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ABSTRACT |
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 TopAbstract IntroductionMethodsResultsDiscussionReferences |
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1. The effects of changes in the mean and amplitude of arterial wall shear stress on endothelium-dependent arterial dilatation of the iliac artery of the anaesthetized dog were examined.
2. Changes in the mean and amplitude of blood flow and wall shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and the stimulation of the left ansa subclavia. Changes in the diameter of a segment of the iliac artery with the endothelium intact, relative to a segment with no endothelium, were used as an index of the release of nitric oxide.
3. The increase in mean blood flow was from 84 ± 12 to 527 ± 53 ml min-1 and in amplitude was from 365 ± 18 to 695 ± 38 ml min-1 (means ± S.E.M.). The increase in mean wall shear stress was from 1.78 ± 0.30 to 7.66 ± 1.01 N m-2 and in amplitude was from 7.37 ± 0.46 to 13.9 ± 2.00 N m-2 (means ± S.E.M.).
4. Increases in mean shear stress caused an increase in the diameter only of the section of artery with endothelium; the slope of the relationship was 0.064 ± 0.006 mm N-1 m2 (mean ± S.E.M., P < 0.001); changes in the amplitude of shear stress did not cause an increase in diameter. Changes in both the mean and amplitude of shear stress had no significant effect on the diameter of the section of artery with no endothelium.
5. These findings coupled with the known anti-atheroma effects of nitric oxide and the effect of shear stress on cell adhesion and platelet aggregation offer a possible explanation for the disposition of atheroma in those parts of the arterial system which have low mean and high amplitude of wall shear stress.
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INTRODUCTION |
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In man the distribution of atherfoma in the arterial system is uneven and those parts of the system which have a relatively low mean and high amplitude of wall shear stress are predisposed to the formation of atheroma (Caro et al. 1978; Cornhill & Hederick 1993; Moore et al. 1994). Since nitric oxide (NO) has effects which tend to prevent atheroma, by reducing arterial wall shear stress, platelet aggregation and cell adhesion (Adams et al. 1997), its mode of production by either mean or amplitude of shear stress could explain this uneven distribution of atheroma.
We have previously shown that there is a quantitative relationship between increases in wall shear stress and diameter in the iliac artery of the dog, which is mediated by NO released from the endothelium (Snow et al. 1994). From these experiments it was not possible to decide which characteristics of shear stress, mean and amplitude, stimulate the release of NO, though increases in steady as opposed to transient flow had a greater effect on arterial diameter. In this series of experiments we have examined the effects of changes in mean and amplitude of wall shear stress on endothelium-mediated arterial dilatation in the iliac artery of the anaesthetized dog as an index of the release of NO. The methods and some of the results have been demonstrated to The Physiological Society (Snow & Pollock, 1995).
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METHODS |
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General methods
This investigation was carried out under licences issued by the Department of Health Ireland as directed by the Cruelty Animals Act Ireland and EU Statutory Instructions. Experiments were carried out in 10 dogs weighing 17.5 kg (mean; range 14.8-20.0 kg). The dogs were sedated with morphine sulphate (10 mg I.M.) and 30 min later were anaesthetized with pentobarbitone (induction 30 mg kg-1 I.V.; maintenance 3 mg kg-1 I.V. every 30 min) through a cannula inserted into the long saphenous vein under local anaesthesia. At the end of the experimental procedures animals were killed using a lethal intravenous injection of pentobarbitone.
Ventilation was delivered via a tracheotomy with a mixture of 40 % oxygen in room air supplied by a Starling Ideal pump. Samples of arterial blood were withdrawn at regular intervals throughout each experiment and the pH, PCO2 and PO2 measured using an IL pH/blood gas analyser (IL, Milan, Italy). End tidal PCO2 was measured using an infrared CO2 analyser (P. K. Morgan Ltd, Gillingham, Kent, UK). The arterial PCO2 was kept within the limits of 34-42 mmHg and the arterial pH between 7.33 and 7.43 either by adjustment of the ventilation or by intravenous injection of 1.0 M NaHCO3. Rectal temperature was recorded and maintained at 37 ± 1 °C by heating lamps and a thermostatically controlled blanket.
The ECG lead II was recorded and used to drive a cardiotachometer. Systemic arterial pressure was recorded through a short nylon cannula inserted into the abdominal aorta via the right femoral artery using a strain gauge pressure manometer (Grass, Quincy, MA, USA) attached to a carrier amplifier (A6WP AstroMed). Blood flow was measured using an ultrasound flowmeter (Transonic Inc., Ithaca, NY, USA). The outside diameter of the iliac artery was measured using disc-shaped piezoelectric crystals (VD5-2NP) attached to a Sonomicrometer 120.0 (Triton Technology Inc., San Diego, CA, USA). This apparatus is capable of measuring distances within the range 2-20 mm with a resolution of ± 0.005 mm (Angus et al. 1983). The ECG, heart rate, arterial pressure, blood flow and diameter measurements were recorded using a thermal array recorder (K2G, AstroMed, Slough, UK).
Surgical procedures
A diagram of the preparation is shown in Fig. 1. The aorta and external iliac arteries were exposed through a retroperitoneal left flank incision. The right iliac artery was tied off around the cannula used for measurement of pressure. An arterial embolectomy catheter (Fogarty No.3, Baxter, Santa Anna, CA, USA) was inserted a distance of 1 cm into the distal portion of the left iliac artery via the deep femoral artery. The balloon of the catheter was distended with saline until it caused about 10 % increase in the diameter of the artery and then moved backwards and forwards over a distance of 1 cm to remove the endothelium. There is histological evidence (Lamping et al. 1985) that this technique removes the endothelium without damaging the underlying smooth muscle, since the muscle still responds to the application of catecholamines and sodium nitroprusside (Snow et al. 1994). The catheter was then replaced by a polythene cannula whose tip lay within the deep femoral artery. Two pairs of piezoelectric crystals were then placed on diametrically opposite sides of the iliac artery, one pair on the section with endothelium removed (D2) and a second pair 4-5 cm upstream on a section of artery with endothelium intact (D1). An ultrasonic blood flow transducer was placed around the artery between D1 and D2. The chest was opened in the 3rd intercostal space, the left stellate ganglion crushed and stimulating electrodes placed around the two branches of the ansa subclavia. The nerves were stimulated supramaximally at frequencies in the range 1-10 Hz using a Grass S88 stimulator.
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Ao, aorta; A, caudal mesenteric artery; B, deep femoral artery; P, cannula inserted through right femoral artery for measurement of pressure; F, ultrasound flow probe. Pairs of piezoelectric crystals were used for measurement of iliac artery diameter at D1 with endothelium intact and at D2 with endothelium removed.
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Experimental protocol
Changes in the mean and amplitude of blood flow in the iliac artery were brought about by varying both the peripheral resistance in the vascular bed fed by the left iliac artery and the stroke volume of the heart. Changes in peripheral resistance were produced by infusing acetylcholine downstream to the sites of diameter measurement in the iliac artery, through the cannula inserted into the deep femoral artery (dose 1-20 
g min-1), a range of infusion rates at which acetylcholine does not recirculate and cause release of NO in the iliac artery (Snow et al. 1994). Changes in stroke volume were brought about by stimulation of the left ansa subclavia and subsequent inotropic effect on the left ventricle with little or no change in heart rate (Furnival et al. 1972).
Calculation of wall shear stress
The mean (Sm) and amplitude (Sa) components of wall shear stress (N m-2) were calculated from internal diameter (D), the mean (Vm) and overall amplitude (Va) of blood velocity, averaged across the artery, the fundamental frequency of oscillation (heart rate) and blood viscosity (, assumed to be 4 mN s m-2). Internal diameter (D) was calculated from the distance between the piezoelectric crystals (corrected for lens effect to obtain external diameter) and the wall thickness of the iliac artery, measured at postmortem using a micrometer gauge. To obtain changes in diameter which are only endothelium dependent, changes in the diameter in the section of artery without endothelium were subtracted from the changes in diameter of artery with endothelium. The velocities (Vm and Va) were calculated from the recorded volume flow waveforms by dividing by the internal cross-sectional area of the artery.
Mean shear stress (Sm) is given by:
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Sm = 8Vm D-1.
| (1) |
Precise calculation of the amplitude component of shear stress (Sa) requires a Fourier analysis of the velocity waveform, calculation of the amplitude component of shear stress for each harmonic and reconstitution of the shear stress waveform (McDonald, 1974; Pedley, 1980). For each harmonic Sa may be calculated from the amplitude of the velocity harmonic (Va) and the frequency:
Sa = Va D-1F ,
| (2) |
where F is a function of the dimensionless constant = D/2(f/
)1/2 (Womersley, 1955), where f is frequency and is the kinematic viscosity. F is evaluated from:
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F= [2J1(i 3/2 )]/[i 3/2 Jo(i 3/2)],
| (2a) |
where Jo and J1 are Bessel functions (Pedley, 1980). In these experiments F was evaluated using the fundamental frequency, a method which underestimates the true value of Sa by 10-20 %.
Statistical analysis
Multiple linear regression analysis was carried out using the SPSS statistical package (version 8, SPSS Inc., Chicago, IL, USA).
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RESULTS |
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When recording began about 2 h after the induction of anaesthesia the heart rate (HR) was 149.5 ± 21.3 beats min-1 (mean ± S.D.), and the mean arterial blood pressure was 114.9 ± 11.8 mmHg (mean ± S.D.). The average mean blood flow in the left iliac artery was 84 ml min-1 (range 55-160 ml min-1) and the amplitude of blood flow was 364 ml min-1 (range 275-440 ml min-1). The mean internal diameter (D1) of the section of artery from which the endothelium had been removed was 3.54 ± 0.62 mm (mean ± S.D.) and of the section of artery with intact endothelium (D2) was 3.19 ± 0.39 mm (mean ± S.D.), this difference in diameter was significant (P < 0.05, Student's paired t test).
Increases in both the mean and amplitude of blood flow in the iliac artery were brought about by peripheral vasodilatation and inotropic stimulation of the heart. An example of records obtained in one dog is shown in Fig. 2A. Blood flow was increased by a combination of a downstream infusion (10 g min-1) of acetylcholine (thus avoiding a direct action of acetylcholine on the endothelium of the iliac artery) and stimulation of the cardiac sympathetic nerves (left ansa subclavia, supramaximal at 5 Hz). Both the mean and amplitude of blood flow were increased, from 50 to 515 ml min-1 and from 343 to 543 ml min-1, respectively; these changes in blood flow were accompanied by small and transient changes in mean arterial blood pressure. About 5 s after the start of the infusion of acetylcholine, peripheral vasodilatation took place, blood pressure fell and both sections of artery decreased in diameter; blood flow increased and was further increased by sympathetic nerve stimulation, which also caused arterial mean pressure to return to control levels. The external diameter of the section of artery with no endothelium (D2) followed without delay the changes in blood pressure. The section of artery with intact endothelium initially followed blood pressure, and only began to dilate about 25 s after the increase in blood flow, continuing to dilate for up to 1 min after the blood flow had been maintained at a steady flow. On this occasion an increase in diameter from 5.17 to 5.56 mm occurred. Figure 2B shows records obtained in the same dog in which the amplitude of blood flow was increased (stimulation of cardiac sympathetic nerves alone), from 268 to 446 ml min-1, with only a small increase in mean flow, from 83 to 89 ml min-1. As might be expected, mean blood pressure increased by 10 mmHg and the diameters of both sections of artery increased in parallel along with blood pressure; the diameter of the section with intact endothelium showed no indication of an additional flow-induced increase in diameter despite the increase in the amplitude of flow.
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ILBF, iliac artery blood flow; BP, blood pressure. A, both mean and amplitude of blood flow were increased by an infusion of acetylcholine (10
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Between eight and ten combinations of local peripheral vasodilatation and cardiac stimulation were carried out in each dog. When cardiac stimulation and local peripheral vasodilatation were combined there were no significant changes in mean arterial blood pressure and heart rate. When cardiac stimulation alone was used, increases in mean blood pressure of 5-10 mmHg occurred without significant changes in heart rate. An example of results obtained in one dog are shown in Fig. 3, where the diameter of the section of artery with intact endothelium (D1) is plotted against both mean and amplitude of shear stress. The diameter of the artery was significantly correlated with mean shear stress (Fig. 3A) but not with amplitude of shear stress (Fig. 3B).
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There is a significant correlation of D1 with Sm (r = 0.95, P < 0.001) but not with Sa.
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Similar results were obtained in all 10 dogs and are shown in Fig. 4A and B where the changes in diameter D1 (corrected for changes in diameter D2) are plotted against mean (Sm) and amplitude (Sa) of shear stress, respectively. The average increase in mean blood flow was about sixfold, from 84 ± 12 to 527 ± 53 ml min-1, and in amplitude of flow about twofold, from 365 ± 18 to 695 ± 38 ml min-1 (means
| D1 = 0.064 (± 0.006)Sm - 0.019 (± 0.008)Sa + 0.068 (± 0.020). | (3) |
The correlation coefficient for D1 on Sm was 0.8 (P < 0.001). The weak (r = -0.47) negative correlation of D1 on Sa was also significant (P < 0.01), but is not thought to be of any physiological significance and is probably related to the calculation of Sa which uses D -2. There was no correlation between Sm and Sa. It may be concluded that only increases in the mean steady-state component of wall shear stress cause arterial dilatation.
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Sm shows a significant positive correlation with the change in diameter (r = 0.8, P < 0.001), whereas Sa shows a negative correlation with the change in diameter (r = -0.47, P < 0.01).
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DISCUSSION |
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Previous results, using methods identical to those described above, have shown that increases in blood flow in the iliac artery of the dog cause an increase in arterial diameter which is completely abolished by the inhibition of nitric oxide synthase and was therefore concluded to be dependent upon the ability of the endothelium to produce NO (Snow et al. 1994). In those experiments we made no attempt to differentiate between the effects of increases in either the mean or the amplitude of oscillatory blood flow as a stimulus to the endothelium. The present experiments were designed to produce changes in the mean and amplitude of oscillatory blood flow in the iliac artery of the dog within the ranges that would be expected to occur on going from rest to exercise. At rest in large conduit arteries mean blood flow is only about one-tenth of the amplitude and in some of the larger conduit arteries such as the abdominal aorta, iliac and femoral arteries there is a significant reversal of blood flow during diastole (e.g. Fig. 2). Therefore the oscillatory forces on the endothelium are much greater than the mean. In contrast during exercise and as imitated in these experiments, mean flow increases by 10-20 times and the amplitude by only about twice and the shear forces on the endothelium are increased accordingly. Thus at rest when the mean shear stress is low there is a correspondingly low stimulus to the production of NO, which may account for the unexpected finding that removal of the endothelium caused an increase in the diameter of the iliac artery implying that the endothelium at rest is under tonic vasoconstriction, e.g. by endothelin.
Calculation of the amplitude component of wall shear stress (Sa) from the amplitude of the velocity waveform, using the fundamental frequency (HR) to calculate , neglects higher frequency components of velocity and underestimates the true value by a variable amount (~10-20 %) which tends to diminish as heart rate increases. This underestimation does not detract from the conclusion that changes in the amplitude of shear stress do not stimulate the endothelium to produce NO as indicated by a lack of dilatation. Further the time course of the response to changes in mean flow and hence Sm is slow (95 % in about 60 s, Fig. 2); this does not rule out an integrated response to a series of oscillations, but make it unlikely that the endothelial cell is responding to transient increases in shear stress on a beat by beat basis. The possible negative effect of an increase in the oscillatory component is doubtful. However, in cultured endothelial cells, induction of constitutive nitric oxide synthase has been shown to be up-regulated by steady-state shear stresses and down-regulated by oscillatory shear stresses (Ziegler et al. 1998).
It has been known for some time (Caro et al. 1978; Glagov et al. 1988) that areas of the arterial system with a low mean wall shear stress are predisposed to the development of atheroma, the 'low mean shear stress hypothesis'; these same areas have a high oscillatory shear stress which led Fry to hypothesize that high shear stresses could damage the endothelium (Fry, 1969). However, the peak shear stresses needed to damage the endothelium are much higher than those normally found in the arterial system, even at the high blood flows seen on exercise (Caro et al. 1978). A more probable explanation of the deleterious effects of high shear rates is the finding that oscillatory shear stress stimulates mononuclear leukocyte adhesion to cultured human endothelial cells (Chappell et al. 1998) and that platelets can be caused to aggregate by exposure to transient high stresses as occurs in the Folts model of coronary arterial thrombosis (Folts, 1976). Also Moore et al. (1994) have shown a significant correlation between an index of oscillatory shear stress (which is effectively a ratio between Sa and Sm) and early atherosclerotic disease in man, suggesting that it is the combination of low mean and high amplitude which predisposes to atheroma.
NO probably prevents the formation of atheroma by activating guanyl cyclase and the production of cGMP, which by relaxing arterial smooth muscle reduces shear stress (Snow et al. 1994) and thereby the stimulus to cell adhesion and platelet aggregation, and also directly inhibits cell adhesion and platelet aggregation (Adams et al. 1997). Furthermore the production of NO is reduced in human atherosclerosis (Oemar et al. 1998). In conclusion our results show that a stimulus for the production of NO by the endothelium is the mean wall shear stress and not the amplitude of shear stress, which along with the anti-atheroma activity of NO provides a possible explanation for the localization of atheroma in those areas of the arterial system subjected to low mean and high amplitude shear stresses.
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REFERENCES |
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| ADAMS M. R., MCCREDIE, R., JESSUP, W., ROBISON, J., SULLIVAN, D. & CELERMAJER, D. S. (1997). Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis 129, 261-269 | [Medline] |
| ANGUS J. A., CAMPBELL, G. R., COCKS, T. M. & MNDERSON, J. A. (1983). Vasodilatation by acetylcholine is endothelium-dependent: a study by sonomicrometry in canine femoral artery in vivo. Journal of Physiology 344, 209-222 | [Abstract] |
| CARO C. G., PEDLEY, T. J., SCHROTER, R. C. & SEED, W. A. (1978). The Mechanics of the Circulation. Oxford University Press, Oxford | |
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| CORNHILL J. F., HEDERICK, E. E. & (PDAY) RESEARCH GROUP (1993). Effects of risk factors on the localization of human atherosclerosis. American Journal of Cardiology Continuing Education Series, part 1, Devlopment of Atherosclerosis. Cahners Publishing Co., New York | |
| FOLTS J. D., CROWELL, E. B. & ROWE, G. C. (1976). Platelet aggregation in a partially obstructed vessel and its elimination with aspirin. Circulation 54, 659-661 | |
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| PEDLEY T. J. (1980). The Fluid Mechanics of Large Blood Vessels. Cambridge University Press. | |
| SNOW H. M., MCAULIFFE, S. J. G., MOORS, J. A. & BROWNLIE, R. (1994). The relationship between blood flow and diameter in the iliac artery of the anaesthetized dog: the role of endothelium-derived relaxing factor and shear stress. Experimental Physiology 79, 635-645 | [Medline] |
| SNOW H. M. & POLLOCK, K. (1995). Mechanical components of the stimulus releasing nitric oxide (NO) from the endothelium of the anaesthetized dog. Journal of Physiology 489.P, 2P | |
| WOMERSLEY J. R. (1955). Method for the calculation of velocity, rate of flow and viscous drag in arteries when the pressure gradient is known. Journal of Physiology 127, 553-563 | |
| ZIEGLER T., BOUZORENE, K., HARRISON, V., BRUNNER, H. R. & HAYOZ, D. (1998). Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arteriosclerosis Thrombosis and Vascular Biology 18, 686-692 | [Abstract/Full Text] |
Corresponding author
H. M. Snow: Department of Physiology, University College Cork, Cork, Ireland.
Email: msnow{at}iol.ie
Author's present address
D. O'Regan: Wellcome Trust Clinical Research Facility, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
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