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Ann Thorac Surg 2000;69:480-485
© 2000 The Society of Thoracic Surgeons

Original Articles

Human aortocoronary grafts and nitric oxide release: relationship to pulsatile pressure

Thomas V. Bilfinger, MDa, George B. Stefano, PhDa

a Division of Cardiothoracic Surgery, Department of Surgery, State University of New York at Stony Brook, Stony Brook, New York, USA

Address reprint requests to Dr Bilfinger, Division of Cardiothoracic Surgery, Department of Surgery, Health Sciences Center/T-19, State University of New York at Stony Brook, Stony Brook, NY 11794-8191
e-mail: bilfinge{at}surg.som.sunysb.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Short and long-term failure of saphenous vein grafts continues to be a significant problem for cardiac surgeons. The purpose of this study was to elucidate the early adaptive changes of human artery and vein conduits with respect to nitric oxide (NO) production under various pressure and pulsatile distention conditions.

Methods. Real-time amperometric NO determinations were made in an in vitro model using human saphenous vein segments (n = 12) and internal thoracic artery segments (n = 8) between 70 and 170 mm Hg, under static conditions recorded with a pressure transducer. Exposing the tissue to morphine (10-6 M) also stimulated NO release. Under conditions in which the conduits were exposed to the respective pressures for 1 hour, they were then examined for their granulocyte-adhering potential using computer-assisted imaging techniques.

Results. A pressure-dependent decrease of NO release was found after 32 minutes of pulsatile pressure (170 mm Hg) in artery and vein, the latter of which appeared to be affected more negatively (p < 0.05; because many more observation points differed significantly after 32 minutes compared to 110 mm Hg values). In vessels maintained for 1 hour at these different pressures and then exposed to morphine (1 µM), stimulated NO release significantly diminished in the veins (artery 37.4 nM NO versus vein 18.1 nM NO; p < 0.05). Increased pressures also correlated with an increase in granulocyte adhesion to veins that could not be reduced following morphine exposure.

Conclusions. Increased pressure and cyclic distention lead to loss of NO release and increased immunocyte adhesion, which are significantly more pronounced in saphenous vein than in internal thoracic artery, suggesting that in the long term this may contribute to the failure of saphenous vein conduits in coronary revascularization.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
The saphenous vein, despite the increasing popularity of arterial conduits for aortocoronary bypass operation, remains the standard for this procedure. Approximately 45% of veins removed 5 to 10 years after implantation contain ruptured plaques, and plaque formation is even higher [1]. Arterial conduits, mainly the internal thoracic artery, are more resistant to atheromatous changes. The question of why the vein graft is less durable has plagued cardiac surgeons for many years.

As more becomes known about endothelial function and behavior, performance of a graft can be correlated to performance of the endothelium [2]. One such correlation that has been shown previously to be important is the production of nitric oxide (NO), which can be affected by various stimuli [2]. For instance, hypertension, specifically angiotensin II-dependent hypertension, blunts endothelial NO production [3]. Therefore, conduits that retain the ability to release NO in response to pharmacologic stimuli stand a better chance of long-term patency [4, 5]. It is surmised that if NO is released in response to pressure, long-term function is improved, though data from long-term studies is not available.

NO is a gas released from vascular endothelial cells, myocardium, and leukocytes, as well as certain cancer cells [6]. It acts as a potent vasodilator by stimulating guanylate cyclase, which converts guanosine triphosphate into guanosine monophosphate. The rise in cyclic guanosine monophosphate inhibits the contractile apparatus of the vascular smooth muscle. The release of NO can be triggered by a number of pharmacologic agents, but also by physical stimuli, such as visible light, electrical field stimulation, and pulsatile pressure [7].

The present study was undertaken to elucidate the influence of hydrostatically produced distention changes and pulsatile pressure on NO release in the saphenous vein and internal thoracic artery. The effect of a spectrum of physiologic pressures and the ability of the endothelium to respond under those conditions were examined.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Saphenous vein segments and internal thoracic artery segments were obtained from patients (n = 12 and 8, respectively) undergoing elective coronary artery bypass grafting for atherosclerotic heart disease, at State University of New York-Stony Brook University Hospital and Medical Center. The patients underwent coronary revascularization for ischemic heart disease only. All of the patients were hypertensive by history, at least. Patients with diabetes or other chronic or acute illnesses aside from the vascular disease were excluded. The vessel segments were placed in a balanced electrolyte solution (Plasmalyte and 5000 U heparin/500 cc) and transported on ice (4°C) to the laboratory. There, the vessel was cut in two. One half was mounted, as indicated in Figure 1, for amperometric NO determination: all side branches were either tied with 4-0 silk or oversewn with 7-0 Prolene (Ethicon, Somerville, NJ) sutures. One end was tied off, whereas the other end was mounted on a vessel cannula. This end was connected to a stopcock. One side was connected to a pressure transducer (Abbott Laboratories, Chicago, IL) coupled with a recorder for continuous pressure recordings (Sirecust 403; Siemens, Erlangen, Germany). The other side was connected to a Harvard pump (Harvard Instruments, Cambridge, MA). NO determinations were made with an amperometric probe (World Precision Instruments, Sarasota, FL) positioned through a side branch in the middle of each vessel. The vessel was placed within the lumen so that its tip did not touch the vessel. The vessel was maintained at 37°C in a bath with 5% CO2. The system was calibrated daily using different concentrations of a nitrosothiol donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; Sigma, St. Louis, MO) to generate the standard curve. S-acetyl-L-penicillamine was used as a negative control. NO gas in solution was measured in real-time with the DUO 18 computer data acquisition system (World Precision Instruments). The vessel was then distended to reach a predetermined pressure. For pulsatile experiments, the cycle was 30 pulses per minute with the pressure between 70 and 170 mm Hg.



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  		Fig 1. Experimental design.

 
Adhesions studies
Human granulocytes were obtained from Long Island Blood Services (Melville, NY). Granulocytes were separated by the standard Ficoll-Hypaque method, as described elsewhere [4, 8]. Following separation, the cells were washed three times in RPMI medium (RPMI, 25 m Hepes; Grand Island Biological, Grand Island, NY). Fluorescence staining of the granulocytes was accomplished using a commercially available kit (Sigma). After Ficoll-Hypaque isolation, granulocytes (10-6 cells/mL) were centrifuged (8000 rpm, 5 minutes) and resuspended in 1 mL of diluent containing PKH26-GL (Sigma). The cells were then processed according to the manufacturer’s instructions. Briefly, cells were incubated in the fluorescent dye solution for 2 minutes, with gentle mixing; the addition of plasma (2 mL) stopped the reaction. The cells were washed in phosphate buffered saline (PBS), diluted, and divided into 100 µL volumes, each containing 409 ± 18 cells.

Human saphenous vein and internal thoracic artery segments were cut into 3-mm ring pieces, then cut longitudinally and rinsed in the same medium described above. The separate cut vessels, endothelial side up, were then encircled with a ring of petroleum jelly. The cells, loaded with the yellow-fluorescing dye, were resuspended in 100 µL volume, and added to the endothelial surface. Each viewing diameter was approximately 400 µm. These experiments were run in parallel to minimize variations due to constitutive NO release. Each treatment lasted for 15 minutes. Subsequently, the vessels were washed with PBS. The cells were added to the vessels after different pressure exposures (110 and 170 mm Hg) for 1 hour, after which the surface of the endothelium was gently washed, and the number of adhering granulocytes counted. To control for the endothelium, the experiments were repeated in vessels that had been physically denuded (by scraping) of the overlying endothelium.

The vessels and adhering granulocytes were visualized by ultraviolet microscopy using a Zeiss Axiphot epifluorescent microscope and image analysis (Compix, Mars, PA). Human granulocytes were monitored after treatment with the dye. The cells were counted rapidly and automatically using color detection software (Compix). Briefly, the examiner selected the yellow fluorescing color by matching it to 16 million color hues already present in the proprietary capture board. Once the color was identified, the size parameters of the yellow fluorescing cells were set; yellow fluorescing objects (debris) with areas below 45 µm2 and above 700 µm2 were ignored. The system then counted the yellow fluorescing cells automatically. Cell viability was determined by trypan blue dye exclusion; greater than 96% of the granulocytes were viable during the course of the experiments.

Direct measurement of NO release
In addition to indirectly measuring the numbers of adhering cells, we measured the endothelial release of NO following exposure to morphine. Results were expressed relative to the basal constitutive level of NO production (1.1 ± 0.5 nM NO).

NO released from the vessels was measured directly using a NO-specific amperometric probe with a tip diameter of 200 µm (World Precision Instruments), as described elsewhere [6, 7]. Briefly, the vessels, endothelial side up, were suspended in 2 mL PBS. The probe was positioned by a micromanipulator (Zeiss-Eppendorff, Erlangen, Germany), attached to the stage of an inverted microscope, 15 µm above the cell surface (Nikon Diaphot, Melville, NY). The system was calibrated daily using different concentrations of SNAP to generate a standard curve. Baseline levels of NO release were determined by measurement of NO release in the absence of any of the agonists. In one instance, NO was measured in the presence of tissue heated to destroy it. The concentration of NO gas in solution was measured and recorded in real-time with the DUO 18 computer data acquisition system (World Precision Instruments). The probe was allowed to equilibrate for 12 hours in cell-free incubation medium before being transferred to vials containing the tissue for another 20 minutes. Manipulation and handling of the tissue was performed only with glass instruments. Each experiment was repeated three or four times, and the mean NO values were graphed. Furthermore, to avoid measuring artifactual drift by the probe, controls for each experiment were performed on the tissue obtained from the same vessel and person.

Statistical analyses
One and two-tailed Students’ t tests were used because each experiment served as its own control. A p value of less than 0.05 was considered significant. Time-sensitive groups were analyzed by paired ANOVA for repeated measures. The experimental values were transferred to Sigma Plot and Sigma Stat (Jandel, Corte Madera, CA) for graphic representation and evaluation.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Both the internal thoracic artery and the saphenous vein released NO in response to transient pressure changes (Fig 2). At 0 mm Hg pressure, the basal NO output of either arteries or veins varied between 0 and 1.1 ± 0.07 nM. The experiments were conducted between the peak high pressures as indicted, and the low pressure of 70 mm Hg. At 110 mm Hg, the NO peak level release appeared to stabilize and remain relatively low (4 to 5 nM for both vessels) for up to 1 hour, indicting the ability of constitutive NO release to pulsate with rapid pressure changes. At 170 mm Hg, there was an initial surge of NO release, which then significantly diminished in time in both vessels. This decrease was statistically significant for arteries and veins (paired ANOVA for repeated measures p < 0.05). The decrease was however more pronounced in the veins, since most observations points were significantly different from the 110 mm Hg value, as opposed to only one point for artery after 32 minutes, indicating that veins do not perform uniformly at high-pressure pulsations for long periods of time. In the saphenous vein, after 32 minutes of pulsation at 170 mm Hg, the peak NO level was 2.0 ± 0.3 nM compared with 4.3 ± 0.5 nM at 110 mm Hg (p < 0.05). Basal levels of NO (in vessels exposed to no pressure for the entire observation period) for both artery and vein were 1.1 ± 0.5 nM and 0.9 ± 0.3 nM, respectively.



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  		Fig 2. NO determinations during pulsatile pressure at 30 cycles per minute with peak pressures of 110 and 170 mm Hg. Both the internal thoracic artery (A) and the saphenous vein (B) released NO in response to transient pressure changes. Arrows indicate p less than 0.05 when comparing the two pressures from four mean replicate values per vessel. In the vein, the decreased NO peak values, after 32 minutes of high-pressure pulsation, were significantly decreased further, as noted by the arrows (p < 0.05).

 
Furthermore, sustained high pressure (170 mm Hg) for 1 hour selectively diminished the constitutive NO-generating capacity of both vessel types as noted by their response to morphine (10-6 M; Fig 3). Previously we demonstrated that morphine stimulates constitutive NO synthase (cNOS)-associated NO release in human endothelial cells, a phenomenon that can be blocked by naloxone and N (omega)-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor [9]. In the present study, upon initial exposure to morphine, both vessels showed a surge of NO (16.40 ± 3.50 nM) regardless of pressure. However, following a second exposure in both vessels, maintained under high pressure, there was a significant decrease in NO peak levels as indicated. The graphed mean values were obtained from four replicates per vessel and compare the peak NO values ± standard error of the mean. Vessels maintained at 70 mm Hg produced the same pattern and levels of NO release as noted for the vessels maintained at 110 mm Hg. In veins, this secondary response to additional morphine was even more pronounced as evident by its comparison with the arterial NO peak value (p < 0.05).



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  		Fig 3. Exposure of blood vessels for 1 hour to constant pressure followed by morphine (10-6 M) exposure. Both the internal thoracic artery (A) and saphenous vein (B), at different pressures, responded differently to the same dose of morphine. A significant increase of NO following the initial morphine exposure (arrows) regardless of the pressure was observed.

 
In examining this phenomenon further, we found that the internal thoracic artery and saphenous vein at different pressures responded differently to the same dose of morphine (Fig 4). In general, there was a significant (p < 0.05) positive increase with morphine at higher pressures. In the artery, increased pressure resulted in increased levels of peak NO release. At 170 mm Hg the level of NO release was significant, compared to the response at 70 mm Hg. However, in the veins the pressure of 170 mm Hg selectively diminished their capacity to generate NO. Here the vessels were kept under constant pressure, for 1 hour and then exposed to morphine (10-6 M). The graphed mean values, obtained from three replicates of the artery per vessel and four replicates of the vein per vessel, compare the peak NO values ± standard error of the mean. The main difference observed was that, at 170 mm Hg, the saphenous vein could not maintain its increase in NO output, which remained flat despite an increase in morphine concentration.



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  		Fig 4. The response of internal thoracic artery and saphenous vein to increasing concentrations of morphine at different pressures.

 
To test the hypothesis that veins exhibit a lower capacity for withstanding and adapting to high pressure, we also examined the ability of human granulocytes to adhere to endothelium after 1 hour of maintaining the respective vessels at the different pressures (Fig 5). Granulocytes adhered to endothelium when exposed to 110 mm Hg, and exposure of the vessels to morphine greatly reduces the number of adhering cells (p < 0.01) in both vessel types. After sustained higher pressure exposure, endothelium of both vessels showed an increased capacity for cell adherence (p < 0.05). However, following morphine exposure, granulocytes exposed to the veins maintained at 170 mm Hg did not exhibit a diminished adherence enhancement compared to artery (p < 0.05), supporting a diminished functional capacity of veins. We also examined the ability of human granulocytes to adhere to the respective endothelium exposed to 1 hour of pressure at 70 mm Hg, and found that adhesiveness can be reduced to the same extent by morphine (10-6 M) exposure (data not shown) as noted in the 110 mm Hg experiment. These data are consistent with the observations presented in Figures 1–4 which, taken together, support the conclusion that venous endothelial function becomes diminished at high pressures.



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  		Fig 5. Granulocyte adhesion to internal thoracic artery or saphenous vein endothelial surface after 1 hour of constant exposure of the vessels to different pressures. (*p < 0.05 for treatments 1 through 3 compared to each other; **p < 0.05 in treatment 4 where artery values are compared to vein, indicating a lack of morphine effect on granulocyte adherence.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
This study demonstrates that venous conduits have a decreased capacity of releasing NO. Not only is that capacity decreased over time, it is also pressure dependent. The internal thoracic artery fared better under the same experimental conditions. Because NO release and immunocyte adhesion are directly linked [10] it is not surprising that veins are more prone to the potential sequelae of immunocyte-induced injury. Taken together, these observations lead us to surmise, as do others [11], that normal endothelial function is a prerequisite for the maintenance of vascular homeostasis.

In this regard, it is important to note that there are differences between arteries and veins in their endothelial cell biology. They include, among other factors, the density of endothelial cell populations per square millimeter of vessel surface, and the concentration and activity of endothelial nitric oxide synthase (eNOS), as well as its coupling to hydrodynamic forces [12, 13]. Further, eNOS has been shown to be important for regulation of basal blood pressure, and abnormal basal NO production has been described in unrelated essential hypertension [14]. These factors deserve mention in view of the historically hypertensive patient population from which the vessel specimens were obtained for the present study.

Among the many actions of endothelial-derived NO, there is a direct link between intimal hyperplasia and endothelial cell dysfunction [15]. In a rabbit model with unilateral iliac balloon angioplasty trauma, oral L-arginine supplementation has been shown to result in more rapid restoration of endothelium-dependent relaxation and an approximately 30% decrease in intimal area after 4 weeks [16]. A reduction of the same magnitude was also reported by McNamara and colleagues [17], who noted that L-arginine’s effect was completely antagonized by L-NAME. These effects seem dependent on inducible nitric oxide synthase (iNOS). Although Davies and colleagues [11] demonstrated in human saphenous vein grafts that cNOS expression is present, supporting our earlier observations [4], and that receptor-independent endothelium-derived relaxation is preserved, other investigators have found that significant decreases in NO-mediated responses occur as the severity of the intimal lesion increases [18]. Evidence suggests that with reasonable perioperative care, the endothelium is usually grossly intact [11]. However, arterial and vein grafts have different responses in NO release, which is a marker for long-term function [4].

Fluid mechanics are known to transiently regulate vascular tone. Specifically, pressure (hypertension) and flow (pregnancy, arteriovenous shunts, and exercise) have been investigated [19]. At present, the discussion is centered on the relative importance of pressure shear stress, and cyclic distention or "stretch" and their contribution to endothelin and NO release. The present study only addressed the contribution of pressure and cyclic stretch to NO production in an in vitro model. The complexity of the mechanics involved is elegantly discussed by Ziegler and colleagues [20], who have shown in their in vitro model that the combination of pressure and oscillatory shear stress downregulates cNOS levels, as well as upregulates transient endothelin-1 expression, when compared with unidirectional shear stress. These findings are consistent with the present observations and those by Champsaur and colleagues [21], who demonstrated in a fetal bypass model that pulsatile perfusion over the first 30 minutes leads to increased flow at a steady pressure when compared with continuous flow, and that thereafter, the vascular resistance slowly increases, suggesting a decrease in NO release. In a study performed by Cross and colleagues [22], endothelium-dependent relaxation in explanted human coronary vein grafts was also shown to be impaired, with no response to acetylcholine, but a significant response to A23187. Because acetylcholine works by receptor-mediated NO release, unlike A23187, which operates by a mechanism independent of that receptor, it has been suggested that although the endothelial NO synthesis capability is preserved, the defect occurs in the signaling pathway.

The well-established response of increased NOS activity in animal models and in vitro systems with increased shear stress can be viewed as an adaptive phenomenon [23] with the goal of the respective endothelial cell to create normal conditions. In the present study, we observed this particular phenomenon, as the low value of the venous cyclical readings with high-pressure distention (170 mm Hg) was diminished after 30 minutes to values seen at 70 mm Hg, suggesting that the vein cannot withstand high-pressure pulsation for long periods, whereas the artery can. Either the high pressure or the greater distention (or both) appears to exhaust venous NO release, as also noted by other investigators [24]. In addition, the general relationship that the same dose of morphine will elicit higher NO release with higher pressure did not hold true for saphenous vein, but remained intact for internal thoracic artery. Saphenous vein at 170 mm Hg, however, produced significantly less peak NO, despite increasing morphine concentrations. At this point it should be noted that morphine, using the µ3 receptor on endothelial cells, is coupled to NO release in a naltrexone and L-NAME-sensitive process [4, 9], allowing for the present conclusions.

A further observation addresses the role of endothelial leukocyte adhesion. Although there are many reports documenting decreased endothelial adhesiveness with increased NO release and the reverse, a pressure-adhesiveness correlation is scarcely documented [2, 25]. Provost and Merhi [25] performed a study in porcine arteries and showed that incremental increases in shear stress resulted in increased neutrophil and platelet adhesion (about 30%), which was further amplified 100-fold by L-NAME, again supporting the data of the present study. This observation also explains the enhanced granulocyte adhesion in veins compared to arteries maintained for 1 hour at 170 mm Hg and then exposed to morphine. Namely, we surmise impaired NO release allowed for the significantly higher level of granulocyte adherence.

Furthermore, Rizzo and colleagues [26], besides demonstrating that acute changes in pressure or shear stress stimulate a rapid release of NO through eNOS activation, using subcellular fractionation of the rat endothelial membranes and their caveolae demonstrated that eNOS is enzymatically active in the caveolae. Thus pressure or flow in situ rapidly activates eNOS by inducing its dissociation from caveolin, the inhibitory protein, and coupling to calmodulin. These data coupled mechanotransduction and eNOS activity, directly supporting the results of the present study. We surmise sustained high pressure may uncouple this process.

In conclusion, after a 30-minute exposure of the saphenous vein to pulsatile arterial pressures, a decrease in the amount of NO released was observed. During the performance of a coronary artery bypass operation, this decrease usually occurs at about the time when protamine is administered to reverse the effect of heparin. We therefore surmise that early vein graft events may well occur during this particular intraoperative timeframe.


   Acknowledgments
 
We wish to express our gratitude to Dr Yu Liu and Mr Federico Casares (a NIDA predoctoral fellow) for their excellent technical assistance. This work was in part supported by NIH grant DA 09010.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication July 12, 1999.




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