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J Thorac Cardiovasc Surg 2008;136:673-680
© 2008 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

A new antispastic solution for arterial grafting: Nicardipine and nitroglycerin cocktail in preparation of internal thoracic and radial arteries for coronary surgery

Guo-Wei He, MD, PhD, DSca,b,c,*, Li Fan, MD, PhDa, Anthony Furnary, MDc, Qin Yang, MD, PhDb

a Nankai University Medical College and TEDA International Cardiovascular Hospital, Tianjin, China
b Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
c Providence Heart and Vascular Institute, Albert Starr Academic Center, Department of Surgery, Oregon Health and Science University, Portland, Oregon

Received for publication October 4, 2007; revisions received November 5, 2007; accepted for publication December 24, 2007.

* Address for reprints: Professor Guo-Wei He, MD, PhD, DSc, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China. (Email: gwhe{at}cuhk.edu.hk).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 
Objective: Antispastic protocols for arterial grafts are important in arterial grafting for coronary artery bypass grafting surgery. We designed a new nicardipine and nitroglycerin cocktail that is composed of a second-generation dihydropyridine calcium antagonist, nicardipine and nitroglycerin (30 µmol/L), and examined its effect in human internal thoracic and radial arteries.

Methods: Human internal thoracic (n = 86) and radial (n = 74) artery segments from 72 patients undergoing coronary artery bypass grafting were studied. Relaxation against 3 classic vasoconstrictors (potassium chloride, thromboxane A2 mimetic U46619, and {alpha}-adrenoceptor agonist norepinephrine) and prophylactic effect on contraction against these vasoconstrictors were examined. The effect of the nicardipine and nitroglycerin cocktail on the endothelial function in internal thoracic and radial arteries was studied in response to acetylcholine.

Results: Nicardipine and nitroglycerin induced almost full relaxation (92.2% ± 4.7% to 97.9% ± 1.0%, P < .001 in internal thoracic arteries and 95.4% ± 1.9% to 96.7% ± 3.3%, P < .001 in radial arteries, n = 6–8) against 3 vasoconstrictors with significant prophylactic effect on contraction (maximal contraction was depressed to 32.5% to 76.4%, P < .05 or P < .001, and EC50s were increased to 5 to 42-fold more, P < .01). After treatment with the nicardipine and nitroglycerin cocktail, the acetylcholine-induced relaxation was unchanged (P > .05).

Conclusion: The use of the nicardipine and nitroglycerin cocktail provides a new antispastic protocol that has rapid onset, full relaxation, and excellent prophylactic effect against all known mechanisms of vasospasm and maximally protects the endothelial and smooth muscle function of the internal thoracic and radial arteries. The cocktail is therefore expected to provide a new method in treating grafts in coronary artery bypass grafting with the best antispastic effect and protection of the graft.

Abbreviations and Acronyms Ach = acetylcholine; CABG = coronary artery bypass grafting; ITA = internal thoracic artery; K+ = potassium chloride; NE = norepinephrine; NG = nicardipine and nitroglycerin; NO = nitric oxide; NTG = nitroglycerin; RA = radial artery; SE = standard error; VG = verapamil and nitroglycerin


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 
The antispastic protocol for arterial grafts is important in arterial grafting for coronary artery bypass grafting (CABG) to maximally reduce vasospasm-related complications.1-4Go The prevention or relief of vasospasm in arterial grafts not only solves the vasospastic problem that reduces the perioperative graft spasm and complications related to it but also plays a role in the long-term patency because of the protective effect of the solution on the endothelium that is related to less surgical manipulation when the artery is relaxed.3,5Go

The antispastic protocol has been evolving since the 1980s. A number of protocols have been recommended.6-27Go In general, choosing a particular protocol depends on the availability of drugs and the preference of the surgeon. An ideal protocol should take into account the following. First, the drugs have to be effective in both relieving and preventing vasospasm. The former refers to the relaxing effect when the vessel is contracted, and the latter refers to preventing contraction by using the drug(s) beforehand. Second, such a protocol should be able to protect the vascular endothelium as much as possible because intact endothelium is a key structure in the prevention of platelet aggregation, thrombosis, intima proliferation, atherosclerosis, and the eventual occlusion of the vessel. Third, the relaxing effect, blockage of the relevant contractile receptors, and membrane potential changes should be temporary, lasting only during the perioperative period. The benefit of an arterial graft is that it is a living vessel, a "living conduit," with most receptor properties preserved, not a "dead fibrotic conduit." This means that the vessel should be able to contract and relax under various conditions. The contraction and relaxation actions are essential for every small to medium-sized artery in maintaining normal function. The rhythmic motion keeps the artery a living conduit that may be protected from intimal proliferation and atherosclerosis, and therefore will have a superior long-term patency. The best preservation of a vessel is to maintain it at physiologic condition with normal receptor properties. Finally, the ideal protocol should be ecumenically acceptable; this is particularly important in current health systems in many countries, particularly in developing countries.

We previously invented a VG (verapamil and nitroglycerin) solution composed of a calcium antagonist, verapamil, and a nitric oxide (NO) donor, glyceryl trinitrate (nitroglycerin [NTG]), for use in both arterial and venous grafting. Because verapamil is not available in all places and its bradycardia effect may prevent the simultaneous use of a beta-blocker, and because new generations of calcium antagonists have been developed, we designed the present study to investigate a new cocktail that is composed of a second-generation dihydropyridine calcium antagonist: nicardipine and NTG (NG). We tested this cocktail with regard to the above aspects and report the excellent effect of this solution on both human internal thoracic arteries (ITAs) and radial arteries (RAs).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Protocol
 Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 
General
Human ITA (n = 86) and RA (n = 74) segments were collected from 72 patients (58 men and 14 women with a mean age of 64.2 ± 0.8 years) undergoing CABG using these grafts. Approval to use discarded RA tissue was given by the institutional review board at St Vincent Hospital, Portland, Oregon. The surgeon or assistant received consent from each patient before the operation. The details of the method to collect and dissect the human arteries were previously described.1,11Go The arteries were cut into 3-mm–long rings and suspended on wires in organ baths.1,11Go

Organ-Bath Technique
A specially designed organ-bath technique was used for this study. The details of the technique have been published.3,28Go Briefly, each arterial ring was stretched up in progressive steps to determine the individual length-tension curve. A computer iterative fitting program (VESTAND 2.1, Yang-Hui He, Princeton University, NJ) was used to determine the exponential line, pressure, and internal diameter. When the transmural pressure on the rings reached 100 mm Hg, determined from their own length-tension curves, the stretch-up procedure was stopped and the rings were released to 90% of their internal circumference at 100 mm Hg. This degree of passive tension was then maintained throughout the experiment.

Because of the importance of endothelium on vascular tone, we intentionally preserved the endothelium by cautiously dissecting and mounting the rings.29,30Go


   Protocol
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 
Effects of Nicardipine and Nitroglycerin Solution
The effect of the NG solution was tested in 2 ways as follows.

Relaxation effect against 3 classic vasoconstrictors
These experiments were designed to investigate the effect of NG solution in relieving vasospasm developed with relation to depolarization of the cellular membrane potential (potassium chloride [K+]), thromboxane A2 (U46619), and {alpha}-adrenoceptors (norepinephrine [NE]).

After the normalization procedure, the vascular rings were equilibrated for at least 1 hour. One of the 3 vasoconstrictors (K+ 75 mmol/L, U46619 10 nM, or NE 10 µmol/L) was added to the organ bath. After the contraction reached a stable level, 30 µmol/L nicardipine and 30 µmol/L NTG were added. The relaxation time course was recorded. The force during relaxation was measured at 1-minute intervals and expressed as a percentage of the force during precontraction.

Prophylactic effect on contraction against three classic vasoconstrictors
To investigate the prophylactic effect of NG solution on contraction induced by 3 classic vasoconstrictors, 2 ITA or RA segments were taken from the same artery and allocated into 2 groups. One was used as control, and the other was used for pretreatment with NG solution. After equilibration for at least 60 minutes, the ITA (n = 8) or RA (n = 7) rings were treated with 30 µM NG for 30 minutes. Cumulative concentration-contraction curves were then established for K+ (5–100 mmol/L), U46619 (–10 log M to –6.5 log M), and NE (–8.5 to –5 log M).

Effect of Nicardipine and Nitroglycerin Solution on the Endothelial Function in Internal Thoracic and Radial Arteries
A clinically usable solution must have no harmful effect on the endothelium. We therefore tested the effect of NG solution on the endothelial function in ITAs and RAs. ITA or RA rings taken from the same patient were allocated into 2 groups. One was treated with NG solution for 30 minutes, and the other was used as control. The rings were normalized as mentioned above and then equilibrated for 60 minutes. Precontraction of the rings was induced by U46619. Cumulative concentration-relaxation curves to acetylcholine (ACh) (–10 to –6.5 log M) were established. At the maximal relaxation to ACh, 30 µM NTG was added if ACh did not induce full relaxation to demonstrate the integrity of the relaxing property.

Design of the Nicardipine and Nitroglycerin Cocktail
In the above protocol, we tested the effect of NG at a concentration of 30 µmol/L (–4.5 log M) on the human ITA and RA segments in the organ chamber. From previous studies,8,11,17,31Go this concentration was expected to have maximal or nearly maximal effect.

Nicardipine and Nitroglycerin Cocktail
The components of the clinical (NG) cocktail are as follows:

Nicardipine hydrochloride 5 mg
NTG 5 mg
8.4% NaHCO3 0.3 mL*
Normosol-R solution 300 ml

This cocktail gives a concentration of approximately 30 µmol/L (–4.5 log M) of nicardipine or 60 µmol/L (–4.3 log M) NTG in an isotonic solution of pH 7.1.

*The pH of NG (nicardipine hydrochloride 5 mg and NTG 5 mg) in Normosol-R solution (300 mL) without adding NaHCO3 is 6.6. When the amount of 8.4% NaHCO3 added is more than 0.3 mL, the solution becomes gradually turbid until pH = 7.4 with 8.4% NaHCO3 0.5 mL added. This, however, does not affect the antispastic effect as seen in the results of the present study because the effect of NG solution at the concentration of 30 µmol/L (–4.5 log M) was tested in the organ bath with a pH of 7.4 and slightly turbid-looking.

Onset of Nicardipine and Nitroglycerin Solution
A clinically useful solution for treating arterial grafts should have a rapid onset to relieve vasospasm as quickly as possible. To test the onset of the NG solution, we recorded the relaxation in 1-minute time intervals against all 3 vasoconstrictors.

Data Analysis
The relaxation of ITA and RA was expressed as a percentage of the vasoconstrictor-induced precontraction. The effective concentration of the constrictor (or dilator) agent that caused 50% of maximal contraction (or relaxation) was defined as EC50. The detailed methods have been published.1,28Go

All values were expressed as mean ± standard error. Statistical comparisons of cumulative contraction force and cumulative percentage of relaxation were performed by 2-way analysis of variance followed by Bonferroni's test. Unpaired t test or analysis of variance was used to test the statistical significance among different constrictors and dilators regarding EC50.

Materials
U46619 was a product of the Cayman Chemical Company (Ann Arbor, Mich). K+, nicardipine hydrochloride, and L-(-)-norepinephrine(+)-bitartrate salt monohydrate were purchased from Sigma-Aldrich Chemical Co (St Louis, Mo). NTG (50 mg/10 mL) was a product of Laboratories Inc. New York ACh was purchased from Sigma-Aldrich Chemical Co. Stock solutions of different concentrations of U46619 and ACh were kept frozen until required. Other reagents were regular chemical reagents from Sigma Chemical Co and stored at room temperature.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 
Resting Parameters of Internal Thoracic and Radial Arteries
The internal diameter of the vessels at an equivalent transmural pressure of 100 mm Hg (D100), determined from the normalization procedure, was 2.6 ± 0.8 mm in ITA and 2.9 ± 0.6 mm in RA segments. The transmural pressure 90% of D100 was 76.3 ± 0.6 mm Hg in ITA and 76.0 ± 0.5 mm Hg in RA (P = .8) segments. The resting force was 3.0 ± 0.1 g in ITA and 1.9 ± 0.1 g in RA (P < .001) segments.

Contraction Force in Internal Thoracic and Radial Arteries
In ITAs, the precontraction force was 1.1 ± 0.03 g to K+, 5.7 ± 0.4 g to U46619 (P < .001 vs K+), and 2.0 ± 0.3 to NE (P > .05 vs K+, P < .001, vs U46619). In RAs, the precontraction force was 1.2 ± 0.07 g to K+, 7.5 ± 0.9 g to U46619 (P < .001, vs K+), and 1.8 ± 0.2 to NE (P > .05 vs K+ and P < .001 vs U46619).

Effects of Nicardipine and Nitroglycerin Solution
Relaxation effect against 3 classic vasoconstrictors
NG at a concentration of 30 µmol/L caused almost full (>90%) relaxation in ITA rings precontracted with 10 nM U46619 (92.2% ± 4.7%, n = 8), 70 mmol/L K+ (93.9% ± 2.6%, n = 8), and 10 µM NE (97.9% ± 1.0%, n = 8) (P > .05) (Go Figure 1, A).


Figure 1
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  		Figure 1. Percentage of relaxation induced by nicardipine (30 µmol/L) and glycerol trinitrate (nitroglycerin, NTG 30 µmol/L) in ITA (A, n = 8) and RA (B, n = 6) rings precontracted by U46619 (10 nM), K+ (70 mmol/L), or NE (10 µM). Values are expressed as mean ± standard error (SE). P > .05 (one-way analysis of variance followed by Bonferroni's multiple comparison test). ITA, Internal thoracic artery; RA, radial artery; NE, norepinephrine; K+, potassium chloride.

 
NG at a concentration of 30 µmol/L induced almost full relaxation in RA rings (95.4% ± 1.9% of U46619 precontraction, 96.7% ± 3.3% of K+ precontraction, and 95.8% ± 1.6% of NE precontraction; n = 6 in each group) (Figure 1, B).

Onset of Nicardipine and Nitroglycerin Solution
The NG solution has a rapid onset of relaxation against all 3 vasoconstrictors, as shown in Go Figure 2. At 5 minutes, the relaxation reached 60.8% ± 6.5% against U46619, 55.6% ± 6.1% against K, and 92.6% ± 3.0% against NE in the ITA rings. Similarly, the relaxation reached 64.4% ± 7.3% against U46619, 63.4% ± 6.3% against K, and 75.1% ± 14.6% against NE in the RA rings. At 20 minutes, the relaxation reached submaximal (77%–96% in ITA rings and 76%–86% in RA rings) and lasted to the end of experiment (>120 minutes, Figure 2).


Figure 2
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  		Figure 2. Onset and time course of the relaxation induced by nicardipine (30 µmol/L) and glycerol trinitrate (nitroglycerin, NTG, 30 µmol/L) in ITA (A, n = 8) and RA (B, n = 6) rings precontracted by U46619 (10 nM), K+ (70 mmol/L), or NE (10 µM). Values are expressed as mean ± SE. Note that in the first 20 minutes, relaxation reached almost the maximal in both ITA and RA rings. NE, Norepinephrine; K+, potassium chloride.

 
Prophylactic Effect on Contraction Against Three Classic Vasoconstrictors (Depression of Contraction by Pretreatment with Nicardipine and Nitroglycerin)
Pretreatment with 30 µmol/L NG for 30 minutes significantly depressed the magnitude of the contraction induced by U46619 (Go Figure 3), K+ (Go Figure 4), and NE (Go Figure 5) in both human ITA (Figures 3–5, A) and RA rings (Figures 3–5, B).


Figure 3
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  		Figure 3. Mean concentration-contraction (g) curves for U46619 (–10 to –6.5 log M) in ITA (A, n = 8) and RA (B, n = 7) rings pretreated with or without (control) treatment of NG (nicardipine 30 µmol/L; NTG 30 µmol/L) for 30 minutes. Values are expressed as mean ± SE. ** P < .01, *** P < .001, compared with control. NG, Nicardipine and nitroglycerin.

 

Figure 4
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  		Figure 4. Mean concentration-contraction (g) curves for K+ (5–100 mmol/L) in ITA (A, n = 8) and RA (B, n = 7) rings pretreated with or without (control) treatment of NG (nicardipine 30 µmol/L; NTG 30 µmol/L) for 30 minutes. Values are expressed as mean ± SE. ** P < .01, *** P < .001, compared with control. NG, Nicardipine and nitroglycerin.

 

Figure 5
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  		Figure 5. Mean concentration- (mmol/L) contraction (g) curves for NE (–8.5 to –5 log M) in (A) ITA (n = 8) and (B) RA (n = 7) rings pretreated with or without (control) treatment of NG (nicardipine 30 µmol/L; NTG 30 µmol/L) for 30 minutes. Values are expressed as mean ± SE. ** P < .01, *** P < .001, compared with control. NG, Nicardipine and nitroglycerin.

 
Pretreatment of ITA and RA with NG also significantly desensitized the vessel to the 3 classic vasoconstrictors. The EC50 values for U46619-contracted ITA and RA rings incubated with NG were 7-fold (P < .001) and 5-fold (P < .01) higher than that of control. In addition, EC50 values of K+ were 6-fold (P < .01) higher than that of control in RA rings and 42-fold (P < .001) higher than that of NE in ITA rings. In addition, the maximal contraction force in treated groups was 76.4% (P < .05), 52.5% (P < .001), and 32.5% (P = .001) of the corresponding control in U46619, K+, and NE-contracted ITA rings and 69.2% (P < .01), 40.3% (P < .05), and 15.6% (P < .001) in RA rings.

Effect of Nicardipine and Nitroglycerin Solution on the Endothelial Function in Internal Thoracic and Radial Arteries
Cumulative concentration-relaxation curves for ACh were established in U46619-contracted ITA and RA rings incubated with or without 30 µmol/L NG (Figure E1.). There were no significant differences with regard to the maximal relaxation or the EC50 in ITAs or RAs (–7.53 ± 0.58 vs –7.19 ± 0.07 log M in ITAs and –7.93 ± 0.88 vs –7.68 ± 0.29 log M in RAs, P > .05).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
Conclusions
 Figure E1
 Figure E2
 References
 
The major findings of this study are as follows: 1) The combination of a second-generation dihydropyridine and NO donor (NTG) can be used for relieving vasospasm in the arterial grafts (both ITA and RA) in CABG. 2) This cocktail may also prevent vasospasm related to a number of vasoconstrictors, including depolarizing mechanism, thromboxane A2, and {alpha}-adrenoceptor–mediated vasospasm. 3) The cocktail maximally protects endothelial function in the arterial grafts.

Vasospasm Problems in Arterial Grafting
From both theoretic and practical aspects, arterial grafting is better than venous grafting. In fact, the patency rates of saphenous vein grafts in the early reports were unsatisfactory. The occlusion rate of saphenous vein grafts in the first year is 10% to 26%.32-34Go By 10 years, 50% of the grafts are occluded35,36Go and of the grafts still patent, 50% show marked atherosclerotic changes.34Go Although compared with 30 years ago, the patency of saphenous vein grafts has improved to 78% at 5 years, 60% at 10 years, and 50% at 15 years because of advances in venous grafting techniques,37Go it is still not comparable to arterial grafting. As a result, arterial grafting has been popular since the 1980s, and ITAs and RAs are most frequently used now.4,36,37Go On the other hand, because of the tendency of vasospasm development in arterial grafts that may cause mortality or morbidity, antispastic protocols became essential for arterial grafting. For ITAs, the use of vasodilator drugs is a routine practice.6,7,9,10,12,13,18,19,25,26Go For RAs, it was the use of calcium antagonists that made the revival of this graft after the initial abandonment,4Go and a number of antispastic protocols have been recommended for RA grafting ever since.11,16,17,20,21-24,27Go However, as to the best antispastic protocol, there is no unanimous opinion because of the variable availability of vasodilator drugs at different locations and the surgeon's preference. Further, the pharmaceutical development may also become a factor in the evolution of the antispastic protocol.

Cause of Vasospasm: Various Vasoconstrictors
We have systemically investigated the effect of various vasodilator drugs on arterial grafts regarding both the vasodilatory effect in established vasoconstriction and the prophylactic effect on vasoconstriction. These studies indicated that there is no single vasodilator drug that is effective against all vasoconstrictors.1,28,30,37-42Go This is because the real cause of vasospasm—the extreme form of vasoconstriction—is unknown, although it may be related to a number of causes.

In general, vasospasm could be the response of a vessel to many stimulants.40Go These stimulants may be physical (eg, mechanical stimulation or temperature changes) or pharmacologic (eg, nerve stimulation or vasoconstrictor substances). Exogenous and endogenous vasoconstrictors are particularly important for vasoconstriction and its extreme form, vasospasm.

There are many vasoconstrictor substances that are related to vasospasm, as we outlined previously.40Go In addition, arginine vasopressin is also a spasmogen for grafts.42Go When vasospasm occurs, it is often unknown which of the above vasoconstrictors is involved and to what degree. The interaction among the vasoconstrictors may also play a role in the mechanism of vasospasm.

In view of the complexity of the mechanism of vasospasm mentioned above, it is difficult to choose the "best" method to solve (relief or prevent) vasospasm. However, it is most likely that vasodilator substance(s) that are effective against all the above mechanisms would be the most reliable clinical method. {alpha}-adrenoceptor antagonists (eg, phentolamine and phenoxybenzamine) are only effective against {alpha}-adrenoceptor agonists but ineffective to any other receptor-mediated (eg, thromboxane A2) or membrane depolarization-mediated (eg, K+) contraction. Similarly, calcium antagonists are particularly effective in reversing or preventing membrane potential depolarizing agent potassium ion-mediated contraction. This is because calcium antagonists particularly inhibit voltage-dependent calcium channels, but they are relatively ineffective in {alpha}-adrenoceptor38Go or other receptors, such as thromboxane A2-mediated contraction. With regard to the clinically useful NO donor NTG and nitroprusside, they are particularly effective in reversing the contraction mediated by a number of receptor-mediated vasoconstrictors, such as {alpha}-adrenoceptor,1,43Go thromboxane A2,1Go angiotensin-II,44Go and the K+-mediated contraction. Further, we have demonstrated that vasodilators that are effective in relaxing contracted vessels may not be as effective in preventing vasoconstriction. This is particularly true for the NO donor NTG.1Go In contrast, calcium antagonists (including nicardipine) are particularly effective in preventing K+-mediated contraction in both the ITA1Go and RA.31Go These observations led us to believe that a combination of vasodilator drugs would be the best choice to prevent or relieve vasospasm.3,8,11,29Go We previously developed a cocktail composed of verapamil and NTG that has been demonstrated to be effective against all the above mechanisms. We demonstrated that among the 3 most important calcium antagonists, dihydropyridine nifedipine was the most potent. However, during that time (1980s), there were no intravenous dihydropyridine preparations available; therefore, verapamil was chosen for the cocktail because it was the next potent calcium antagonist. Verapamil had a good relaxation effect, better than diltiazem, and it was available as an intravenous preparation. The topical and intraluminal uses of VG solution have been proved effective in arterial grafting,3,8,11Go and even intracoronary artery injection through catheterization was reported by us17Go and others.45,46Go However, verapamil has a bradycardia effect, particularly when beta-blockers are used, and therefore simultaneous systemic use of verapamil and beta-blockers is usually contraindicated. Instead, nicardipine, as the second generation of dihydropyridine calcium antagonist, is used frequently during CABG for intravenous dripping as an antispastic protocol for arterial grafting.22Go We previously demonstrated that nicardipine has a satisfactory relaxation effect on arterial grafts such as ITA and RA against depolarizing mechanisms.31,47Go We therefore designed the present study to develop a new cocktail for an antispastic protocol.

The present study investigated the effect of this cocktail solution on the 2 major arterial grafts: ITA and RA. We therefore have good reason to believe that this cocktail would provide excellent antispastic effect in clinical use for arterial grafting. The solution is designed mainly for topical spray or intraluminal injection into arterial grafts because it is made of intravenous injection preparations, as we previously used for VG solution. In fact, the VG solution was used by others in catheterization for either coronary artery45Go or neuroendovascular surgery.46Go We anticipate that this new NG cocktail can also be used for these purposes. Figure E2 illustrates the antispastic mechanism of the NG cocktail that is effective against known vasoconstrictors.

Integrity of Function of Endothelium and Smooth Muscle
The key role of endothelium in maintaining vascular tone and preventing atherosclerosis has been well documented. Our results have clearly shown that the NG solution has no adverse effect on endothelium; in other words, the endothelium of ITAs and RAs is well preserved by the NG solution, demonstrated by normal endothelium-dependent relaxation to ACh after treatment with NG for more than 30 minutes (Figure E1).

Further, dihydropyridine derivatives have been demonstrated to relax blood vessels through endothelium-dependent mechanisms by increasing endothelial nitric oxide synthase expression in the endothelial cell, in addition to its calcium antagonism mechanism in the smooth muscle.48Go Therefore, the use of dihydropyridine derivatives may provide an additional benefit in the protection of endothelium-smooth muscle function in the grafts.

A common idea in antispastic protocols in CABG is to make the grafts fully relaxed with the expectation of no contraction at all. The ideal is that this may make the graft a "well-dilated" conduit to maximally carry blood flow to the coronary system. A typical example of this kind of antispastic protocol is using phenoxybenzamine,21Go which is a "permanent" inhibitor of {alpha}-adrenoceptor, meaning that once phenoxybenzamine is used, the {alpha}-adrenoceptor of the vessel is permanently deactivated. However, there are 2 concerns about this concept. First, as expected, the specific {alpha}-adrenoceptor inhibitor phenoxybenzamine has little or no effect against all other vasoconstrictors, as mentioned before. Second, we believe that in CABG, a graft should have its integrity regarding its receptors allocated in both endothelium and smooth muscle. A well-functioning graft should be able to relax and contract; it is the balance between contraction and relaxation that maintains the graft as a "living conduit." The normal contraction and relaxation of a vessel is a basic physiologic requirement to maintain its function. For example, when the saphenous vein graft is prepared by distention under high pressure, the structure of the wall of the vein is destroyed and the vein becomes a "dead conduit," which is the major reason for the low patency of the venous graft. We therefore designed our antispastic protocols to maximally maintain the integrity of the vessel, both the endothelium and smooth muscle. The new NG cocktail fulfills this requirement because it maximally protects the endothelium and the receptors of the smooth muscle.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
Figure E1
 Figure E2
 References
 
The use of second-generation dihydropyridine, nicardipine and NO donor NTG cocktail, provides a new antispastic protocol that has a rapid onset, full relaxation, and an excellent prophylactic effect against all known mechanisms of vasospasm and maximally protects the endothelial and smooth muscle function of the ITA and RA. The cocktail is therefore expected to provide a new method in treating grafts during CABG with the best antispastic effect and protection of the graft.


   Figure E1
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
 Figure E1
Figure E2
 References
 

Figure 1
Mean concentration- (log M) relaxation (%) curves for ACh (–10 to –6.5 log M) in U46619-contracted ITA (A, n = 6) and RA (B, n = 8) rings pretreated with or without NG (nicardipine 30 µmol/L; NTG 30 µmol/L) for 30 minutes. Values are expressed as mean ± SE. P > .05, compared with control (2-way analysis of variance followed by Bonferroni tests). NG, Nicardipine and nitroglycerin.



   Figure E2
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
References
 

Figure 2
Schema showing the mechanism of the antispastic effect of NG cocktail. Nicardipine, as a calcium channel blocker, is particularly effective against the mechanism of vasoconstriction through membrane depolarization that is voltage-dependent31Go but less effective in receptor-mediated mechanisms. In contrast, NTG, as an NO donor, is effective in all mechanisms and particularly effective in receptor-mediated mechanisms.1Go NG, Nicardipine and nitroglycerin; NTG, nitroglycerin; PGF 2{alpha}, prostaglandin F2{alpha}; 5-HT, 5-hydroxytryptamine.



   Acknowledgments
 
The technical assistance of the cardiac surgeons and nurses in the cardiovascular operating room (Kay Metsger, Victor Bayley, Wendy Buckham, Verna Hilburger, Donna DiModica, and Kate Donaldson) at St Vincent Hospital is gratefully acknowledged.


   Footnotes
 
This work was fully supported by Research Grants Council of the Hong Kong Special Administrative Region (Project No. CUHK4383/03M, CUHK4651/07M) and CUHK Direct Grant 2041164, 4450171, 4450169, 2041305, 4450231, China, and grants from Providence St Vincent Medical Foundation, Portland, Oregon.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Protocol
 Results
 Discussion
 Conclusions
 Figure E1
 Figure E2
 References
 

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