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Surg Today Jpn J Surg (1995) 25:293-298

© Springer-Verlag 1995

Review Article

Late Graft Failure of Autologous Vein Grafts for Arterial Occlusive Disease: Clinical and Experimental Studies HIROYUKIITOH, KIMIHIROKOMORI,TOSHIHIROONOHARA,SATORUFUNAHASHI,KENICHIROOKADOME, and KEIZO SUGIMACHI Second Department of Surgery,Facultyof Medicine,KyushuUniversity,3-1-1 Maidashi,Higashi-ku,Fukuoka,812 Japan

Abstract: Late graft failure following arterial reconstructive surgery, especiallyafter infrainguinal reconstruction, remains a major concern for vascular surgeons. To more effectively predict the outcome of reconstructed arteries, we herein propose an intraoperative flow waveform analysis which correlates well with the long-term patency rate of grafts. According to this ttow waveform analysis, late graft failure was occasionally seen in grafts with type lI waveforms when poor distal runoff vessels had been shown by the preoperative arteriogram. Next, to investigate which events occurring in autologous vein grafts under abnormal hemodynamics may contribute to late graft failure, a distal poor-runoff model was made in the canine femoral artery. In this review, we present the results of our investigation on autoiogous vein grafts using this poor-runoff model. We also relate our recent findings on the function of regenerated endothelium in autologous vein grafts. Key Words: flow waveform analysis, autologous vein graft,

late graft failure, prostacyclin, endothelium-derived relaxing factor (EDRF)

outcome, various methods of detecting technical failure during the operation, especially to prevent early graft failure, have been proposed; 4-6 however, no definitive methods for preventing late graft failure have yet been discovered. We herein propose an intraoperative flow waveform analysis which aims to predict the outcome of reconstructed arteries at the time of surgery more accurately, in accordance with our previous report documenting that flow waveforms correlated well with graft outcome. 7-1° Moreover, late graft failure is occasionally encountered in grafts with intraoperatively obtained type II flow waveforms, which indicates abnormal hemodynamic conditions. 7-1° Thus, we consider that impairment of the autologous vein graft wall which occurs under abnormal flow conditions and is not seen under normal flow conditions probably contributes to graft failure. In this review, we present some interesting findings of arterially transplanted autologous vein grafts, especially with regard to intimal thickening and the functions of regenerated endothelium, using an experimental distal poor-runoff model.

Introduction

The incidence of late graft failure following arterial reconstructive surgery for occlusive diseases, especially after infrainguinal arterial reconstruction, is still a significant problem for vascular surgeons. Even when autologous vein grafts, the most suitable grafts from the available materials, are used, late graft failure sometimes occurs. 1-3 In an attempt to improve graft

Reprint requests to: K. Sugimachi (Received for publication on Sept. 6, 1993; accepted on Nov. 10, 1994) Presented at the 21st Annual Meeting of the Society for Clinical Vascular Surgery held in Palm Desert, California, March 24-28, 1993.

Clinical Background

The long-term patency of reconstructed arteries could be greatly improved if vascular surgeons had the ability to predict graft outcome at the time of arterial reconstruction. Thus, to more effectively predict the possibility of late graft failure, we established an intraoperative flow waveform analysis. 7 Figure 1 shows the electromagnetically determined flow waveform patterns and the correlation between flow waveforms and the long-term patency rate. The flow waveforms measured after the completion of arterial reconstruction were classified as types 0, I, II, III, or IV, with good long-term graft outcome being expected when either type 0 or I flow waveforms of a reconstructed

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H. Itoh et al.: Late Failure of Autologous Vein Grafts

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artery are obtained during surgery. In such cases, the operation can be promptly concluded. In contrast, reconstructed arteries with type II flow waveforms, characterized by a gentle sloping in the last half of diastole, result in late occlusions in one-third of all patients 2 to 3 years after surgery. When type II flow waveforms are obtained, every effort should be made to determine their cause during the operation. If no cause can be found, the operation should be completed and strict follow-up of the patient conducted and the patient should be administered anticoagulants or anti-platelet agents. This type of flow waveform is frequently encountered when poor distal runoff vessels have been seen in the preoperative arteriograms. 8'1°'al These findings agree with previous reports that the angiographic assessment of runoff is a reliable indicator for graft prognosis following infrainguinal arterial reconstruction. 12-a5 Reconstructed arteries with types III or IV flow waveforms occlude soon after the operation, and immediate procedures such as thrombectomy, repair of an anastomosis, or other additional bypass procedures are needed, y-l° Based on these results, we consider abnormal blood flow to be one of the causes of late graft failure. Therefore, to improve long-term patency, the abnormalities of autologous vein grafts under abnormal flow conditions, such as those seen in type II flow waveforms, should be further investigated.

Fig. 1. Electromagnetically determined flow waveforms and the correlation between these flow waveforms and the long-term patency rate. Open circles indicate patent cases, and closed circles, occluded ones. The ordinate indicates the postoperative year when the last examination of patency was performed

Experimental Studies The Canine Distal Poor-Runoff Model and Intimal Thickening of Autologous Vein Grafts Intimal hyperplasia has been generally accepted as one of the main causes of late graft failure, i6-1s and the correlation between hemodynamics and intimal hyperplasia of the vein graft has been investigated under various conditions. Shin et al. reported that increased intimal hyperplasia was associated with decreased distal blood flow, 19 while Berguer et al. described increased intimal hyperplasia with low flow velocities, z° Our previous study showed that low shear stress increased intimal thickening,21 and close correlations between intimal hyperplasia with vein wall tension 2z and wall tangential stress ~3 have also been reported. These results indicate that abnormal conditions in hemodynamics lead to increased intimal hyperplasia of autologous vein grafts. To investigate the influence of abnormal flow conditions on arterially transplanted autologous vein grafts, we developed a model of abnormal blood flow conditions, very similar to those seen in clinical cases, which demonstrated a type II flow waveform using canine hind limb arteries. 24 In the canine model of distal poor runoff, the popliteal artery and all its branches, except for the first branch of the caudal femoral artery, were ligated and divided (Fig. 2a). Two weeks after making the poor-runoff model, the collateral vessels had fully developed and the hemodynamic conditions had stabilized. The flow

H. Itoh et al.: Late Failure of Autologous Vein Grafts

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waveform of the femoral artery in the poor runoff limb was type II and the mean flow rate was significantly lower than that of the control normal-flow limb (Fig. 2b). More than 2 weeks after making the poor-runoff model, by the time the collateral vessels had developed, the femoral artery was replaced with a reversed vein graft using the femoral vein in an end-to-end fashion. The grafts that had been implanted into the contralateral leg under normal flow conditions served as controls. The extent of intimal thickening in the vein grafts under abnormal flow conditions was found to be statistically significant when compared with that under normal flow conditions. 24-26 The progression of intimal thickening was particularly rapid within the first month after implantation. Two factors that might contribute to the enhanced intimal thickening which occurs under abnormal blood flow conditions were previously elucidated in our earlier experiments using this poor-runoff model. One of these factors was an enhanced permeability of the neointima in the vein graft noted within 4 weeks of graft implantation. 2s Permeability of the endothelial cells was reported to be associated with cell turnover processes, z7 and increased wall permeability caused by delayed endothelialization was thought to induce an intimal hyperplasia. 28 The other factor was enhanced platelet adherence on the intima of vein grafts in the early period after implantation. 26 In fact, Ross reported on the platelet-derived growth factor (PDGF) and the relationship between the mechanisms of intimal hyperplasia generation in arteriosclerosis and the role played by platelets. 29'~° Fuster and Chesebro also described the relationship between improved results of autologous vein grafts in aortocoronary

Fig. 2. a Distal poor-runoff model of the canine femoral artery a, femoral artery; b, distal caudal femoral artery; c, popliteal artery. b Flow waveforms of the canine distal poor-runoff model 2 weeks after the operation. The control limb shows a type 0 flow waveform, while the poor-runoff limb indicates a type II flow waveform.

bypass and antiplatelet therapy, and the close correlation between intimal thickening and platelets. 31 Thus, enhanced platelet adherence on vein grafts under abnormal flow conditions in the early period after implantation may lead to increased levels of PDGF and intimal hyperplasia.

Functions of Regenerated Endothelium in Autologous Vein Grafts In addition to intimal hyperplasia, platelet thrombus and the progression of atherosclerosis are other important factors in determining the patency of vein grafts. Interactions between aggregating platelets and the endothelium and smooth muscle of the vessel wall also play an important role in these processes. Prostacyclin (PGI2) and endothelium-derived relaxing factor (EDRF) are the vasoactive substances liberated from the endothelium which modulate these interactions by their anticoagulant activity. In the next step of our study, we investigated whether PGI2 production and endothelium-dependent responses were modulated in the regenerated endothelium of an autologous vein graft. Studies of cell cultures or canine vessels showed that PGI2 production is more enhanced when the endothelium is exposed to a pulsatile blood ltow than to a steady flOWo32-34 AS a preliminary step, we examined the PGIz production of endothelial cells in canine femoral arteries using an ex vivo perfusion system which could produce a normal flow waveform of either a type 0 or an abnormal type II flow waveform by changing the duration of the magnetic valve being open. 3s The results showed that PQIz production in arterial endothelial cells was greater when perfused

296

H. Itoh et al.: Late Failure of Autologous Vein Grafts

with a normal blood flow waveform than with an abnormal flow waveform. Next, we investigated PGIe production in the regenerated endothelial cells of an autologous vein graft using the canine poor distal-runoff model. 36 Hemodynamic impairment of the regenerated endothelial cells of vein grafts was then examined. Arterially implanted autologous vein grafts in the normal and abnormal runoff limbs were perfused in the ex vivo closed circuit at 3 days, then 1, 2, 3, and 4 weeks following implantation. After being perfused for the first 30min, the stimulated PGI2 production was measured under exposure to arachidonic acid for the following 30rain in steady flow conditions. As a result, the stimulated PGI2 production increased in both groups after implantation. At 2 weeks, when endothelialization was complete, PGIe production in the poor runoff limb was impaired, compared with that of the control limb, and at 4 weeks, the difference was statistically significant (Fig. 3). Some reports document that the PGI2 production of vein grafts after implantation increased with the increase in regenerating endothelial cells;37-44 however, other reports on the complete arterialization of vein grafts 37' 41 found that the capacity of vein grafts to produce prostacyclin could not undergo complete arterialization. 38-4°'42'43 Thus, it is likely that the regenerating endothelial cells of vein grafts are functionally impaired, even under normal blood flow conditions. Our results suggest that the impaired PGIe production of the vein graft in a distal poor-runoff limb may lead to decreased anticoagulation ability and, subsequently, low graft patency in reconstructed arteries.

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One of the other vasoreactive substances liberated from the endothelium is EDRF. EDRF not only relaxes vascular smooth muscles, but it reduces platelet adhesion and is also a potent anti-aggregatory substance. One EDRF has been identified as nitric oxide45-47 or a donor of nitric oxide which is produced from L-arginine. 48 EDRF can be released in response to aggregating platelets and certain products released from platelets. The action of EDRF is mediated through the direct activation of guanylate cyclase and hence, the production of 3',5'-cyclic guanosine monophosphate (cGMP). The elevation of c-GMP levels in the smooth muscle cells and platelets relaxes the smooth muscle and inhibits platelet aggregation. 49 A recent report suggests that nitric oxide may function as a modulator of vascular smooth muscle cell mitogenesis and proliferation by a c-GMP mediated mechanism. 5° During grafting procedures, the delicate endothelial cell layer of the vein graft is inevitably damaged to some extent. With one experimental design, segments of the jugular vein were grafted in a reversed position into the carotid arteries of rabbits. After 4 weeks, the grafts were removed, and the endotheliumdependent responses were examined in vitro. Figure 4 shows the tracing of changes in isometric tension of the unoperated jugular veins and the autologous vein grafts both with and without endothelium. Acetylcholine was added during contractions evoked by prostaglandin Fea, and although this caused endothelium-dependent relaxation in the unoperated jugular veins, no endothelium-dependent relaxation was observed 51 in the vein grafts. One of the possible mechanisms of impairment of endothelium-dependent

H. Itoh et al.: Late Failure of Autologous Vein Grafts

relaxation in vein grafts is that the production of cGMP in vein graft smooth muscle may be impaired. 52 As described above, the actions of E D R F are mediated by increased production of cGMP through the direct activation of soluble guanylate cyclase. 49'53's4 Although the endothelium-mediated production of cGMP was significantly reduced in rabbit vein grafts, that evoked by nitric oxide and SIN-1 (the activated metabolite of molsidomine~'56), which induce endotheliumindependent relaxation, remained unchanged. These results suggest that the potency of smooth muscles to produce cGMP would seem to remain unaltered in vein grafts. 52 Recently, we found that endotheliumdependent relaxation to adenosine diphosphate (ADP) was impaired under poor runoff conditions in the canine femoral artery. 57 Thus, the dysfunction of the endothelium in terms of the decreased production of EDRF, as well as decreased PGI 2 production under conditions of abnormal flow, may increase platelet aggregation and eventually facilitate the occurrence of late graft failure. Conclusion

This review presents several findings contributing to late graft failure in autologous vein grafts from an experimental point of view based on clinical experience. In summary: 1. Late graft failure frequently occurs in grafts with preoperative poor distal runoff limbs and/or in limbs with an intraoperative abnormal flow waveform. Under such flow conditions, intimal thickening can be enhanced. 2. Hyperpermeability of the neointima in vein grafts and an enhanced platelet adherence in the intima under abnormal flow conditions may also play an important role. 3. Endothelial dysfunction, such as the impairment of PGI2 production of the regenerated endothelium under abnormal flow conditions, which may augment thrombogenicity, is an additional factor that could contribute to late graft failure. References 1. Veith FJ, Gupta SK, Ascer E, White-Flores S, Samson RH, Scher LA, Towne JB, Bernhard VM, Bonier P, Flinn WR, Astelford P, Yao JST, Bergan JJ (1986) Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg 3:104-114 2. Quinones-Baldrich WJ, Prego AN, Ucelay-Gomez R, Freischlag JA, Ahn SS, Baker JD, Machleder HI, Moore WS (1992) Longterm results of infrainguinal revascularization with polytetrafluoroethylene: A ten-year experience. J Vasc Surg 16:209-217

297 3. Bernhard VM (1989) Bypass to popliteal and infrapopliteal arteries. In: Rutherford RB (ed) Vascular Surgery, 3rd edn. Saunders, Philadelphia, pp 692-704 4. Coelho JCU, Flanigan DP, Schuler JJ, Machi J, Beitler JC (1982) Detection of vascular defects during operation by imaging ultrasound. Ann Surg 196:473-480 5. Dardik H, Ibrahim IM, Koslow A, Dardik II (1978) Evaluation of intraoperative arteriography as a routine for vascular reconstructions. Surg Gynecol Obstet 147:853-858 6. Ascer E, Veith FJ, Morin L, Lesser ML, Gupta SK, Samson RH, Scher LA, White-Flores SA (1984) Components of outflow resistence and their correlation with graft patency in lower extremity arterial reconstructions. J Vasc Surg 1:817-828 7. Inokuchi K, Kusaba A, Kiyose T (1979) Flow waveform analysis in vascular surgery. Am J Surg 138:219-223 8. Okadome K, Mii S, Onohara T, Fukuda A, Muto Y, Sugimachi K (1990) A new assessment of arteriographic runoff for predicting of femoropopliteal arterial reconstructions. Vasc Surg 24:145-150 9. Okadome K, Taizo M, Eguchi H, Muto K, Sugimachi K (1986) Flow waveform assessment of polytetrafluoroethylene grafts for reconstruction of lower extremity arteries. A preliminary report. J Vasc Surg 4:277-283 10. Komori K, Okadome K, Funahashi S, Itoh H, Odashiro T, Ishii T, Sugimachi K (1993) Correlation of long-term results of extraanatomic bypass and flow waveform analysis. Eur J Vasc Surg 7:479-482 11. Okadome K, Onohara T, Yamamura S, Mii S, Sugimachi K (1991) Evaluation of proposed standards for runoff in femoropopliteal arterial reconstructions; Correlation between runoff score and flow waveform pattern. A preliminary report. J Cardiovasc Surg 32:353-359 12. Cutler BS, Thompson JE, Kleinsesser LJ, Hempel GK (1976) Autologous saphenous vein femoropopliteal bypass: Analysis of 298 cases. Surgery 79:325-331 13. Menzonian JO, LaMorte WW, Cantelmo NL, Doyle J, Sidawy AN, Savenor A (1985) The preoperative angiogram as a predictor of peripheral vascular runoff. Am J Surg 150:346-352 14. Peterkin GA, Manabe S, LaMorte WW, Menzonian JO (1988) Evaluation of a standard reporting system for preoperative angiograms in infi'ainguinal bypass procedures: Angiographic correlates of measured runoff resistance. J Vasc Surg 7:379385 15. Karacagil S, Almgren B, Bergstrom R, Bowald S, Eriksson I (1989) Postoperative predictive value of a new method of intraoperative angiographic assessment of runoff in femoropopliteal bypass grafting. J Vasc Surg 10:400-407 16. Chervu A, Moore WS (1990) An overview of intimal hyperplasia. Surg Gynecol Obstet 171:433-447 17. Karayannacos PE, Hostetler JR, Bond MG, Kakos GS, Williams RA, Kilman JW, Vasco JS (1978) Late failure in vein grafts: Mediating factors in subendothelial fibromuscular hyperplasia. Ann Surg 187:183-188 18. Gunstensen J, Smith RC, EL-Maraghi N, Julian J, Belbeck L (1982) Intimal hyperplasia in autogenous veins used for arterial replacement. Can J Surg 25:158-161 19. Shin CS; Hatem JN, Abachi IF (1978) Effect of diminished distal blood flow on the morphologic changes in autogenous vein grafts. Surg Gynecol Obstet 147:189-191 20. Berguer R, Higgins RF, Reddy DJ (1980) lntimal hyperplasia: An experimental study. Arch Surg 115:332-335 21. Morinaga K, Okadome K, Kuroki M, Miyazaki T, Muto Y, Inokuchi K (1985) Effect of wall shear stress on intimal thickening of arterially transplanted autoveins in dogs. J Vasc Surg 2:430-433 22. Karayannacos PE, Rittgers SE, Kakos GS, Williams TE, Mechstroth CV, Vaseo JS (1980) Potential role of velocity and wall tension in vein graft failure. J Cardiovasc Surg 21:171178

298 23. Zwolak RM, Adams MC, Clowes AW (1987) Kinetics of vein graft hyperplasia: Association with tangential stress. J Vasc Surg 5:126-136 24. Morinaga K, Eguchi H, Miyazaki T, Okadome K, Sugimachi K (1987) Development and regression of intimal thickening of arterially transplanted autologous vein grafts in dogs. J Vasc Surg 5:719-730 25. Mii S, Okadome K, Onohara T, Yamamura S, Sugimachi K (1990) Intimal thickening and permeability of arterial autogenous vein graft in a cahine poor-runoff model: Transmission electron microscopic evidence. Surgery 108:81-89 26. Yukizane T, Okadome K, Eguchi H, Muto Y, Sugimachi K (1991) Isotopic study of the effects of platelets on development of intimal thickening in autogenous vein grafts in dogs. Br J Surg 78:297-302 27. Lin SJ, Jan KM, Schuessler G, Weinbaum S, Chien S (1988) Enhanced macromolecular permeability of aortic endothelial cells in association with mitosis. Atherosclerosis 73:223-232 28. Dilley RJ, McGeachie JK, Prendergast FJ (1983) Experimental vein grafts in the rat: Re-endothelialization and permeability to albumin. Br J Surg 70:7-12 29. Ross R, Glomset J, Kariya B, Harder L (1974) A plateletdependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 71:1207-1210 30. Ross R (1986) The pathogenesis of atherosclerosis. N Engl J Med 314:488-500 31. Fuster V, Chesebro JH (1986) Role of platelet and platelet inhibitors in aorto-coronary artery vein graft disease. Circulation 73:227-232 32. Frangos JA, Eskin SG, McIntire LV, Ives CL (1985) Flow effects on prostacyclin production by cultured human endothelial cells. Science 227:1477-1479 33. Brunkwall JS, Stanley LC, Graham LM, Burkel WE (1988) Influence of pressure, flow rate, and pulsatility on release of 6keto-PGF1 and thromboxane B2 in ex vivo-perfused canine veins. J Vasc Surg 7:99-107 34. Brunkwall JS, Stanley JC, Graham LM, Burkel WE, Bergqvist D (1989) Arterial 6-keto-PGF1 and TxB2 release in ex vivo perfused canine vessels: Effects of pulse rate, pulsatility, altered pressure and flow rate. Eur J Vasc Surg 3:219-225 35. Onohara T, Okadome K, Yamamura S, Mii S, Sugimachi K (1991) Simulated blood flow and the effects on prostacyclin production in the dog femoral artery. Circ Res 68:1095-1099 36. Onohara T, Okadome K, Yamamura S, Komori K, Ishii T, Odashiro T, Sugimachi K (1993) Impaired endothelial prostacyclin production of the canine vein graft in a poor distal runoff limb. Surgery 113:700-708 37. Henderson VJ, Mitchell RS, Kosek JC, Cohen RG, Miller DC (1986) Biochemical (functional) adaptation of "arterialized" vein grafts. Ann Surg 203:339-345 38. Eldor A, Hoover EL, Pett SB, Gay WA, Alonso DR, Weksler BB (1981) Prostacyclin production by arterialized autogenous venous grafts in dogs. Prostaglandins 22:485-498 39. Cahill PD, Brown BA, Handen CE, Kosek JC, Miller DC (1987) Incomplete biochemical adaptation of vein grafts to the arterial environment in terms of prostacyclin production. J Vasc Surg 6:496-503 40. Hoover EL, Pett SB, Eldor A, Alonso D, Subramanian VA, Weksler B, Gay WA (1981) The effects of crystalloid potassium cardioplegic solution on arterialized canine vein grafts. Circulation 64 [Suppl 2]:96-100

H. Itoh et al.: Late Failure of A u t o l o g o u s Vein Grafts 41. Petry JJ, Burstein S, Chang WHJ, Wortham K, Sedor C, Hunter SA (1982) Prostacyclin production by vein grafts in the arterial circulation: A study in rats. Prostaglandins Leukot Med 9:511-516 42. Castellarnau C, Cullare C, Lopez S, Bonnin O, Montesinos A, Guix M, Rutllant MLL (1989) Prostacyclin and thromboxane production by autogenous femoral veins grafted into the arterial circulation of the dog. Thromb Haemost 61:279-285 43. Bush HE, Jakubowski JA, Curl GR, Deykin D, Nebseth DC (1986) The natural history of endothelial structure and function in arterialized vein grafts. J Vasc Surg 3:204-215 44. Fann JI, Sokoloff MH, Sarris GE, Yun KL, Kosek JC, Miller DC (1990) The reversibility of canine vein-graft arterialization. Circulation 82 [Suppl 4] :9-18 45. Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endotheliumderived relaxing factor. Nature 327:524-527 46. Furchgott RF (1988) Studies on relaxation of rabbit aorta by sodium nitrate: The basis for the proposal that the acidactivatable inhibitory factor from bovine retractor penis is inorganic nitrate and the endothelium-derived relaxing factor is nitric oxide. In: Vanhoutte PM (ed) Mechanisms of vasodilatation. Raven, New York, pp 401-414 47. Ignarro LJ, Byrns RE, Wood KS (1988) Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical. In: Vanhoutte PM (ed) Mechanisms of vasodilatation. Raven, New York, pp 427-435 48. Myers PR, Minor RJ, Guerra R, Bates JN, Harrison DG (1990) Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature 345:161-163 49. Komori K, Okadome K, Sugimachi K (1991) Endotheliumderived relaxing factor and vein grafts. Br J Surg 78:1027-1030 50. Scott-Burden T, Vanhoutte PM (1993) The endothelium as a regulator of vascular smooth muscle proliferation. Circulation 87 [Suppl 5]:V51-V55 51. Komori K, Gloviczki P, Bourchier RG, Miller VM, Vanhoutte PM (1990) Endothelium-dependent relaxations in response to aggregating platelets are impaired in reversed vein grafts. J Vasc Surg 12:139-147 52. Komori K, Schini VB, Gloviczki P, Bourchier RG, Vanhoutte PM (1991) The impairment of endothelium-dependent relaxations in reversed vein grafts is associated with a reduced production of cyclic guanosine monophosphate. J Vasc Surg 14:67-75 53. Vane JR, Anggard EE, Botting RM (1990) Regulatory functions of the vascular endothelium. N Engl J Med 323:27-36 54. Diamond J, Chu EB (1983) Possible role for cyclic GMP in endothelium-dependent relaxation of rabbit aorta by acetylcholine: Comparison with nitroglycerin. Res Commun Chem Pathol Pharmachol 41:369-381 55. Bohme E, Grossman G, Spies C (1983) Effects of molsidomine and other NO-containing vasodilators on cyclic GMP formation. Eur Heart J 4:19-24 56. Komori K, Vanhoutte PM (1989) Effects of SIN-1 on electrical and mechanical properties in the canine saphenous vein. J Cardiovasc Pharmacol 14:$62-$66 57. Komori K, Ishii T, Mawatari K, Odashiro T, Itoh H, Okadome K, Sugimachi K (to be published) Endothelium-dependent relaxations to adenosine diphosphate is impaired under poor runoff conditions in the canine femoral artery. J Surg Res