7
In vivo and in vitro studies of microvessels have provided evidence that the endothelium can contribute to circulatory homeostasis by a shear stress–dependent regulation of skeletal muscle vascular resistance, which can be stimulated by increases in either blood flow or viscosity.8 9 10 To assess the importance of the shear stress–dependent mechanism in the adaptation to exercise and its possible participation in the regulation of peripheral resistance, we examined whether the magnitude and/or mediation of flow-induced dilation is different in isolated arterioles from EX versus SED rats.
Arterioles of rat gracilis muscle were chosen for the present study because the microcirculation of skeletal muscle is responsible for a sizable fraction of peripheral resistance. Also, we have used arterioles in which we have shown previously that endothelial changes do occur in response to exercise training.7 We have used relatively mild and short-term daily exercise activity16 23 because we were particularly interested in the early functional changes of arterioles in response to intermittent increases in blood flow, before the appearance of resting bradycardia, structural changes in the arteriolar wall, and metabolic alteration in skeletal muscle. To avoid the interference of local mechanisms that also participate in the regulation of arteriolar diameter, the changes in diameter to increases in flow were investigated in isolated arterioles in the presence of constant intravascular pressure.10 24 We found that the active, but not the passive, diameters of arterioles of EX rats were significantly reduced compared with those of SED rats. This is in agreement with our previous findings,7 which show that there is a significantly greater pressure-induced endothelium-independent myogenic tone in arterioles of EX compared with SED rats,24 and the findings of a recent whole-animal study by Lash et al,25 who showed a greater increase in hind-limb resistance in response to carotid occlusions in EX compared with SED rats.
Augmentation of Flow-Induced Dilation in Response to Exercise
In response to increases in perfusate flow, arterioles of EX rats exhibited a significantly enhanced dilation compared with those of SED rats at corresponding flow rates. This enhancement is dependent on factors produced in the endothelium, because removal of the endothelium eliminated flow-dependent dilation in arterioles of both groups. Previous studies demonstrated that the primary stimulus for dilation during increases in flow is the increase in wall shear stress.8 9 10 Indeed, we found that shear stress–induced increases in arteriolar diameters were augmented in EX compared with SED rats (Fig 2⇑). Fig 2⇑ also demonstrates that the increased sensitivity to shear stress lowers the set point of the negative-feedback regulation of shear stress, shifting the “maintained” level of shear stress from 25 to 35 dyne/cm2 in SED arterioles to 15 to 20 dyne/cm2 in EX arterioles. After removal of the endothelium, arterioles do not regulate shear stress (because of the absence of vasodilation); therefore, shear stress increases greatly, as a function of perfusate flow, in both groups of arterioles (Fig 2⇑).
Augmentation of Nitric Oxide–Mediated and Prostaglandin-Mediated Flow-Dependent Dilation
In arterioles of both SED and EX rats, inhibition of either nitric oxide or prostaglandin synthesis alone significantly reduced the dilation to increases in flow. The proportional participation of these factors was ≈41% and 46% in SED arterioles and 42% and 40% in EX arterioles, respectively, accounting nearly completely for the mediation of the response. Combined administration of these two inhibitors nearly eliminated flow-induced dilation of both SED and EX arterioles. These findings confirmed our previous results showing that in arterioles of rat gracilis muscle both nitric oxide and prostaglandins are involved in the mediation of dilation following increases in perfusate flow10 26 and suggest that the enhanced flow-dependent dilation is due to the increased release of both nitric oxide and prostaglandins from the arteriolar endothelium.
Because responses to sodium nitroprusside and PGE2 were similar in arterioles of SED and EX rats (Table⇑), an altered responsiveness of arteriolar smooth muscle to nitric oxide and prostaglandins is unlikely to be the cause for the enhanced flow-induced dilation. Rather, this seems to be due to an alteration of the function of arteriolar endothelium, as suggested by our previous studies. We found a significant augmentation in dilation of EX arterioles to acetylcholine and l-arginine,7 responses known to be mediated by endothelium-derived nitric oxide,20 21 22 indicating that both agonist- and flow-induced nitric oxide synthesis is augmented in arteriolar endothelium as a result of daily exercise. The finding that dilations to arachidonic acid were not affected in EX arterioles (Table⇑) may be explained by the fact that dilation to this agent is seldom dose dependent and/or that shear stress–induced mobilization of arachidonic acid uses intracellular dilator pathways that differ from those of exogenously administered arachidonic acid.
Although the present study does not provide direct evidence, we assume that the reason for the observed changes is due to the prevailing hemodynamic conditions, primarily to the periodically increased flow (shear stress) to which these arterioles are exposed during treadmill exercise. Whatever the reason, it seems that exercise upregulates both endothelial nitric oxide and prostaglandin synthesis. One can speculate that either the sensitivity of the rheo (flow) receptors is enhanced or that there is a shared pathway (from the rheoreceptors to the endothelial enzymes that synthesize these mediators) that is upregulated after exercise training. In this context, an enhanced nitric oxide–mediated dilation to bradykinin in coronary resistance arteries of exercise-trained pigs has also been reported recently.27 Previous studies also indicate that the cellular signal transduction pathways for the initiation of the synthesis of nitric oxide and prostaglandins may be related28 and that the release of nitric oxide and prostaglandins or the inhibition of their synthesis, in many cases, may be coupled.10 29 30 It was recently demonstrated that increases in flow can enhance Ca2+ influx31 in endothelial cells, which is necessary for both prostaglandin and nitric oxide synthesis.32
Enhanced Flow-Induced Dilation and Autoregulation
Changes in the structure of the peripheral vasculature are believed to be a major factor in the adaptation to exercise training.1 2 Indeed, previous investigation of the microcirculation of exercised animals revealed significant morphological changes in the vascular wall as well as changes in the structure of arteriolar networks16 23 after longer exercise programs.16 In the present study, there were no differences in the passive diameters of arterioles of SED and EX rats, findings that lend support to the hypothesis that even preceding the structural changes in the arteriolar wall, there is an early change in the vasoactive function of arteriolar endothelium that may be the first important step in the adaptive process to exercise training. The slightly augmented pressure-induced arteriolar tone after exercise training, initiated most likely by the variation of hemodynamic forces during exercise, may serve to counterbalance the enhanced flow-dependent dilation. The augmentation of flow-dependent dilation after exercise training indicates an enhanced dilator capacity, promoting a decrease in skeletal muscle arteriolar resistance at the onset and during exercise. It allows for rapid increases in blood flow to exercising skeletal muscle, without the expense of great elevations of systemic blood pressure and shear stress, thereby minimizing energy dissipation in the circulation. On the basis of present and previous3 4 5 6 7 8 9 findings, shear stress–elicited release of endothelial factors should be considered to contribute to exercise hyperemia, since the current theory of myogenic and metabolic regulation of blood flow cannot satisfactorily explain the development of exercise hyperemia.33
In conclusion, the present study is the first to demonstrate an enhanced flow (shear stress)–induced dilation in skeletal muscle arterioles of exercised rats; this enhancement is mainly due to an upregulation of endothelial nitric oxide and prostaglandin synthesis. Thus, the present findings suggest an important role for the enhanced sensitivity to shear stress of endothelium of skeletal muscle arterioles during the adaptation of the peripheral circulation in response to periodic exercise. These findings advance the concept that the vasoactive function of endothelium is in a dynamic equilibrium with the local hemodynamic environment and responds to it by eliciting changes in vessel diameter, with a resultant change in blood flow in accordance with the prevailing physiological conditions.
This study was supported by grants from the National Institutes of Health (HL-46813 and P01 HL-43023). We thank Peter Bednarik for assisting in the statistical analysis of the data. We also wish to acknowledge the excellent secretarial assistance of Johanna Di Mento and Annette Ecke.
- Received June 20, 1994.
- Accepted December 13, 1994.
- © 1995 American Heart Association, Inc.
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