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Ann Thorac Surg 2000;69:513-519
© 2000 The Society of Thoracic Surgeons

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Original Articles

Platelets and prostacyclin in arterial bypasses: implications for coronary artery surgery

^a Division of Angiology, Institut de Recherches Servier, Suresnes, France

Address reprint requests to Dr Fabiani, Department of Cardiovascular Surgery, Hôpital Broussais, 96, rue Didot, 75014 Paris, France
e-mail: jnfabian{at}club-internet.fr

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. We investigated effects of platelets and prostacyclin formation in human internal mammary (IMA) and radial (RA) arteries.

Methods. IMA and RA segments were suspended in organ bath with increasing concentrations of platelets. Experiments were applied with and without ketanserin, a 5HT₂ receptor antagonist, or U3405, a TXA₂ receptor antagonist. The release of prostacyclin (PGI₂) was assessed by enzyme immunoassay in vessels without endothelium, before and after contraction with angiotensin (AT) I–II.

Results. In IMA and RA with endothelium, platelets caused contractions, significantly enhanced in arteries without endothelium. Contractions to platelets were higher in RA than in IMA. U3405 reduced the platelet induced contractions in RA but not in IMA. Ketanserin inhibited the platelet induced contractions in IMA and RA. The basal release of PGI₂ was more important in IMA than in RA. Addition of AT/I–II significantly reduced the release of PGI₂ in IMA but not in RA.

Conclusions. The RA responds more powerfully to platelets than IMA. Protective system with PGI₂ seems to be more powerless in RA than in IMA. This accentuates the importance of antispastic and antiplatelet drugs when arteries are used for coronary artery bypass surgery.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
The radial artery (RA) has been used in aortocoronary bypass surgery [1] but was abandoned because of a high incidence of narrowing and occlusion [2]. Finally, revival of the RA was reported with success by Acar and colleagues [3].

We have analyzed [4] some vasoreactive properties of the RA and compared them with those of the internal mammary artery (IMA). The results of this study showed that the contractions of the RA to agents such as 5-hydroxytryptamine and a thromboxane A2 mimetic, were higher than in the IMA, emphasizing the importance of antispastic drugs when the RA is used for coronary artery bypass surgery.

Yang and coworkers [5] have shown that aggregating platelets may contribute to the occurrence of coronary artery bypass graft occlusion. Platelets are the primary source of serotonin and thromboxane in the vascular system.

Moreover, it has been demonstrated that the IMA produces more prostacyclin (PGI₂) than the saphenous vein [6]. Because PGI₂ is a potent vasodilator and inhibitor of platelet function, these results provide a possible biochemical explanation for the clinically observed better patency rate of IMA grafts. Other studies [7–10] have shown that angiotensin (AT II) can interact with the synthesis or release of PGI₂. AT II is a potent endogenous vasoconstrictor and circulates at augmented levels during and after coronary artery bypass surgery [11, 12], but little is known about the effects of AT II on arterial bypass grafts.

Biologic characteristics of blood vessels include structure and function of endothelium and smooth muscle. Although it is unclear what characteristics influence long-term patency, those factors may be related to the ability of the vessel to release vasodilator and antiplatelet aggregation substances and to spastic characteristics.

The goals of the present study were to: (1) analyze the contractile effects of human washed platelets on the human IMA and RA; (2) characterize the responses of the IMA and RA to AT I and II; and (3) examine the release of PGI₂ before and after application of AT I and II.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Sampling of the blood vessels
The RA and IMA were obtained intraoperatively from 35 patients undergoing elective coronary artery bypass. The RA were removed together with their pedicle including two satellite veins and the surrounding fat tissue. The IMA were obtained from the left anterior thoracic wall. They were used in situ and not as free grafts. No intraluminal flushing was performed on these vessels. No bulldog clamps were applied. The vessels were left with blood circulating inside until the pericardium was opened and the lengths required to reach the target vessels were obtained. The conduit was then cut and the distal extra length was taken for experimental work. The investigated IMA segments were taken proximal to the epigastric bifurcation.

Most of the patients were taking oral anti-anginal medication (ß-adrenoceptor blockers, calcium channel blockers, and long-acting nitrates).

Arterial segments
Vessel segments obtained for this study were immediately placed in a container with oxygenated, physiologic salt solution (Krebs), maintained at 4°C, rinsed free of clotted blood, and then transferred to the laboratory. The mean time between harvesting and experimentation was 0.5 to 1 hour. The vessel was then pinned out in a dish coated with silicone rubber, and the surrounding adipous tissue was removed under magnification. The vessel was then cut into 3 mm long segments that were then suspended on wires in organ baths. The Krebs solution had the following composition (mM): NaCl 118.3, KCl 4.7, NaHCO₃ 25, MgSO₄ 1.2, KH₂PO₄ 1.2, CaCl₂ 2.5, glucose 11. The solution was aerated with a gas mixture of 95% O₂–5% CO₂ at 37°C.

Organ-bath technique
Artery ring segments were mounted on two stainless steel wires in a 20 ml water jacketed glass organ bath (Fig 1). The upper wire was attached to a force transducer (EMKA Technologies, Paris, France). The lower wire was fixed to a micrometer (Palmer Bioscience, Sheerness, UK). Diameters of ring segments were different according to the type of vessel. Therefore, a normalization procedure was performed to standardize baseline resting length. The full description and technical details of this normalization procedure have been published [4]. This method allows maximum tension development while standardizing resting tension independent from vessel diameter. Ring segments were allowed to relax for 90 minutes and were rinsed many times in the organ bath in oxygenated, normothermic Krebs solution, at this optimal resting length.

View larger version (20K): [in this window] [in a new window]   Fig 1. Organ bath apparatus with strain gauge transducer. (a) = 20 ml water jacketed glass organ bath; (b) = artery ring segment mounted on two stainless steel wires; (c) = lower wire fixed to a micrometer; (d) = upper wire attached to a force transducer.

Protocol for platelets
The functional integrity of the endothelium was assessed by precontracting the arterial rings with noradrenaline (10 µM) and then adding acetylcholine (1 µM) to the organ bath. The responses were expressed as a percentage of the contraction in response to noradrenaline (10 µM).

After washing, a cumulative dose-response curve was obtained by the addition of increasing concentrations of platelets (1 to 25 x 10⁶/mL). Platelets readily aggregate at the concentrations used in the organ bath. After extensive washing, the antagonist to be tested (ketanserin, a 5HT₂ receptor antagonist or Bay U3405, a TXA₂ receptor antagonist) was added to the organ bath of segments without endothelium and 15 minutes later, a second cumulative dose-response curve to the platelets was obtained.

AT I and II protocol
The endothelium was mechanically removed from the arteries: The absence of the endothelium was checked by precontracting the rings with noradrenaline (10 µM) and then adding acetylcholine (1 µM) to the organ bath. After washing, single contractions were induced by addition of AT I (1 µM) or AT II (1 µM), and the rings were rinsed repeatedly after application of the single contraction. After the third application, indomethacin (1 µM) was added to the organ bath and addition of AT I (1 µM) or AT II (1 µM) was applied.

Enzyme immunoassay
In a number of experiments, the release of PGI₂ by IMA and RA was assessed. At the beginning of each experiment, rings were incubated in 12 mL of Krebs solution and aliquots of 1 mL were taken after 20 minutes. After extensively washing, indomethacin (1 µM) was added to the organ bath and after an incubation time of 20 minutes, aliquots of 1 mL were taken. For some segments, AT I (1 µM) or AT II (1 µM) were added to the bath and aliquots were taken after an incubation period of 20 minutes.

The aliquots were stored at -20°C and the content of 6-keto-prostaglandin F₁, the stable metabolite of PGI2, was measured by enzyme immunoassay using 6-keto-prostaglandin F₁ kits (Cayman Chemical Company, Ann Arbor, MI).

Drugs
The following pharmacologic agents were used (dissolved in distilled water or in the solvent specified and further dilutions were made in distilled water): acetylcholine (Sigma; St Quentin Fallavier, France), AT I and II (Sigma), Bay U3405 (IDRS, Suresnes, France), indomethacin (Sigma, dissolved in DMSO), ketanserin (Janssen Pharmaceutica; Beerse, Belgium; dissolved in DMSO), and noradrenaline (Sigma).

Data analysis
Forces generated by the vessels were digitalized by a personal computer using the Moise 3 software package (EMKA Technologies). Several parameters were studied in order to characterize arterial segments reactivity: (1) contraction force normalized to noradrenaline and expressed as percent of noradrenaline contraction; (2) sensitivity, measured by effective drug concentration producing 50% of maximum contraction (EC50). EC50 was calculated from contraction response curves generated by a sigmoidal curve model for every ring segment. EC50 parameter was determined by nonlinear curve fitting regression with the simplex algorithm [21] using Michaelis and Menten equation (1913): E = (E_max x Cⁿ)/(ECⁿ ± Cⁿ) with E = contraction, E_max = maximum contraction, C = concentration, EC = EC50, and n = Hill’s coefficient.

Statistical significance
The data were reported as mean ± standard error of the mean. In all experiments, n was the number of segments. Data were evaluated for statistical significance by applying the unpaired t test. A probability value of less than 0.05 (p < 0.05) was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Contractions with platelets
In IMA rings with endothelium, aggregating platelets caused only weak contractions (19.6% ± 2.6%) (n = 19). More pronounced contractions were observed in rings without endothelium (41.1% ± 6.2%, p = 0.002) (n = 17) (Fig 2A). The responses were expressed as a percentage of the contraction obtained with noradrenaline (10 µM).

View larger version (26K): [in this window] [in a new window]   Fig 2. Human internal mammary artery. (A) Dose-response curve to platelets (1–25 x 106/mL); without endothelium (black), with endothelium (white). (B) Dose-response curve to platelets (1–25 x 106/mL) in segments without endothelium in the absence or presence of ketanserin (1 µM) and Bay U3405 (1 µM). The responses are expressed as a percent of the contraction obtained with noradrenaline (10 µM).

View larger version (25K): [in this window] [in a new window]   Fig 3. Human radial artery. (A) Dose-response curve to platelets (1–25 x 106/mL); without endothelium (black), with endothelium (white). (B) Dose-response curve to platelets (1–25 x 106/mL) in segments without endothelium in the absence or presence of ketanserin (1 µM) and Bay U3405 (1 µM). The responses are expressed as a percent of the contraction obtained with noradrenaline (10 µM).

For arteries without endothelium, the TXA₂ receptor antagonist Bay U3405 (1 µM) reduced the contractions induced by platelets in the RA (39.4% ± 1.0%, n = 3 segments, p = 0.03) but not in the IMA (24.0% ± 5.0%, n = 6). The 5HT₂ receptor antagonist ketanserin (1 µM) inhibited the platelet-induced contractions in both arteries (IMA: 13.7% ± 3.4%, n = 6, p = 0.02; RA: 28.9% ± 1.4%, n = 6, p = 0.01) (Figs 2B and 3B).

With regard to the sensitivity to platelets, there was no significant difference between the IMA and the RA with endothelium (IMA: 6.1 ± 1.2 x 10⁶ platelets/ml; RA: 4.9 ± 2.7 x 10⁶ platelets/ml) nor without endothelium (IMA: 6.2 ± 1.6 x 10⁶ platelets/ml; RA: 3.3 ± 0.8 x 10⁶ platelets/ml).

Contractions to AT I and II
A first application of AT I and II caused contraction of the IMA and the RA without endothelium. Subsequent additions of AT I and AT II caused contractions with a lower amplitude in the two vessels, even though the rings were rinsed repeatedly after each application (Angiotensin tachyphylaxis).

After the third trial, the responses were stabilized (IMA: AT I = 53.9% ± 18.1%, n = 10; AT II = 106.2% ± 35.7%, n = 6. RA: AT I = 81.5% ± 24.6%, n = 4; AT II = 118.0% ± 28.5%, n = 3). The responses are expressed as percentage of the contraction in response to noradrenaline (10 µM).

Indomethacin potentiated the responses of the IMA to AT I (157.8% ± 26.7%, n = 10, p = 0.005 and not significantly for AT II (155.3% ± 46.3%, n = 6). Indomethacin did not significantly alter the response to AT I (73.5% ± 26.7%, n = 4) nor to AT II (72.7% ± 28.4%, n = 3) in the RA (Figs 4 and 5).

View larger version (25K): [in this window] [in a new window]   Fig 4. Contractions of the internal mammary artery to angiotensin I and II with and without indomethacin. (AT I = angiotensin I (1 µM); AT II = angiotensin II (1 µM); INDO = indomethacin (1 µM).)

View larger version (17K): [in this window] [in a new window]   Fig 5. Contractions of the radial artery to angiotensin I and II with and without indomethacin. (AT I = angiotensin I (1 µM); AT II = angiotensin II (1 µM); INDO = indomethacin (1 µM).)

In the presence of indomethacin, the production of 6-keto-prostaglandin F₁ was reduced to 3.2 ± 0.3 pg/mg for the IMA (n = 19, p = 0.0001) and nonsignificantly reduced to 2.7 ± 0.6 pg/mg for the RA (n = 6).

Addition of AT I and AT II significantly reduced the release of PGI2 in the IMA (AT I: 4.0 ± 0.6 pg/mg, n = 15, p = 0.0001; AT II: 4.3 ± 0.3 pg/mg, n = 14, p = 0.0001) but not in the RA (AT I: 3.6 ± 0.5, n = 8; AT II: 4.2 ± 0.6, n = 6).

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Methodology
Organ-bath technique
The use of arterial ring segments suspended under isometric tension in the controlled environment of an organ bath provides a precise method to measure changes in circumferential force caused by vasoconstrictor or vasodilator agents [4].

Vessels
Surgical handling of coronary bypass vessels can profoundly affect their biologic properties. In this study, arterial segments were obtained before any storage or dilation. They were immediately placed in oxygenated Krebs, at 4°C. Time delay to the laboratory was 0.5 to 1 hour.

Patients
At least one of these cardiovascular risk factors was found in all patients of this study: hypercholesterolemia, diabetes, hypertension, and smoking. Bypass graft function and patency are known to be negatively influenced by cardiovascular risk factors.

Choice of the RA
The RA has proved to be an interesting and effective conduit for revascularization of the myocardium. The graft appears to be a reasonable alternative to other types of conduits to complement the left IMA [3].

Effects of platelets
In artery rings with endothelium, the contractions evoked by aggregating platelets are weaker than those noted in tissues without endothelium. Aggregating platelets release adenosine nucleotides which can induce endothelium-dependent relaxation in human arteries [13]. This mechanism must be mediated by release of nitric oxide [14] since L-N^G-monomethylarginine (L-NMMA)—an inhibitor of nitric oxide formation—inhibits relaxation induced by platelets [15]. The results obtained in these arteries confirm the importance of an intact endothelium which can prevent aggregation of platelets and vasospasm induced by platelet-derived vasoconstrictors.

In IMA and RA rings without endothelium, aggregating platelets induced an important contraction. This contraction was significantly greater in the RA. The difference in the response of the two vessels to platelets could be explained by the anatomic dissimilarities among the IMA and the RA [16]. In this study, the harvesting site of the IMA segments was proximal to the epigastric bifurcation. This is an important aspect because the harvesting site may be closely related to the content of the media in terms of smooth muscle cells or elastic lamellae. The media of the distal IMA has usually a high content of smooth muscle cells with 9 to 12 elastic lamellae in the media. The media of the superior epigastric artery is almost purely muscular. The RA is a muscular artery, the media consists mainly of smooth muscle cells. The stronger contraction of the RA to platelets may be the result of this greater content of smooth muscle cells in the arterial wall. In a previous study [4], we have demonstrated that the RA with or without endothelium had stronger contraction to serotonin and thromboxane A2 than the IMA, respectively, with or without endothelium. This may be another explanation for the stronger contraction of the RA to platelets in comparison with the IMA.

Although the RA contracts to platelets with a higher force than the IMA, there is no significant difference with regard to the sensitivity to platelets between the two arteries. Although sensitivity to aggregating platelets may be a factor in initiating spasm in these arteries, the RA does not appear to be more susceptible to platelet-induced vasospasm than the IMA. In the same way, we have found in a previous study that the RA and the IMA had an equal sensitivity to serotonin [4].

The experiments with ketanserin—a 5HT₂ receptor antagonist—and Bay U3405—a TXA₂ receptor antagonist—show that the contraction induced by platelets in the IMA is dominantly mediated by 5HT and may be also by TXA₂. However, the contraction induced by platelets in the radial artery is mediated by both 5HT and TXA₂.

Moreover, in the internal mammary and radial arteries, ketanserin and Bay U3405 reduced the platelet-induced contraction. Previous studies [17] have shown that the systematic use of low-dose aspirin results in a reduced platelet-induced contraction in coronary arteries, supporting the role of TXA₂ in this contraction.

As suggested by He and Yang [18], arterial grafts may be functionally classified as type I (somatic arteries), type II (splanchnic arteries), and type III (limb arteries). The types II and III are more prone to vasospasm. In this classification, the IMA belongs to the type I and the RA belongs to the type III. Our study supports this functional classification and provides scientific evidence that the RA is more reactive to platelet-derived vasoconstrictive substances (such as serotonin and thromboxane A₂).

This study thus confirms that either a 5HT₂ receptor antagonist or a TXA₂ receptor antagonist, or a combination of both, can be beneficial for the bypass grafts and help to prevent vasospasm.

PGI₂ production
PGI₂ is a potent vasodilator and inhibitor of platelet adherence and aggregation. Various areas of the vascular system are different in their ability to produce PGI₂. The arteries are able to produce more PGI₂ than veins in both endothelial and smooth muscle cells [19]. That may offer an explanation for the widely reported clinical results documenting the superior patency of internal mammary grafts in comparison with saphenous vein grafts. In our study, the PGI₂ basal production was greater in IMA than in RA.

AT I and AT II caused contractions of the internal mammary and radial arteries without endothelium. He and associates [20] have demonstrated that the RA has higher contractile response to both endothelin-1 and AT II than the IMA. The active octapeptide AT II is an endogenous vasoconstrictor. The plasma level of AT II has been measured to be elevated during and after cardiopulmonary bypass and presumed to be one of the factors responsible to postoperative hypertension [11, 12]. It could be one of the causes of vasospasm in arterial bypasses, especially when the endothelium is not intact.

Addition of indomethacin, a cyclooxygenase inhibitor, potentiated the responses to AT I and II in the IMA, indicating that the release of a vasodilator prostaglandin might modulate the effects of AT I and II.

Previous studies [7–10] have shown that AT II can interact with the synthesis or release of PGI₂. The mechanism involved in the activation of the eicosanoid system by AT I–II is far from clear. AT II stimulation of vascular smooth muscle results in a myriad of intracellular signals that interact to produce the final physiologic response of the cell. A study in rat aorta [8] has shown that protein kinase C mediates AT II-induced contractions and that the secondary release of both endothelin and PGI₂ during AT II-induced contractions is mediated, at least in part, by protein kinase C. Yilmaz and coworkers [9] have demonstrated that, among various areas of the vascular system, the main endothelial humoral factor which modulates the effect of AT II is EDRF or PGI₂. Nakagawa and associates [10] have shown that AT II stimulates prostaglandin release in blood vessels via activation of AT I receptors present in endothelium but also in vascular smooth muscle cells without necessary integrity of the endothelium.

In this study, we assessed the release of PGI₂ after application of AT I and AT II in vessels without endothelium. We also measured the release of PGI₂ after addition of indomethacin in vessels without endothelium. Logically, because indomethacin blocks the cyclooxygenase pathway, the release of PGI₂ was reduced in the presence of indomethacin, significantly in the IMA and not significantly in the RA. Similar results were obtained, after application of AT I and AT II in vessels without endothelium, indicating that these peptides might interfere with the biosynthesis of PGI₂ and, more precisely, might inhibit the production of PGI₂ by smooth muscle cells. AT I, and especially AT II, caused important contractions of the internal mammary and radial arteries without endothelium which do not implicate thromboxane A₂ but may result, at least in part, and especially for the IMA, from an inhibition of PGI₂ release by smooth muscle cells.

Conclusion
Levels of AT II are augmented during and after coronary artery bypass surgery, and endothelial function may be altered in the vessels of patients with cardiovascular risk factors. Implications are that important precautions should be taken before and after coronary surgery by treating the patients with antispastic drugs that inhibit the production and the effect of AT II such as ACE-inhibitors or calcium-channel blockers. Moreover, the increased response of the RA to platelets in comparison with the IMA accentuates the importance of antispastic and antiplatelet drugs for optimal prevention of spasm and occlusion when arterial conduits, especially the RA, are used for coronary artery bypass surgery.

	Acknowledgments

 
We thank Mrs Yvette Menant and Mrs Véronique Barou for their help with the experiments reported in this article.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chardigny, C. I. Articles by Verbeuren, T. J. Search for Related Content PubMed PubMed Citation Articles by Chardigny, C. I. Articles by Verbeuren, T. J.