Ann Thorac Surg 1998;65:1621-1624
© 1998 The Society of Thoracic Surgeons
Original articles: cardiovascular
Atrial Natriuretic Peptide-Induced Release of Cyclic Guanosine Monophosphate by Coronary Bypass Grafts
Johannes Bonatti, MDa,
Wolfgang Dichtl, MDa,
Erika A. Dworzak, MDa,
Herwig Antretter, MDa,
Felix Unger, MDa,
Bernd Puschendorf, MDa,
Otto E. Dapunt, MDa
a Division of Cardiac Surgery, University Clinic of Surgery, and Institute of Clinical Chemistry and Biochemistry, Innsbruck, Austria
Accepted for publication January 20, 1998.
Address reprint requests to Dr Bonatti, Division of Cardiac Surgery, University Clinic of Surgery, Anichstrasse 35, A-6020 Innsbruck, Austria
e-mail: (johannes.o.bonatti{at}uibk.ac.at)
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Abstract
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Background. Superior long-term patency rates of the internal mammary artery (IMA) versus saphenous vein (SV) after coronary artery bypass grafting are well documented. Higher production rates of vasodilating and platelet-inhibiting mediators (prostacyclin and nitric oxide) by the IMA seem to have a major impact on its long-term durability and resistance to coronary artery graft disease. For the right gastroepiploic artery (RGEA) marked release of protective mediators is reported as well. The vasodilating effect of cyclic guanosine monophosphate (cGMP) released after stimulation by atrial natriuretic peptide might serve as another graft protective system. The aim of the present study was to determine cGMP release by IMA, RGEA, and SV after atrial natriuretic peptide challenge.
Methods. Samples of human IMA (n = 19), RGEA (n = 7), and SV (n = 18) discarded during coronary artery bypass grafting were stimulated with 10-6 mol/L atrial natriuretic peptide after a resting phase in nutrient me-dium. Release of cGMP was determined by 125-iodide radioimmunoassay.
Results. Basal cGMP production rates of the IMA (759.9 ± 277.0 fmol/cm2) and RGEA (739.9 ± 186.0 fmol/cm2) were higher than production rates of SV (281.2 ± 64.0 fmol/cm2). Application of atrial natriuretic peptide led to a statistically significant increase of cGMP release in IMA grafts (1,939.3 ± 778.0 fmol/cm2), whereas RGEA (618.4 ± 141.3 fmol/cm2) and SV (221.7 ± 64.5 fmol/cm2) remained at basal levels (p < 0.05).
Conclusions. From these data we conclude that the IMA in comparison with the RGEA and SV produces more extracellular cGMP when stimulated by atrial natriuretic peptide. This effect might support the cGMP-mediated protective properties of nitric oxide and could underline the extraordinary suitability of the IMA as a bypass conduit.
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Introduction
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Superior long-term patency rates of the internal mammary artery (IMA) versus saphenous vein (SV) grafts after coronary artery bypass grafting are well documented in the literature [1]. One reason that is thought to be responsible for these better patency rates is the increased production of the vasodilating and platelet-inhibiting mediators prostacyclin and nitric oxide by IMA endothelial cells [2, 3]. For the right gastroepiploic artery (RGEA), which has also been used as a coronary artery bypass grafting conduit with promising short- and intermediate-term results, [4] marked release of protective mediators is reported as well [5].
The vasodilating effect of atrial natriuretic peptide (ANP) is an extensively described pathophysiologic mechanism that seems to serve as an organ-protective system in stress situations [6, 7]. Vasodilation caused by ANP is reported to be mediated by cyclic guanosine monophosphate (cGMP), which is generated by a cell membrane-bound guanylate cyclase and secreted into the vessel lumen. An inhibiting effect of ANP on norepinephrine-induced contractions of the IMA has been shown in organ bath experiments [8]. Direct ANP-induced release of cGMP by the IMA and SV grafts, as well as the reactivity of the RGEA to ANP have been investigated on endothelially denuded samples of these vessels [9, 10]. The aim of the present study was to determine the extracellular release of cGMP by intact portions of IMA, SV, and RGEA after stimulation by ANP.
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Material and methods
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Samples
Saphenous veins, IMA, and RGEA were obtained intraoperatively from patients undergoing coronary artery bypass grafting. The IMA (n = 19) and RGEA (n = 7) were both dissected in a broad pedicle from the left or right anterior thoracic wall and from the omentum during coronary artery bypass grafting. The distal portions of the vessels were used for laboratory analysis and care was taken not to damage them. Pieces of SV (n = 18) were excised after typical harvesting and preparation. The study protocol was approved by the institutional committee of medical ethics and written informed consent was obtained from each patient. Specimens were transported in cold HEPES medium (DEM-F-12-(HAM) 1:1 with HEPES 15 mmol without L-glutamine; Biological Industries, Kibbuz Beit Haemek, Israel). Transport times were kept as short as possible and were shorter than 60 minutes in all patients. After cleaning the vessels from adherent tissue they were opened longitudinally to expose the endothelium and then measured and weighed. The specimens were again stored in HEPES medium and incubated with air and carbon dioxide in a 95%/5% ratio at 37°C. Aliquots of 250 µL were taken at 15 and 30 minutes. After this incubation period of 30 minutes a 10-6 mol/L solution of ANP (ANP Penninsula) was added and 250 µL of the bathing medium was removed after 20 and 60 minutes, frozen, and stored at -20°C until determination of cGMP.
Determination of cGMP
Concentrations of cGMP were determined using a 125I radioimmunoassay (Amersham International, Buckinghamshire, England). After thawing and acetylation with a solution of acetanhydrid and thiethylamine, aliquots were incubated with antiserum and 125I-marked cGMP. After an incubation period of 24 hours at 4°C, separation of unbound antibodies was performed using antiimmunoglobulin G antibodies and samples were analyzed by gamma counter.
Statistical analysis
Results are expressed as mean value ± standard error of the mean. Analysis of variance for repeated measures was performed to determine time-dependent differences of cGMP release within and between grafts. A p value of less than 0.05 was regarded as statistically significant. Statistical calculations were done on SPSS for Windows.
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Results
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Basal release of cGMP by saphenous vein was 201.4 ± 55.0 fmol/cm2 after 15 minutes and 281.2 ± 64.0 fmol/cm2 after 30 minutes. After stimulation with ANP, cGMP levels in the medium were 221.7 ± 64.5 fmol/cm2 after 20 minutes and 276.8 ± 64.4 fmol/cm2 after 60 minutes. Unstimulated cGMP production by the RGEA reached 739.9 ± 186.0 fmol/cm2 after 15 minutes and 649.6 ± 141.2 fmol/cm2 after 30 minutes. Stimulated release was 618.4 ± 141.3 fmol/cm2 after 20 minutes and 632.8 ± 151.6 fmol/cm2 after 60 minutes. Internal mammary artery specimens showed a basal cGMP release of 759.9 ± 277.0 fmol/cm2 after 15 minutes and 637.1 ± 187.3 fmol/cm2 after 30 minutes. Atrial natriuretic peptide-stimulated concentrations were 1,939.3 ± 778.0 fmol/cm2 after 20 minutes and 1,929.6 ± 665.1 fmol/cm2 after 60 minutes. The analysis of variance for repeated measures revealed a p value of 0.018 for within graft effects and a p value of 0.049 for between graft effects. These results are depicted in Figure 1.
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Fig 1. Basal cyclic guanosine monophosphate (cyclic GMP) production rates, indicated as fmol/cm2 per time unit, of the internal mammary artery (IMA) and right gastroepiploic artery (RGEA) were higher than production rates of saphenous vein (SV). Atrial natriuretic peptide (ANP) stimulation led to a statistically significant increase of cyclic guanosine monophosphate release in internal mammary artery grafts, whereas right gastroepiploic artery and saphenous vein remained at basal levels (p = 0.018 for within-graft effects, p = 0.049 for between-graft effects by analysis of variance for repeated measures).
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Comment
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Coronary artery graft disease, which may lead to graft stenosis or occlusion, has been described as a special pathologic entity [11] and arterial grafts are apparently less prone to development of the disease than veins. Vasodilation, platelet inhibition, and neutralization of oxygen-free radicals by locally produced mediators seems to be a major factor contributing to the excellent patency rates of the IMA. Two major systems, the prostacyclin system and the nitric oxide/endothelium-derived relaxing factor system, which after activation of both systems, lead to vasodilation and platelet inhibition have been described previously. Increased prostacyclin production by the IMA versus the SV was reported by Subramanian and associates [3] and Chaikhouni and coworkers [12]; similar production rates of prostacyclin by the RGEA were demonstrated by Oku and colleagues [13]. Increased endothelium-dependent relaxation of the IMA in comparison to the SV was shown in contraction/relaxation experiments by Lüscher and associates [2], the corresponding agent proved to be nitric oxide. This nitric oxide-mediated mechanism was demonstrated for the RGEA as well [14].
Atrial natriuretic peptide is secreted by right atrial myocytes and causes diuresis, excretion of sodium, and hypotension [15]. A marked vasodilating effect has been demonstrated [16]. This effect is mediated by cGMP, which is synthesized by a cell membrane-bound guanylate cyclase.
Increased blood levels of ANP have been shown for a variety of cardiac dysfunctions and diseases [17] and in the period after cardiopulmonary bypass [18]. A reduction of norepinephrine-induced contractions of the IMA after application of ANP has been demonstrated previously [8]. In the cited study SV, in comparison with the IMA, showed increased norepinephrine-induced contractions after application of ANP, an effect that was potentiated after removal of endothelium. A recent article on the influence of ANP and C-type natriuretic peptide on intracellular cGMP production of coronary bypass grafts [9] showed that the IMA and SV express both forms of natriuretic peptide receptor, but that ANP reacts predominantly on the IMA, whereas C-type natriuretic peptide has more influence on SV. This is in accordance with our results. In another recent study by Ikeda and colleagues [10] ANP stimulated cGMP production in endothelially denuded samples of IMA and RGEA more than in such samples of SV. This seems to be contrary to our results, but the intention of our study was to evaluate extracellular cGMP release, which was surprisingly higher in IMA than in the RGEA.
The fact that in our study basal cGMP release by SVs was significantly lower than by IMA and RGEA was not surprising as it perfectly fits the needs of arteries for prevention of undesired contraction. Stimulation by ANP caused an approximately threefold increase of cGMP release in the IMA, whereas the RGEA and SV remained at basal cGMP levels.
Different biochemical reactions of RGEA and IMA have been reported [19, 20] and clinically a marked trend toward development of spasm has been observed by surgeons using the RGEA as a coronary bypass graft [21]. In our opinion the differences between IMA and RGEA concerning reaction to ANP might be explained by different physiologic tasks of the two vessels. The IMA as a nutrient vessel of the thoracic wall and the diaphragm requires vasodilation during sympathetic activity and stress, the RGEA as a nutrient vessel of the stomach should dilate in parasympathetic state and digestion. According to clinical investigations increased flow of RGEA bypass grafts after food ingestion has been demonstrated [22] and differences in reactivity of the RGEA to histamine, which acts as a gastrointestinal mediator, were shown as well [14].
From the above data we conclude that ANP challenge, which occurs not only during the period after cardiopulmonary bypass, but might also be faced in the immediate postoperative and long-term after coronary artery bypass grafting leads to marked release of cGMP in IMA grafts. The fact that the IMA is equipped with a protective cGMP system that can be stimulated by ANP might further underline its extraordinary suitability as a coronary artery bypass graft.
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Acknowledgments
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This study was in part sponsored by the Österreichische Nationalbank Projekt no. 4322.
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References
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- Loop F.D., Lytle B.W., Cosgrove D.M., et al. Influence of the internal-mammary-artery graft on 10-year survival and other cardiac events. N Engl J Med 1986;314:1-6.[Abstract]
- Luscher T.F., Diederich D., Siebenmann R., et al. Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med 1988;319:462-467.[Abstract]
- Subramanian V.A., Hernandez Y., Tack-Goldman K., Grabowski E.F., Weksler B.B. Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts. Surgery 1986;100:376-383.[Medline]
- Grandjean J.G., Boonstra P.W., den Heyer P., Ebels T. Arterial revascularization with the right gastroepiploic artery and internal mammary arteries in 300 patients. J Thorac Cardiovasc Surg 1994;107:1309-1315.[Abstract/Free Full Text]
- O’Neil G.S., Chester A.H., Allen S.P., et al. Endothelial function of human gastroepiploic artery. Implications for its use as a bypass graft. J Thorac Cardiovasc Surg 1991;102:561-565.[Abstract]
- Espiner E.A., Nicholls M.G., Yandle T.G., et al. Studies on the secretion, metabolism and action of atrial natriuretic peptide in man. J Hypertens 1986;4(Suppl):85-91.[Medline]
- Petzl D.H., Hartter E., Osterode W., Bohm H., Woloszczuk W. Atrial natriuretic peptide release due to physical exercise in healthy persons and in cardiac patients. Klin Wochenschr 1987;65:194-196.[Medline]
- Aardal S., Helle K.B., Svendsen E. In vitro responses to atrial natriuretic polypeptide in human vessels commonly used as aortocoronary bypass grafts. Scand J Thorac Cardiovasc Surg 1992;26:135-141.[Medline]
- Zhang L.M., Castresana M.R., McDonald M.H., Johnson J.H., Newman W.H. Response of human artery, vein, and cultured smooth muscle cells to atrial and C-type natriuretic peptides. Crit Care Med 1996;24:306-310.[Medline]
- Ikeda T., Itoh H., Komatsu Y., et al. Natriuretic peptide receptors in human artery and vein and rabbit vein graft. Hypertension 1996;27:833-837.[Abstract/Free Full Text]
- Yang Z., Oemar B., Luscher T.F. Mechanism of coronary bypass graft disease. Schweiz Med Wochenschr 1993;123:422-427.[Medline]
- Chaikhouni A., Crawford F.A., Kochel P.J., Olanoff L.S., Halushka P.V. Human internal mammary artery produces more prostacyclin than saphenous vein. J Thorac Cardiovasc Surg 1986;92:88-91.[Abstract]
- Oku T., Yamane S., Suma H., et al. Comparison of prostacyclin production of human gastroepiploic artery and saphenous vein. Ann Thorac Surg 1990;49:767-770.[Abstract]
- Ochiai M., Ohno M., Taguchi J., et al. Responses of human gastroepiploic arteries to vasoactive substances: comparison with responses of internal mammary arteries and saphenous veins. J Thorac Cardiovasc Surg 1992;104:453-458.[Abstract]
- Rosenzweig A., Seidman C.E. Atrial natriuretic factor and related peptide hormones. Annu Rev Biochem 1991;60:229-255.[Medline]
- Wei C.M., Kim C.H., Khraibi A.A., Miller V.M., Burnett J.C., Jr, Buhler F.R. Atrial natriuretic peptide and C-type natriuretic peptide in spontaneously hypertensive rats and their vasorelaxing actions in vitro. Hypertension 1987;117:1930-1937.
- Vorderwinkler K.P., Artner-Dworzak E., Jakob G., et al. Release of cyclic guanosine monophosphate evaluated as a diagnostic tool in cardiac diseases. Clin Chem 1991;37:186-190.[Abstract/Free Full Text]
- Kross J., Dries D.J., Kumar P., Bakhos M., Mathru M. Atrial natriuretic peptide may not play a role in diuresis and natriuresis after cardiac operations. J Thorac Cardiovasc Surg 1992;103:1168-1171.[Abstract]
- Koike R., Suma H., Kondo K., et al. Pharmacological response of internal mammary artery and gastroepiploic artery. Ann Thorac Surg 1990;50:384-386.[Abstract]
- Dignan R.J., Yeh T., Jr, Dyke C.M., et al. Reactivity of gastroepiploic and internal mammary arteries. Relevance to coronary artery bypass grafting. J Thorac Cardiovasc Surg 1992;103:116-122.[Abstract]
- Suma H., Wanibuchi Y., Terada Y., Fukuda S., Takayama T., Furuta S. The right gastroepiploic artery graft. Clinical and angiographic midterm results in 200 patients. J Thorac Cardiovasc Surg 1993;105:615-622.[Abstract]
- Takayama T., Suma H., Wanibuchi Y., Tohda E., Matsunaka T., Yamashita S. Physiological and pharmacological responses of arterial graft flow after coronary artery bypass grafting measured with an implantable ultrasonic Doppler miniprobe. Circulation 1992;86(Suppl 2):217-223.
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Abstract
Introduction
