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Ann Thorac Surg 2004;77:108-114
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Effect of moderate pressure distention on the human saphenous vein vasomotor function

Elena B. Okon, PhDa*, Michael J. Millar, BSa, Christine M. Crowley, PhDa, Jamil G. Bashir, MDb, Richard C. Cook, MDb, York N. Hsiang, MDb, Bruce McManus, MD, PhDa, Cornelis van Breemen, PhDa

a The iCAPTURE Centre, Department of Pathology and Laboratory Medicine, University of British Columbia and St. Paul Hospital, Vancouver, British Columbia, Canada
b Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada

Accepted for publication June 5, 2003.

* Address reprint requests to Dr Okon, iCAPTURE Centre, Rm 292, St. Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada
e-mail: eokon{at}mrl.ubc.ca


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Manual pressure distension, which is commonly applied to the human saphenous vein graft for coronary artery bypass, is believed to have detrimental consequences for the graft patency. The vasomotor function of the vein after distention during surgical preparation for grafting and after distention in laboratory conditions at pressure of 50 to 600 mm Hg was studied. The effect of a combination of vasodilative agents to prevent vasospasm was also tested.

METHODS: The contractile and dilatory responses of distended and undistended human saphenous veins and those after drug treatment were examined in organ baths under isometric conditions.

RESULTS: Distention at the pressure range 100 to 300 mm Hg resulted in an increased contractile response of the saphenous vein to both {alpha}-adrenergic activation with 50 µmol/L phenylephrine (153.73% ± 15.69%) and depolarization with 80 mmol/L K+ (141.03% ± 15.13%) in comparison with the undistended vein and did not impair the relaxation. In contrast manual distention during surgical preparation abolished the contractile response and impaired the relaxation. The application of a combination of vasodilative drugs ({alpha}-adrenergic antagonist phenoxybenzamine, 10 µmol/L, Rho-kinase inhibitor HA-1077, 50 µmol/L, and calcium blocker nicardipine, 1 µmol/L) eliminated the contractile response of the vein to phenylephrine and 80 mmol/L K+. This effect was sustained more than 20 hours after the washout of the drugs.

CONCLUSIONS: The distention of the human saphenous vein at moderate pressure combined with the application of the effective combination of vasodilative drugs before grafting into the arterial circulation could be a beneficial alternative to the current practice of uncontrolled pressure distension.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Manual distention with uncontrolled pressure is a routine part of surgical preparation of the human saphenous vein (HSV) for grafting [1, 2] with the objectives to check for leaks and to prevent vasospasm induced by trauma and hypoxia during the surgery and postsurgery stages [3]. It has been shown however that uncontrolled pressure distention damages the vasomotor function of HSV [4], decreases nitric oxide release [2, 5], induces thrombosis [6], and provokes mitogenic activity resulting in neointimal hyperplasia and wall thickening [7]. The high rate of failure of the HSV graft due to occlusion has been documented [3, 8, 9]. It has thus been suggested that the uncontrolled pressure distention decreased the long-term patency of the HSV graft [1, 2], which otherwise provides a convenient conduit for revascularization.

The effect of moderate pressure distention on vasomotor function is less studied and data are controversial. The impairment of contractile responsiveness and endothelium-dependent relaxation has been shown in HSV [10, 11] although increased norepinephrine reactivity [12] has also been observed.

Distension with the patient's own arterial pressure preserved biochemical characteristics and medial and endothelial function of venous graft [13]. A short-term application of pulsatile arterial pressure 120/80 mm Hg to HSV augmented the ensuing contractile responses to stimuli [14, 15], increased NO production [16], and improved the endothelium-dependent dilation [15]. Higher pulsatile pressure decreased the NO production [17].

The beneficial effect of vasodilative drugs on the vasospasm prevention [18, 19], endothelium preservation, and arteriosclerosis progression [20, 21] in humans and the graft patency [22] has been reported. A combination of drugs has been shown to be more effective than a drug targeting only one mechanism of contraction. Recent studies demonstrated that inhibition of the Rho-dependent Ca2+ sensitization effectively prevented vasospasm in human conduits [4, 23]. Hence a combination of drugs including Rho-kinase inhibitor could permit the avoidance of pressure distention as a method to overcome vasospasm.

In the present article we investigate the effect of pressure distention on HSV vasomotor function and provide evidence suggesting that distension of HSV with moderate pressure and topical application of an effective drug combination before grafting the vein in the arterial bed could be an alternative to harmful high-pressure distention.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Sample preparation and equilibration
Intact and distended segments of human saphenous veins were collected from 78 patients (aged 41 to 78 years) at Saint Paul's Hospital (Vancouver, Canada) undergoing coronary artery bypass grafting with the approval of the Institutional Research Ethics Board. The vein was harvested through a single incision, isolated from surrounding tissues, and placed in Plasma-Lyte (Baxter Healthcare Corp, Deerfield, IL). Segments were cut from veins of randomly selected patients and used as control "undistended" veins or for distention in the laboratory conditions. The vein was cannulated and distended with pressure about 1 atm by injection of Plasma-Lyte. The segments cut after this procedure were termed "distended with uncontrolled pressure."

All segments were collected in vials with cold RPMI medium 1640 (Sigma), transported to the laboratory within 15 minutes after collecting, placed into a refrigerator at 4°C, and used in experiments on the same day or on the next day if obtained in the afternoon. From the intact segment assigned for the distention under laboratory conditions a 4-mm ring was cut from the middle or distal part to be used as a control in isometric studies. The ends of the segments of the vein were then cannulated and attached through a three-way tap to a manometer for continual measurement of applied pressure. Using a syringe attached to the third port the vein was first gently washed of blood and filled with physiologic buffer solution (PBS). The distal end of the vein was then clamped and the specimen was distended with PBS at 23°C for 2 minutes by application of the designated pressure in the range of 50 to 600 mm Hg. On release of the pressure a 4-mm section of the vein was dissected from the distended part of the vein for isometric study. The diameter of the vein was measured before and during the distention. The ratio of the diameter under the distention to the diameter before the distention was calculated and named "circumferential enlargement."

For the studying of isometric tension 4-mm vein segments were suspended between two stainless steel clips, placed for 2 hours in glass jacketed tissue baths containing 10 mL oxygenated PBS solution (pH 7.6) at 37°C, and equilibrated during 45 minutes to 2 g resting tension. The vessels were challenged thereafter twice with 80 mmol/L K+ buffer obtained from PBS by replacement of NaCl by KCl. In some experiments with the intact vein the resting tension was set at the higher level for imitation of the arterial pressure. For this purpose the resting tension was calculated for each vessel according the Laplace equation and was 8 to 18 g, depending on the vessel size and its compliance. The contraction of the equilibrated vessels was stimulated with 50 µmol/L phenylephrine or 100 nmol/L of thromboxane A2 analogue U46619. The vasodilatory drugs were used on the intact vein, added after the first control contraction. Pretreatment with vasodilators lasted 30 minutes before stimulation of the next contraction. After one contraction in the presence of drugs was performed, the solution was changed every 15 minutes to facilitate washout of drugs. Endothelium-dependent relaxation was studied with acetylcholine added in a cumulative manner to veins precontracted with 50 µmol/L phenylephrine.

Computer recording was accomplished through force-displacement transducers (FT03E; Grass Instrument Division, Astro-Med Inc, Warwick, RI), connected with OCTAL Bridge and MacLab 8/s or Power Lab 8/s system (ADInstruments, Pty Ltd, Castle Hill, Australia). Chart’c/a9 recording software (ADInstruments, Mountain View, CA) was used for data acquisition.

Histology
The rings of vessels were fixed in 10% buffered (pH 7.4) formalin phosphate for 12 to 24 hours and embedded in paraffin. Sections were cut at 4 µm onto microscope slides and stained with modified Movat's pentachrome or with antibodies (dilution factor of 1:2000) to factor VIII-related antigen for endothelial cells. Image acquisition and processing were performed using a Nikon MicroPhot microscope (Nikon Inc, Garden City, NY) and a SPOT digital camera (Diagnostic Instrument Inc, Sterling Heights, MI) for picture capturing and ImageProPlus5 software for image processing.

Statistical analysis
The data are expressed as mean ± SEM. The relaxation (Fig 1) is presented as the percentage of the initial contraction. The design of the experiments allowed the paired sample t test to be used when comparing the effects of controlled pressure distention (Fig 2). Student's t test was used for comparison of the reactions of undistended veins and veins distended under operating room conditions. The multiple Tukey-Kramer HSD test (JMP, version 4.0.2, SAS Institute, Cary, NC) was used for comparison of the contractile responses recorded at different controlled resting tensions. The effects of the combination of vasodilators were assessed in a similar fashion. The two-way analysis of variance (ANOVA) test was used for acetylcholine concentration response curves comparison (JMP, version 4.0.2, SAS Institute).



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  		Fig 1. Acetylcholine (ACh)-induced vasodilation of human saphenous vein precontracted with 50 µmol/L phenylephrine after 2 minutes distention with pressure 150 mm Hg (diamonds) compared with control (circles) undistended segments of veins (n = 5; p < 0.05).

 


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  		Fig 2. Responses to (A) depolarization (80 mmol/L K+) and (B) {alpha}-adrenergic stimulation (50 µmol/L phenylephrine) of human saphenous vein distended with pressures 50 to 600 mm Hg compared with undistended veins (cubic polynomial fitting of the mean points; R2 = 0.93 for 80 mmol/L K+ and 0.94 for phenylephrine; total number of patients = 36, n = 4 to 7 for each point. For the 100 to 300 mm Hg entire group, n = 27, the difference between distended and undistended veins is significant with p < 0.05).

 

   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Organ bath studies
Uncontrolled manual distention under operating room conditions impaired smooth muscle and endothelial cell functions of the HSV. Contractile responses of distended segments of HSV to depolarization with 80 mmol/L K+ and {alpha}-adrenergic stimulation with phenylephrine on average are much less in amplitude than those of undistended segments (Fig 3, A and C).



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  		Fig 3. (A) Traces of responses of undistended (undist) and distended (dist) human saphenous vein (HSV) to 80 mmol/L K+ (thin line) and 50 µmol/L phenylephrine (PE [thick line]). (B) Traces of responses of undistended and distended HSV precontracted with 50 µmol/L PE to 1 and 10 µmol/L acetylcholine (ACh). (C) Mean responses for 80 mmol/L K+ and phenylephrine (PE): n = 42 undistended rings from 12 patients; n = 16 distended rings from 10 patients; p < 0.0001 for 80 mmol/L K+ and phenylephrine. (D) Mean acetylcholine relaxation responses in undistended (n = 39 rings from 12 patients) and distended (n = 16 rings from 10 patients) HSV (p < 0.005 for 1 µmol/L acetylcholine; p < 0.01 for 10 µmol/L acetylcholine).

 
Uncontrolled distention also disrupted endothelial function. Acetylcholine added in two concentrations (1 µmol/L and 10 µmol/L) relaxed the rings from the undistended segments (Fig 3, B and D). On average, responses were significantly depressed in the distended samples as compared with the undistended HSV segments.

In contrast to the detrimental effect of uncontrolled pressure distention on the HSV responsiveness, distention at moderate pressure in the range 100 to 300 mm Hg, which is in excess of the physiologic range, caused enhancement of the contractile responses to both depolarization and {alpha}-adrenergic stimulation of the HSV (Fig 2). The increase of force development after distention at 100 to 300 mm was to 141.03% ± 15.13% for 80 mmol/L K+-induced and 153.73% ± 15.69% for phenylephrine-induced contraction on average for the entire group of samples. The distention at 600 mm Hg however caused a considerable decrease to 55.9% ± 9.47% and 80.01% ± 7.32% of the control contraction for 80 mmol/L K+ and phenylephrine respectively.

It was noted that the inhibitory effect of pressure distension on vessel contractility occurred in those cases where the diameter increase was greatest. Consequently the response to the depolarization (Fig 4, A) and {alpha}-adrenergic stimulation (Fig 4, B) was plotted versus circumferential enlargement of the vessels during distention. Cubic polynomial fitting of these plots revealed a bell-shaped dependence of the amplitude of the response on the change of the diameter of the vessel. The enlargement during distention by about 50% of the initial diameter was most effective in enhancing contractile responses to stimuli. Circumferential enlargement of the HSV 2.0 times or more of its original diameter caused a profound decrease of contractility of the vein to about 20% of control values.



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  		Fig 4. Relative increases in contraction of human saphenous vein in response to (A) 80 mmol/L K+ and (B) 50 µmol/L phenylephrine after distention 50 to 600 mm Hg, versus circumferential enlargement (cubic polynomial fitting; R2 = 0.50 for 80 mmol/L K+ and 0.57 for phenylephrine; n = 23).

 
Pressure distention in the range 50 to 300 mm Hg did not impair endothelium-dependent relaxation of the HSV in response to acetylcholine. Moreover distention at pressure ranging 100 to 300 mm Hg tended to enhance dilation. The enhancement at pressure of 150 mm Hg reached a level of significance (Fig 1). Values of percentage of maximal dilation in distended rings versus control rings from the same veins were respectively 24.95% ± 11.24% versus 29.11% ± 8.9% for 50 mm Hg; 40.1% ± 10.87% versus 33.49% ± 9.21% for 100 mm Hg; 47.7% ± 9.64% versus 30.17% ± 9.3% for 200 mm Hg; 41.1% ± 6.83% versus 31.14% ± 4.94% for 250 mm Hg; and 34.7% ± 13.3% versus 28.0% ± 7.24% for 300 mm Hg. The 50% effective concentration values did not differ significantly in any group.

The risk of vasospasm of HSV after its grafting in the arterial bed could be decreased [24]. We have explored the efficiency of vasoconstriction of HSV if the lumen pressure had been raised to the level, which this vein would have experienced in the arterial circulation. The increased pressure was imitated by the increased resting tension equivalent to the pressures of 120 mm Hg and 150 mm Hg vessels. In contrast to the increased responsiveness of the vessels primed with 100 to 300 mm Hg and then tested at the normal resting tension of 2 g, the vessels equilibrated at the elevated resting tension, which imitated the arterial pressure, demonstrated inhibited responsiveness to {alpha}-adrenergic stimulation: 30.8% ± 16.4% and 20.8% ± 11.5% of the initial value for 120 mm Hg and 150 mm Hg, respectively (Fig 5).



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  		Fig 5. Contractile ability of human saphenous vein in the presence of 50 µmol/L phenylephrine at resting tensions equivalent to arterial pressures of 120 mm Hg and 150 mm Hg as percent of control contraction (*p < 0.01 versus 20 mm Hg; n = 5).

 
The combination of phenoxybenzamine (10 µmol/L), nicardipine (10 µmol/L), and HA-1077 (50 µmol/L) completely abolished force development in response to {alpha}-adrenergic stimulation (50 µmol/L phenylephrine) from the onset of its addition for as long as 20 hours after washout of the vasodilators (Fig 6, A). The thromboxane receptor stimulated contraction induced by 100 nmol/L 9,11-dideoxy-11{alpha},9{alpha}-epoxymenthano-prostaglandin F2{alpha} (U46619) was also significantly inhibited by the vasodilatory combination (Fig 6, B). The inhibition was sustained throughout the experiment. In addition the vasodilator combination completely abolished the depolarization-induced contraction (Fig 6, C) with 80 mmol/L K+. Recovery was slow and incomplete with only 26.2% ± 9.4% of the initial contractile response after 20 hours.



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  		Fig 6. Effect of combination of phenoxybenzamine (10 µmol/L), nicardipine (10 µmol/L), and HA-1077 (50 µmol/L) on the contractile response to (A) 50 µmol/L phenylephrine (solid circles), (B) 100 nmol/L U46619 (open circles), and (C) 80 mmol/L K+ (triangles) in the undistended human saphenous vein from the onset of addition (time = 0 hours) and during 20 hours after the washout of the vasodilators (the response after drug application is presented as percentage of the first control contraction; p < 0.001; n = 5).

 
Histology of HSV samples
Movat's stained cross-sections of undistended and distended HSV samples (Fig 7, A and C) demonstrated that each segment type was composed of intimal, medial, and adventitial layers. The media is composed of several smooth muscle layers, which explains the ability of the intact vein to develop prominent force. The distended vessel is overstretched: the ratio thickness-to-diameter is roughly one half of the undistended vessel; the adventitia is partly split off. Each segment type had dark factor VIII–related antigen staining (Fig 7, B and D), indicating the presence of the endothelial cell layer.



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  		Fig 7. Movat stained undistended (A) and distended (C) human saphenous vein segments. The same undistended (B) and distended (D) segments labeled with factor VIII–related antigen (representative of n = 5 for each group). All scale bars are equal to 0.5 mm.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Manual distention with uncontrolled pressure in the operating room attenuated the contractile ability and impaired the endothelial function of the human saphenous vein (Fig 3). This trauma can accelerate proliferation and neointima formation and decrease the patency of the vein graft [2, 7]. In contrast moderate pressure distention (100 to 300 mm Hg) augments the contractile responses to depolarization and {alpha}-adrenergic stimulation in human saphenous veins (Fig 2). Moreover the endothelium dependent dilation was either unchanged by moderate pressure distention or even enhanced at 150 mm Hg (Fig 1). Thus there exists a wide range of moderate distention pressure, which is in excess of the range of physiologic blood pressure, that does not impair vessel function. Distension with pressure in this range is sufficient for checking for leaks and the ability of the conduit to withstand arterial pressure without detrimental biochemical or structural consequences for HSV [1, 25].

The augmentation of the contractile response to endogenous stimuli may increase the risk of vasospasm however. A combination of drugs that induce vasodilation by different mechanisms has been suggested for the prevention of vasospasm in human vascular tissue [18, 19]. Such drug treatment could also have a direct beneficial effect by decreasing smooth muscle cell proliferation as has been shown with long-acting calcium antagonists in human arteries [21] or with verapamil in rabbit vein graft [22].

In this study we have used the combination of phenoxybenzamine, nicardipine, and HA-1077 (Fig 6) targeting three different mechanisms underlying force development: receptor stimulation, calcium entry, and Rho-kinase activation respectively. Rho-kinase has been recently implicated in the main pathway signaling human smooth muscle contraction [4, 23]. Topical application of a long-acting combination of vasodilators, which impedes multiple contraction pathways, such as used in this study instead of high pressure distention may be a promising step toward preventing vasospasm and improving the outcome of coronary artery bypass surgery. The application of these drugs to the HSV to be used for bypass grafting will prevent vasospasm during surgery until normal arterial circulation is established. Based on our data (Fig 5) and in agreement with others [24] that contractile activity of the HSV is significantly decreased at arterial pressure, one would surmise that arterial pressure would prevent vein occlusion after grafting once the vasodilator combination wears off.

The excessive distention of human saphenous vein resulted in impaired endothelium-dependent dilation (Fig 3). The distended vein nevertheless demonstrates the intensive factor VIII–related antigen staining (Fig 7, D). This finding suggests within the limits of accuracy of light microscopy that the impairment of the endothelium-dependent dilation results from dysfunction of endothelial cells rather than from denudation. Alternatively the intensive staining in distended vessels could be explained by overexpression of von Willebrand factor by survived traumatized cells, which also contributes to intimal hyperplasia and smooth muscle cells proliferation [26].

The augmented reactivity to {alpha}-adrenergic stimulation after distention with pressure up to 450 mm Hg has been noted previously [12] whereas the opposite results were observed at pressure 300 mm Hg [11]. The discrepancies may be due to differences in experimental protocols and vessel handling. Particularly the low phenylephrine concentration, 1 µmol/L, used for stimulation after distention of HSV with 300 mm Hg [11] is much less than the phenylephrine 50% effective concentration, 12 to 14 µmol/L [4, 14].

Cyclic stretching also enhanced the contractile response of HSV [14, 15], which was prevented by placing an external stent around the vessel during the application of the pulsatile pressure [15]. Signaling of mechanical stimuli in smooth muscle is thought to be mediated through reorganization of the cytoskeleton [27, 28]. Rho kinase is a multifunctional mediator involved in mechanotransduction and cytoskeleton reorganization [28] and neointima formation [29, 30]. Smooth muscle gene expression related to differentiation is regulated by Rho-mediated actin polymerization [31]. Rho-kinase was also implicated in the mechanism of NO-induced dilation in the rat aorta [32] and relaxation in the cultured smooth muscle cells initiated by cyclic GMP [33]. It has been suggested that the signaling pathways for the cytoskeleton reorganization, vasomotor function and regulation of gene expression and cell phenotype are closely integrated [27]. Therefore similar mechanisms could underlie the effects of distention on vasomotor function and remodeling of vascular cells, transforming them into synthetic phenotype.

Our data suggest that the circumferential stretch rather than pressure itself is the factor affecting vasomotor function (Fig 4). This finding may provide a partial explanation for the beneficial effect derived from external stents [34]. Protection of veins against overstretching is probably an important reason for long-term patency seen in venous grafts where the vein is harvested with the surrounding tissue [35]. Accordingly estimation of the vein diameter during distention could be a predictive factor for graft patency.

In conclusion uncontrolled pressure distension of the human saphenous vein induces injury of smooth muscle and endothelium, which contributes to vein graft failure. Exposure of veins to moderate distention pressure, while measuring the circumferential enlargement, to check for leaks and for the ability of the conduit to withstand arterial pressure combined with topical application of an effective combination of long-acting vasodilators before grafting the vein into arterial circulation could be an effective alternative to the current practice of uncontrolled pressure distention.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by a Grant-in-Aid from the Heart and Stroke Foundation of British Columbia and Yukon. We greatly appreciate the cooperation of cardiac surgeons, residents, and nurses of St. Paul's Hospital and thank the Registry of the iCAPTURE Centre of the University of British Columbia for supplying the saphenous veins.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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A. W.Y. Chung, P. Rauniyar, H. Luo, Y. N. Hsiang, C. van Breemen, and E. B. Okon
Pharmacologic relaxation of vein grafts is beneficial compared with pressure distention caused by upregulation of endothelial nitric oxide synthase and nitric oxide production
J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 925 - 932.
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