Eur J Cardiothorac Surg 2008;34:536-541. doi:10.1016/j.ejcts.2008.05.050
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
A comparative study on in vitro and in vivo effects of topical vasodilators in human internal mammary, radial artery and great saphenous vein
Rongjing Dinga,b,c,*,
Wenhui Fenga,
Hongwei Lia,
Lei Wanga,
Dalian Lia,
Zhiguang Chenga,
Jianzhong Guoa,
Dayi Huc
a Heart Center of Beijing Friendship Hospital Affiliated Capital University of Medical Science, China
b Cardiology Department of Zhongshan Hospital Affiliated Dalian University, China
c Heart Center of Beijing University People's Hospital, China
Received 4 November 2007;
received in revised form 1 May 2008;
accepted 20 May 2008.
* Corresponding author. Tel.: +86 13552548612. (Email: drj2003{at}sina.com).
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Abstract
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Objective: As an important prognostic factor of coronary artery bypass grafting (CABG), graft vasospasm can be observed in all currently used graft conduits. Radial artery (RA) vasospasm is more prone to occur in comparisons with internal mammary artery (IMA) and great saphenous vein (GSV). There is still controversy about which antispasmodic agent is superior to different grafts, especially to RA conduits. The aim of this pilot study was to investigate the relaxation response of four topical vasodilators to different in vitro grafts and how these vasodilators affect the blood flow of the vessel in situ during RA harvesting. Materials and methods: Vasodilatory properties of diltiazem, nitroglycerin, urapidil and nicorandil were compared in matched patient-specific segments of RA, IMA and GSV harvested from 12 patients. The vasodilatory response of the RA to intraradial administration of nitroglycerin, diltiazem and urapidil was compared in vivo (n
= 10 per group) by assessing the free blood flow of RA. Results: (1) The maximal relaxations occurring with urapidil, nitroglycerin and nicorandil in IMA, RA and SGV were significantly greater than that with diltiazem. The reactivity of all three graft conduits showed similar relaxation with nitroglycerin or with diltiazem, but the relaxation with urapidil in RA showed greater than that of IMA and GSV, and RA and GSV showed greater relaxation with nicorandil than IMA. (2) A dose of 10–5
mol/l of nitroglycerin, urapidil and nicorandil but not diltiazem significantly inhibited the RA response to PE. (3) In vivo, urapidil and nitroglycerin significantly increased the RA blood flow, the potency of which was greater than that caused by diltiazem. Conclusions: (1) Comparing with nicorandil, urapidil and diltiazem, nitroglycerin caused a significant relaxation in all three graft vessels tested. (2) Nitroglycerin, nicorandil and urapidil were more effective in preventing RA spasm than diltiazem.
Key Words: Coronary artery bypass grafting • Vasospasm • Diltiazem • Nitroglycerin • Urapidil • Nicorandil
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1. Introduction
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As an important prognostic factor of coronary artery bypass grafting (CABG), the graft vasospasm elevates the incidence of angina and AMI during perioperation and intima hyperplasia of grafted vessels [1]. The vasospasm can occur in all the currently used graft conduits, internal mammary artery (IMA), radial artery (RA) and great saphenous vein (GSV). RA has more propensity for vasospasm, as documented by clinical evidence and by study of isolated arterial segments with the use of organ-chamber method [2–8]. Chardigny et al. showed that RA had a greater contractile response to noradrenalin, endothelin 1, angiotensin II and serotonin than IMA [7,8]. Many studies emphasize the necessity for pharmacologic intervention to prevent vasospasm when these conduits are employed [3,9–12]. The incidence of RA spasm decreased with the use of vasodilators, but an angiographic study revealed 1–9.7% of cases of RA spasm in the early and medium term after CABG [3,10–13]. How to choose the right drug to prevent vasospasm is still a matter of controversy.
We tried to compare the vasodilatory and antispasmodic properties of diltiazem, nitroglycerin, urapidil and nicorandil and RA, IMA and GSV relaxation responses to these systemic vasodilators. The in vitro response was assessed by the use of organ-chamber method and the in vivo response by measuring RA free blood flow.
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2. Material and methods
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The study was approved by the ethics committee of our university hospital; we obtained informed consent from the 42 patients enrolled in the study who were undergoing primary CABG; 30 for in vivo study and 12 for in vitro study.
Patients received preoperative cardiac treatment, such as β-blockers, calcium channel blockers, ACEI, nitrates and anticoagulants. Vasodilators were discontinued at 24 h preoperation, heparin 12 h preoperation and aspirin and clopidogrel 5 days preoperation. The β-blockers were continuously used. Poor ventricular function (EF < 40%) or abnormal hemodynamic features (BP < 90/60 mmHg), resting sinusal bradycardia (<55 beats/min), unstable angina, renal insufficiency (serum creatinine level >1.9 mg/dl) and glibenclamide/insulin treatment were the preoperative exclusion criteria. Hemodynamically unstable patients requiring infusion of the above drugs intraoperatively were also excluded.
For in vitro studies, the mean age of patients was 60 ± 8.33 years (range 46–73); seven males, five females, seven smokers, eight with hypertension, six diabetics and seven hyperlipidemia. Matched patient-specific segments of RA, IMA and GSV that would otherwise be discarded were obtained from the 12 patients. The vessels were harvested with the accompanying fat pedicle and placed in ice-cold physiologic salt Krebs-Henseleit (KH) solution (NaCl, 118 mmol/l; KCl, 4.75 mmol/l; CaCl2, 2.54 mmol/l; KH2PO4, 1.19 mmol/l; MgSO4, 1.19 mmol/l; NaHCO3, 25 mmol/l; glucose, 5.0 mmol/l; pH 7.35–7.45) and prepared freshly for studies of vascular function.
Each vessel was carefully dissected from their surrounding fat tissue and cut into one ring of 3 mm. A total of 2–3 rings were obtained from each vessel segment and relaxation studies conducted in different rings of the same vessel. The rings of IMA (n
= 12), RA (n
= 36) and GSV (n
= 12) were placed in organ chambers (37 °C) containing 10 ml KH solution, suspended between two tungsten stirrups for measurement of isometric tension as described [16] and constantly aerated with 95% O2/5% CO2. Each vessel was then progressively stretched in 2-g increments to its optimal resting tension to produce a maximal response to 80 mEq of KCl. Vessels were then allowed to equilibrate for 1 h before the administration of vasoactive drugs as described. Viability of vessels was tested by KCl and endothelial function by acetylcholine (Ach) level. Vessels with Ach <50% or contraction tone increase <1.0 g were discarded.
Relaxation studies were performed after vessels were contracted with 10–5
mol/l phenylephrine (PE, Sigma, St. Louis, MO). Vessel segments (IMA, RA, GSV) were then exposed to incremental doses (10–8 to 10–4
mol/l) of nitroglycerin (n
= 12) (Beijing Yimin Pharmaco), urapidil (n
= 12) (ALTAMA Pharmaco, Germany), diltiazem (n
= 12) (Tianjin Tianbian Pharmaco, China) and nicorandil (n
= 12) (Beijing Sihuan Kebao Pharmaco), and dose–response curves were recorded. After that, the ability to prevent RA spasm (five groups, six rings in each group) was assessed by dose–response curves to 10–8 to 10–5
mol/l PE in baths containing KH solution alone or 10–5
mol/l concentrations of nitroglycerin, diltiazem, urapidil or nicorandil.
For in vivo study, 30 patients were divided into three groups of 10 each for treatment with nitroglycerin, diltiazem or urapidil. Patients in the three vasodilator treatment groups did not differ in demographics, cardiac status, pre-existing disease or preoperative therapy (Table 1
). The distal end of the RA was dissected as a pedicle. Diathermy and hemoclips were used to control side branches. Each artery was allowed to bleed freely for 30 s (preoperative flow). Mean arterial pressure (MAP) and heart rate were simultaneously measured. Then patients received a bolus infusion of nitroglycerin, 200 µg [9]; diltiazem, 3 mg; or urapidil, 5 mg systemically to the distal end of the RA, and the distal end of the RA was occluded with a hemoclip 5 min after each dosing; then RA free blood flow was measured again for 30 s. The doses of diltiazem and urapidil were chosen from clinical practices and those of all three drugs chosen not to cause abnormal hemodynamic features. Hemodynamic measurements taken at the time were defined as postoperative measurement.
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3. Statistical analysis
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SPSS for Windows (version 11.5) was used for statistical analysis. Data are mean ± SD for continuous variables and number of occurrences for non-continuous variables. Vessel relaxation is expressed as percentage reduction in tension induced by PE. The median effective dose (EC50) represents the drug concentration of producing 50% maximal relaxation/contraction. The maximal relaxation/contraction as appropriate (E
max) and EC50 were calculated as described [17]. One-way ANOVA and post-hoc analysis or chi-square and paired t-test analysis were used as appropriate to compare differences of in vitro dose–response for nitroglycerin, urapidil, nicorandil and diltiazem and in preoperative patient data and in vivo. EC50 and the relaxation between two drugs were compared by one-way ANOVA and post-hoc analysis. A p value <0.05 was considered significant.
‘Sensitivity’, measured by the EC50 value, is used throughout this article to describe the location of the concentration–contraction curve. ‘Reactivity’ (E
max), measured as the maximal developed tension (g), describes the range of responses.
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4. Results
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4.1 Relaxation of vessels with urapidil, nitroglycerin, nicorandil and diltiazem
E
max was significantly greater with urapidil, nitroglycerin and nicorandil in RA, IMA and SGV as compared with diltiazem. There was no significant difference in E
max with urapidil, nitroglycerin and nicorandil in RA, IMA and SGV (see Fig. 1
).
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Fig. 1. Relaxation with vasodilators in IMA (A), RA (B) and GSV (C), 12 rings for urapidil, nitroglycerin, nicorandil and diltiazem, respectively and contracted with 10–5
mol/l PE. Relaxation was recorded in response to the indicated doses of urapidil, nitroglycerin, nicorandil and diltiazem as described in Table 3. Data are mean ± SD%. (*) Significant effects are shown in bold. *p
< 0.05.
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Comparing the sensitivity to vasodilators of RA, IMA and GSV, the sensitivity of IMA to nitroglycerin was greater than that to urapidil and nicorandil (p
= 0.028 and p
= 0.035, respectively), all were greater than that to diltiazem (p
= 0.023, p
= 0.004 and p
= 0.034, respectively). The sensitivity of RA and GSV was greater to nitroglycerin and nicorandil than that to urapidil (RA: p
= 0.005 and p
= 0.012; GSV: p
= 0.011 and p
= 0.023, respectively), and was greater than that to diltiazem (RA: p
= 0.002 and p
= 0.001; GSV: p
= 0.006 and p
= 0.009, respectively). The sensitivity of RA and GSV to urapidil was greater than that to diltiazem (p
= 0.033 and p
= 0.019, respectively) (Table 2
).
Comparing the reactivity to vasodilators of RA, IMA and GSV, the reactivity to urapidil of RA was superior to that of IMA and both were superior to that of GSV (RA vs IMA: p
= 0.023; IMA vs GSV: p
< 0.001; RA vs GSV: p
< 0.001). The reactivity to nicorandil of RA was similar to that of GSV and superior to that of IMA (RA vs GSV: p
= 0.823; RA vs IMA: p
= 0.034). Nitroglycerin showed maximal relaxation to all RA, IMA, and GSV and diltiazem showed minimum relaxation to all RA, IMA and GSV (Table 3
).
4.2 In vitro prevention of RA spasm
PE increased RA tone with an EC50 of 2.99 ± 0.45 µmol/l. A dose of 10–5mol/l nitroglycerin, urapidil and nicorandil significantly inhibited the RA response to PE [EC50 5.60 ± 0.53 µmol/l (p
< 0.001), 5.40 ± 0.44 µmol/l (p
< 0.001), 5.20 ± 0.40 µmol/l (p
< 0.001), respectively] but not diltiazem [EC50 3.01 ± 0.44 µmol/l (p
= 0.927)] (see Fig. 2
).
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Fig. 2. Prevention of RA vasospasm. The EC50 of the vasoconstrictor response to PE was significantly higher for nitroglycerin, urapidil and nicorandil. The data are obtained from six patients and expressed as mean ± SEM and *p
< 0.001 vs control. nitro: nitroglycerin, dil: diltiazem, ura: urapidil, nico: nicorandil.
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4.3 In vivo radial vasodilation
Because isolated vessels may not completely reflect events in vivo, RA vasodilatory response to intraradial nitroglycerin, urapidil and diltiazem was compared in vivo by measuring free flow of RA. Change in RA free blood flow at pre- and post-intervention differed significantly with urapidil and nitroglycerin treatment (p
= 0.042 and p
< 0.001, respectively) but not diltiazem (p
= 0.759). Diltiazem also produced less increment in free flow than did urapidil and nitroglycerin (p
= 0.042). The mean values of heart rate and MAP did not differ significantly among groups during the RA flow measurements (p
> 0.05) (Table 4
).
Neither systemic vasopressor nor any other vasodilator was administered during the study period. The researchers found no adverse reactions such as hypotension (<60 mmHg MAP), bradycardia (<55 beats/min) or heart blockage necessitating pharmacologic treatment or temporary pacing during the study period.
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5. Discussion
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The data presented in this study demonstrated that the three coronary bypass conduits have significantly greater in vitro maximal relaxation with nitroglycerin, urapidil and nicorandil than with diltiazem. Comparing to diltiazem, urapidil and nicorandil, nitroglycerin caused a similar significant relaxation in all three graft vessels. Our in vitro observations revealed similar results. Administration of nitroglycerin or urapidil in RA of CABG patients induced a significantly greater increment in RA free blood flow than did diltiazem. It was concluded that nitroglycerin can be used in preventing all three graft vasospasms and nitroglycerin, nicorandil and urapidil were more effective in preventing RA spasm than diltiazem.
Clinical practice has revealed the benefit of antispasmodic agents, diltiazem or nitroglycerin selected by most surgeons to prevent vasospasm [9–12]. However, Moran et al. randomized 115 patients receiving RA to diltiazem, 180 mg QD for 1 year or no treatment. Angiography at 1 year showed no difference and there were no clinical differences in symptoms or complications at 30 months follow-up [13]. Gaudino et al. [14] randomized 100 consecutive patients receiving RA grafts to diltiazem or no therapy. All patients were evaluated clinically and with TI201 myocardial scintography but no difference was found. In addition, 83 underwent angiography. Patency rate was over 95% in both groups and there was no difference between the groups. Twelve patients had assessment of the vasospastic response of RA to serotonin. Diltiazem did not attenuate this response. Our finding showed that the three coronary bypass conduits were significantly greater in vitro maximal relaxation with nitroglycerin, urapidil and nicorandil than with diltiazem as compared with other reports [15,16], also in vitro maximal relaxation with urapidil and nicorandil were significantly greater than with diltiazem. In the in vivo study, we came to the same conclusion that nitroglycerin and urapidil were more effective in free flow increments than diltiazem and that the dosage of three drugs in our study caused no adverse effect. The result of our study confirmed the conclusions in several clinical studies referred above. It was speculated that diltiazem might not be necessary for the prevention of vasospasm. One study demonstrated that a vasoconstrictor mediating increase in blood pressure actually increased blood flow in RA but was not dependent upon vasodilator [17]. Our in vivo study found that the blood flow significantly increased in nitroglycerin and urapidil group while the blood pressure in different groups was similar, showing that vasodilator is still important in treating vasospasm.
Our study also showed that nitroglycerin caused a similarly more significant relaxation in all three graft vessels, but urapidil and nicorandil caused significantly greater relaxation in RA than in IMA. It indicated that nitroglycerin can cause full relaxation to all three conduits but urapidil and nicorandil only mediates full relaxation to RA. Therefore only nitroglycerin can be an overall antispasmodic agent. Some studies showed that nitrates can only be used as an effective antispasmodic drug, not as a preventive drug because of the development of tolerance. We found that nitroglycerin was more effective in preventing PE-induced RA spasm than diltiazem in comparison with another report showing nitroglycerin was more effective in preventing U46619-induced RA spasm than diltiazem [15]. Our result was in accordance with that of Nisanoglu et al. [18], which was that the application of nitroglycerin can effectively prevent perioperative spasm of RA in CABG patients.
Previous studies found that the vasodilatory response of IMA or RA precontracted with PE to non-selective 
-acceptor blockers such as tolazoline, phenoxybenzamine and phentolamine to be great, but the use of -receptor blockers was limited to affecting such systemic hemodynamic conditions as hypotension and increased heart rate. With its vasodilative effect, urapidil is a selective 1-receptor blocker and inhibitor of 5-HTA release. It is mainly used to lower blood pressure and treat heart failure. We found that the relaxation of RA with urapidil was similar to that of nitroglycerin and nicorandil but greater than that of diltiazem. The relaxation response with urapidil in RA was superior to that in IMA and GSV. In addition, the free flow increment in RA with urapidil treatment was the same as that with nitroglycerin, even at a low dose of 5 mg and was superior to that with diltiazem. Therefore urapidil can be a new selective antispasmodic drug to RA, especially in CABG patients with heart dysfunction.
One study documented the increased potency of ATP-dependent potassium-channel openers in RA as compared with that in IMA [19]. Differences in the density of KATP channels in RA and IMA could contribute to the different sensitivity of radial and mammary arteries to potassium-channel-opening drugs; alternatively the subtype of KATP channel could differ between the vessels. In our study, comparing with the other three vasodilators, the effect of nicorandil on relaxation in RA was similar to that of nitroglycerin but greater than that of urapidil and diltiazem so that nicorandil can be a better selective vasodilation in RA.
This study strongly supports the continuous use of nitroglycerin in revascularization surgery to reduce the incidence of spasm with CABG. Other classes of drugs, such as urapidil and nicorandil, may be more effective than diltiazem in decreasing RA spasm due to receptor activation such as noradrenalin.
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Acknowledgments
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We thank Professor Liu Qigui in Dalian Medical University who helped with statistics and Professor Tang Zaosu in Beijing University who revised the paper.
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References
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Abstract
1. Introduction
