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Eur J Cardiothorac Surg 2003;24:541-546
© 2003 Elsevier Science NL

Effect of ascorbic acid on endothelium-dependent vasodilatation of human arterial conduits for coronary artery bypass grafting

Omar Mangoush, Koki Nakamura, Sharif Al-Ruzzeh, Thanos Athanasiou, Adrian Chester, Mohamed Amrani*

National Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK

Received 16 March 2003; received in revised form 14 June 2003; accepted 19 June 2003.

* Corresponding author. Tel.: +44-1895-828550; fax: +44-1895-828002
e-mail: mr.amrani{at}rbh.nthames.nhs.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Techniques aimed at improving the performance of arterial conduits will maximize the clinical benefit achievable with coronary artery bypass surgery. Controlling oxidant stress could be a strategy for preventing early graft deterioration. We tested the effect of a free radical scavenger, ascorbic acid (vitamin C), on preserving the endothelium-dependent vasodilatation function in vitro of radial artery and internal thoracic artery. We also tested its effect on the amount of reactive oxygen species (ROS) generated by each graft. Methods: Radial artery (RA, n=25) and internal thoracic (ITA, n=19) segments were obtained from coronary artery bypass grafting patients. Each segment was divided into 3–4 mm vascular rings and incubated with or without ascorbic acid (10-3 mol/l) for 1 h or 72 h. Using the organ bath technique, the endothelium-dependent vasodilatation function was tested in vitro by the addition of cumulative concentrations of acetylcholine (10-9–10-5 mol/l) following vasocontraction by endothelin-1 (3x10-8 mol/l). ROS were measured by using chemiluminescence technique at 1-h and after 72 h incubation with or without ascorbic acid. Results: There were no differences in the vasodilatation function between control and ascorbic acid group of both arteries in the 1-hour incubation experiment. However, in the 72 h incubation experiment, ascorbic acid preserved the endothelium-dependent vasodilatation function of RA compared with control group (35.8±2.2% vs. 25.9±2.1%; P=0.005), but not ITA (39±3.5% vs. 40.5±9.3%; P=0.438). After 72 h incubation, RA generated significantly more free radicals compared with 1 h (133.7±151.5 vs. 16.8±16.8 cps/mgx100; P=0.01); however, AA has no statistically significant effect on decreasing the amount of free radicals generated by both arteries. Conclusions: In RA, ascorbic acid is able to preserve the endothelium-dependent vasodilatation function after 72 h incubation, but not after 1 h. However, the mechanism of action of AA is not completely understood. This finding could open the door for understanding the role of oxidant stress and antioxidants in preserving the endothelial function of coronary artery bypass grafts.

Key Words: Vitamin C • Radial artery • Oxidant stress

Abbreviations: AA, ascorbic acid • ACE, angiotensin-converting enzyme • ACh, acetylcholine • CABG, coronary artery bypass grafting • ET-1, endothelin-1 • ITA, internal thoracic artery • RA, radial artery • NO•, nitric oxide • O2•-, superoxide radical • OH•, hydroxyl radical • ONOO•, peroxynitrite • SOD, superoxide dismutase • SNP, sodium nitroprusside • CL, chemiluminescence


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
The internal thoracic artery (ITA) is the gold standard conduit for coronary artery bypass grafting (CABG). However, the radial artery (RA) has recently gained acceptance as an alternative arterial conduit, and has been shown to be superior to that of the saphenous vein [1]. Many interventions have been developed to improve the performance of RA. These include the use of better harvesting techniques as well as phenoxybenzamine, papaverine and Ca2+ channel blockers to treat peri-operative graft spasm [2,3].

The performance of conduits is governed by many factors, one of which is the damage to the vessel wall caused by the generation of oxygen free radicals. These include superoxide (O2•-), which consumes nitric oxide (NO•) and produces peroxynitrite (ONOO•), as well as hydroxyl radical (OH•). This process decreases the NO•-mediated endothelium-dependent vasodilatation of coronary grafts. There is direct evidence of the role of oxidant stress in the development of atherosclerosis in humans [4]. Morphological studies of the native vessels showed that RA has more prevalence of intimal thickening, medial sclerosis and medial calcification compared with ITA [5]. Thus, the RA could be more susceptible to oxidant stress than ITA. Reducing the oxidant stress could be a suitable therapeutic strategy in the management of arterial conduits.

In our previous studies we had used in vitro storage of blood vessels to induce deterioration of endothelial function [6]. This attenuation in the ability of cells to release NO•, has been shown to be prevented by statins [6]. We believe that this may be due to the antioxidant capacity of these drugs. The aim of this study is to assess the in vitro effect of ascorbic acid (AA) in preserving NO•-mediated, endothelium-dependent vasodilatation function of RA and ITA, using the organ bath technique. We will also assess the ability of AA in decreasing the oxidant stress experienced by these grafts, using chemiluminescence (CL) technique.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Specimen collection and incubation
RA and ITA samples were collected from patients who underwent CABG. The study was performed with the approval of the local research ethical committee. Written consent was obtained from all patients prior to surgery. Specimens of 1–2 cm in length were excised from the distal or proximal end of RA and the distal end of ITA before flushing or spraying the conduit with any chemical or the use of systemic vasodilators. Samples were placed in 199-tissue culture medium (Sigma, Dorset, UK) at 4 °C for 30 min before dissection under light microscope. All connective tissues were dissected and the vessel divided into rings of 3–4 mm in length.

Each specimen of RA or ITA contributed an equal number of rings to both AA and control groups. Vascular rings were incubated for 1 h in Dulbecco's modified Eagle's medium (DMEM, D6046; Sigma) in the absence (8 rings of RA and 8 rings of ITA) or the presence of 10-3 mol/l of AA (ICN Biomedicals Inc., Aurora, OH) (8 rings of RA and 8 rings of ITA). Penicillin–streptomycin solution (P0781, Sigma), L-glutamine (G7513, Sigma) and foetal bovine serum (F7524, Sigma) was added to DMEM media, incubated under 37 °C and aerated with 95% O2 and 5% CO2. The same experiment was repeated with an incubation period of 72 h, control groups (17 rings of RA and 11 rings of ITA) and AA groups (17 rings of RA and 11 rings of ITA).

For chemiluminescence study, segments of ITA and RA were divided into three rings of 2–3 mm in length and each ring was opened longitudinally to expose the endothelial layer. The first and second rings were incubated without AA and the third ring was incubated with AA (10-3 mol/l) in DMEM medium, as above. CL was measured after 1 h in the first ring and after 72 h in the second and third rings.

2.2. Organ bath experiment
After 1 or 72 h incubation, vascular rings were mounted over two L-shaped metal hooks in isolated organ baths, containing modified Tyrode's solution, composed of (mmol/l): NaCl 136.9, NaHCO3 11.9, KCl 2.7, NaH2PO4 0.4, MgCl2 2.5, CaCl2 2.5, glucose 11.1, and disodium ethylenediaminetetraacetic acid 0.04. The solution was gassed continuously with 95% O2 and 5% CO2 at 37 °C. One hook was attached to a force-displacement transducer and this was fixed to a Grass 7D polygraph (Grass Instruments, Quincy, MA), which monitored and recorded changes in the vessel wall tension. The other hook was fixed to a screw gauge, which was used to stretch the ring segment.

2.3. Vascular function study
The endothelial function of vascular rings was assessed as previously reported [7]. Briefly, an initial tension (80 mN for RA and 50 mN for ITA) was applied to the ring segment, which was allowed to relax and to equilibrate for 30 min at a stable level of tension. After equilibration the ring was challenged with 90 mmol/l KCl, to assess the viability of each segment. At plateau, the bath was washed out, and the procedure repeated again until two consecutive responses to KCl were within 10% of each other. The vessels were then challenged with 3x10-8 mol/l of Endothelin-1 (ET-1), to induce a tension within each ring. At plateau the ring was challenged with cumulative concentrations of acetylcholine (10-9–10-5), to induce endothelium dependent vasodilatation. Once the maximum effect of acetylcholine had been achieved, the endothelium-independent vasodilatation was tested by adding 10-5 mol/l of sodium nitroprusside (SNP), to determine the maximal relaxation achievable for each segment.

2.4. Chemiluminescence study
Superoxide production was measured in ITA and RA by lucigenin-inhanced chemiluminescence, using previously described and validated method [8,9]. Vascular segments were added to 100 µl of Krebs–HEPES buffer with 0.02 mM lucigenin in 96-well opaque plate. Using MicroBeta Trilux (Wallac Oy, Finland), at room temperature and after dark adaptation CL was measured at 1-min intervals. The result was given as maximum CL, cps/mg wet weightx100 after subtraction of background luminescence.

2.5. Analysis of data
SPSS for windows (version 11.0.0) was used for statistical analyses. Variables were expressed as mean±standard error of mean (SEM). pEC50 values were obtained by taking the -log10 of the graphic estimation from log-concentration–response curves of the concentration required for 50% of the maximum response. Statistical significance was assessed by t-test for symmetrical data, and Mann–Whitney test and Kolmogorov-Smirnov tests for asymmetrical data. A P-value of less than 0.05 was considered statistically significant. The value n represents the number of patients.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics for the organ bath experiment
Segments of RA and ITA were obtained from 38 patients. There were 29 males and nine females, with an average age of 65.8±8.7 years. Nineteen patients contributed with RA, 13 with ITA and six with both arteries. Patient characteristics, risk factors and medication are shown in Table 1.


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  		Table 1. Patient characteristics (per segment)

 
3.2. Vascular function
3.2.1. Vasocontraction responses
The vasocontraction responses (mN) to 90 mmol/l of KCl and to 3x10-8 mol/l of ET-1 decreased in all groups after 72 h incubation compared to 1 h, but this decrease was only significant in the response of the AA group of ITA to KCl (P=0.017). Also, there were no significant differences in vasocontraction responses to KCl or ET-1 between control groups and AA groups of both arteries in both experiments (see Table 2).


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  		Table 2. Vasocontraction response to KCl and ET-1

 
3.2.2. Vasodilatation responses
3.2.2.1. One-hour incubation
Segments of RA and ITA relaxed in a concentration-dependent manner in response to acetylcholine (10-9–10-5 mol/l). There was no significant differences in vasodilatation response to acetylcholine between control groups and AA groups of RA and ITA; Fig. 1 and Table 3. Also, there was no significant difference in the vasodilatation response as well as pEC50 between control groups and AA groups, in both arteries, in response to SNP; see Table 3 and Fig. 4.



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  		Fig. 1. RA and ITA vasodilatation response to acetylcholine after 1 h incubation. Empty and filled circles represent ascorbic acid (AA) and control groups, respectively, and each circle and bar represents mean±SEM (% of contraction by Endothelin-1). There was no significant difference between the control and ascorbic acid group.

 

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  		Table 3. Vasodilative response to ACh, SNP and superoxide generation

 


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  		Fig. 4. Vasodilative response of RA and ITA to SNP and acetylcholine after 1 and 72 h incubation with and without AA (% of contraction by ET-1). Black and grey bars represent SNP and acetylcholine, respectively.

 
3.2.2.2. Seventy-two-hour incubation
There was no significant difference in maximal vasodilatation response to acetylcholine between control groups of both arteries (P=0.108). The response to acetylcholine in RA was increased from 25.9±2.1% in the control group to 35.8±2.2% following incubation with AA (P=0.005; Fig. 2) . However, there was no significant difference in pEC50 between the two groups. This effect was not seen in ITA, where the vasodilatation responses in the control group and the AA group were 39±3.5% and 40.5±9.3%, respectively (P=0.438). On the other hand, there was no significant difference in the vasodilatation response between control group and AA group, in both arteries, in response to SNP; see Table 3 and Figs. 3 and 4 .



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  		Fig. 2. RA and ITA vasodilatation response to acetylcholine after 72 h incubation. Empty and filled circles represent ascorbic acid (AA) and control groups, respectively, and each circle and bar represents mean±SEM (% of contraction by Endothelin-1). There was a significant difference between the control and ascorbic acid group of RA. +P<=0.01; {ddagger}P<=0.001.

 


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  		Fig. 3. RA and ITA time-related deterioration of vasodilatation by acetylcholine. Filled and unfilled circles represent the 2 h and 24 h incubations, respectively. Filled and unfilled triangles represent the 48 h and 72 h incubations, respectively. Each circle (or triangle) and bar represents the mean±SEM (% of contraction by Endothelin-1). ET-1, endothelin-1. *P<0.05, #P<0.01, {dagger}P<0.001, {ddagger}P<0.0001 vs. the value at 2 h in each artery.

 
3.3. Superoxide production
Although after 1 h incubation ITA (n=6) generated more O2•- than RA (n=6), which was not statistically significant, after 72 h the level of O2•- generated by ITA (n=6) did not change, while it increased significantly in the case of RA (n=6) (P=0.01) (see Table 3 and Fig. 5) . AA did decrease the amount of O2•- generated by RA, but not ITA. However, these changes were not statistically significant.



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  		Fig. 5. Superoxide generation after 1 and 72 h incubation with and without AA. Black, dark grey and white bars represent control groups after 1 h, control groups after 72 h and AA groups after 72 h incubation, respectively. Values represent counts per second per mg wet weight of tissuex100. RA-72 h control is significantly higher than 1 h.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
This study shows that AA significantly preserves the endothelium-dependent vasodilatation function of the RA after 72 h incubation, but not after 1 h incubation. However, AA does not exert any effect on the ITA. We have previously shown that when arterial segments are stored in culture media their endothelial vasodilatation function deteriorates, in time-related fashion [6]. In an unpublished data, the vasodilatation function of RA decreased from 56.3±7.3% at 2 h to 20.2±1.5% at 72 h incubation, and to a lesser extent the ITA decreased from 40.0±5.2% at 2 h to 20.2±1.9% at 72 h, see Fig. 3. Therefore, we opted to design our experiment to incubate arteries for 1 h and 72 h. We believe that this deterioration in the endothelial function is due to oxidant damage, a process that may be responsible for postoperative decline of graft function. Understanding the mechanism behind this decline of endothelial function may help us build a better strategy to improve the graft performance.

Endothelial cells generate free radicals as a by-product of oxidative metabolism. These products play an important role in cell signalling. Under some circumstances they have the capacity to cause cell damage, but endothelial cells, under normal physiological conditions, are equipped to minimize this insult. The preservation of endothelial cell viability is vital for preventing early pathological changes and the maintenance of long-term patency of vascular grafts [10]. In patients with coronary artery disease, vascular extracellular superoxide dismutase (EC-SOD), one of the endothelial cell defence mechanisms against O2•- activity, is substantially reduced [11]. Moreover, Mugge et al. [12] have shown that inhibition of SOD by diethyldithiocarbamate (DETC) in rabbit aorta significantly decreases the endothelium-dependent vasodilatation, as a result of decreased bioavailability of NO•. Their results demonstrate that antioxidants play an important role in protecting the endothelial function. O2•- and HO. radicals have been implicated in the pathogenesis of many cardiovascular diseases, including atherosclerosis, diabetes and hypertension, as well as reperfusion injury. It has been proposed that eliminating these radicals from the plasma before they are taken up by peripheral tissues may improve the prognosis of such diseases [13].

AA is one of the water-soluble antioxidants in the defence system against reactive oxygen species (ROS) and protects against degenerative processes caused by oxidant stress [14]. There is a large body of epidemiological studies which have shown that populations with a high intake of antioxidants, including AA, have a lower rate of cardiovascular diseases than populations with a low intake [15]. We opted to use a 10-3 mol/l concentration of AA because the intracellular concentration of ascorbate in human tissue is roughly 10-3 mol/l [16,17] and a concentration lower than 0.5x10-3 mol/l was not effective as an antioxidant [18].

In this study, as expected, RA responses to vasoconstrictors (KCl and ET-1) were higher than ITA, due to its prominent musculature. On the other hand, AA groups in both arteries showed lower contractile responses to vasoconstrictors compared with control groups; however, these differences were not statistically significant. To clarify the effect of AA on the contractile response of RA to ET-1, we measured the concentration–response curve of RA to ET-1 (10-10–10-6 mol/l) without (n=5) and with AA (n=5) after a 72 h incubation period. The response was expressed as a percentage of contraction by KCl. The dose–response curve did not reach a plateau, even with a dose of 10-6 mol/l of ET-1, therefore we were not able to assess pEC50. However, both curves (control and AA) were lying on each other and reached a maximum response of 77.4±34.9% and 78.4±36.4%, respectively.

There was no effect of AA on the vasodilatation function of both arteries after 1 h incubation, possibly because the endothelium did not deteriorate significantly during that time, or because AA needs more time to exert its effect. However, AA was able to preserve the endothelium-dependent vasodilatation function of RA, but not ITA after 72 h incubation. It is clear that ITA differs from RA in the way it handles oxidant stress. It is likely that ITA has a stronger endogenous antioxidant defence system than RA, which might make it more resistant to endothelial damage and hence has a better performance as a conduit for myocardial revascularization [19]. This finding is in agreement with previous experience with statin effects on RA and ITA [6]. Although AA decreased the O2•- generated by both arteries after 72 h incubation, but its effect was not statistically significant. Therefore, it is possible that AA improves the vasodilatation function by preventing the oxidation of tetrahydrobiopterin (BH4), which act as a co-factor for eNOS during NO• production as suggested by d'Uscio et al. and Heller et al. [20,21].

In conclusion, the present study suggests that AA preserves the endothelium-dependent vasodilatation function of human RA. However, we are not advocating the use of AA in clinical practice, but this is a step in understanding the mechanism governing coronary grafts performance and the apparent differences in the clinical performance between different grafts.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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