preventive effect of nicardipine on hyperplastic changes in venous bypass grafts

World J. Surg. 17, 94-100, 1993 ~ World Journal of Surgery �9 1993 by the Soci~t6

lnternationale de Chirurgie

Preventive Effect of Nicardipine on Hyperplastic Changes in Venous Bypass Grafts

0 z c a n GOkqe, M.D. , ~ i~dem G6k~e, M.D. , Salih Gfinel, M.D. , Akin 0 z d e n , M.D. , K e m a l Ht iseyino~lu, M.D. , 0 z c a n U~ar, M.D. , and Yticel Gtingen, M.D.

Departments of General Surgery and Internal Medicine, Firat University School of Medicine Elazi~, and Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey

Nicardipine is a relatively new calcium channel blocker with important properties that could result in attenuation of the adverse proliferative changes in autogenous vein bypass grafts. In this experimental, randomized, controlled study, the effect of nicardipine on the pathologic findings in aortoaortic bypass grafts was assessed. Forty-two male rabbits (Ory- cytolagus cuniculus) were randomized to three groups: group 1 received nicardipine and groups 2 and 3 placebo for 4 weeks, after which an aortoaortic bypass was realized with an autogenous inferior vena cava segment. During the following 4 weeks, groups 1 and 2 received nicardipine, and placebo was continued in group 3. The animals were sacrificed at the end of the study to permit removal and evaluation of the bypass grafts. The mean intimal and medial thickness values for groups 1 and 2 were lower than those for group 3, indicating that nicardipine has a significant preventive effect on the hyperplastic changes in venous bypass grafts compared to placebo. The mean intimal and medial thickness values of group 1 were also lower than those of group 2, and the differences carried statistical relevance, suggesting that the use of nicardipine before grafting could potentiate its protective effect. To provide stimulus for further research, an attempt is made to relate the hyperplasia-preventing effect of nicardipine to possible mechanisms.

Bypass grafts using autogenous veins are prone to occlusion. Early occlusions present as mural thrombi and fibrin deposits that overlie areas of endothelial cell loss associated with the trauma of vein harvesting or of the changed arterial dynamics after grafting [1]. Late occlusions present as fibromuscular hyperplasia or atheromatous plaques [2, 3], both viewed as causally related to earlier endothelial injury because the intima underlying injured endothelium tends to accumulate lipids [4] and fibrin [5] and to thicken, probably owing to smooth muscle cells that migrate from the media and proliferate [6]. Thrombo- cyte activation is thought to contribute significantly to these proliferative changes [1] by the attendant secretion of potent factors that stimulate cellular migration and growth [7].

Nicardipine is a relatively new calcium channel blocker (CCB) with several important characteristics that could enable it to counteract the adverse changes in venous bypass grafts. In addition to its potent vasodilatory action [8, 9], nicardipine has

Reprint requests: 0zcan G6k~e, M.D., University of Cambridge, Department of Surgery, Level 9, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom.

been reported to inhibit smooth muscle cell migration [10] and platelet aggregation [11] and to induce the recovery of cellular functions after injury [12]. The affinity of nicardipine for vascular smooth muscle is higher than that of many other CCBs [13], leading to its increasing use for the treatment of hypertension and vascular diseases.

Preliminary studies concerned with the heart and arterial vessels have aroused the hope of attenuating the structural changes of high wall tension with CCBs [14]. We showed that nicardipine treatment results in significant decreases in the thickness of the interventricular septum and the left ventricular posterior wall in humans with essential hypertension [15], suggesting the possibility of reversing or at least attenuating the hypertrophic cardiac changes accompanying hypertension with the long-term use of the drug.

The CCBs may exert similar beneficial effects on veins. The pronounced vascular selectivity of nicardipine may render it particularly valuable for decreasing the changes induced in veins by "arterialization," that is, by exposure to abnormally high intravascular pressures through connections with arteries. To test the validity of this view, we investigated the effect of nicardipine on arteriovenous fistulas (AVFs) in rabbits and observed impressive preventive action on wall hyperplasia in the venous side of the AVF [16]. As the pathogenesis of AVF failure [17] is similar to that of vein bypass graft occlusion, we argued that nicardipine would be expected to reduce luminal narrowing in vein bypass grafts as well as in AVFs. We thus planned this experimental, randomized, controlled study, in which we evaluated the effect of nicardipine on the pathologic changes in inferior vena caval segments after their use as aortoaortic bypass grafts.

Mater i a l and M e t h o d s

Forty-two male rabbits (Orycytolagus cuniculus) bred in iden- tical conditions were randomized to three groups in this study. Group 1 received nicardipine and groups 2 and 3 placebo for 4 weeks, after which an aortoaortic bypass was created under ether anesthesia. Following laparotomy, the inferior vena cava

O, G6kqe: Nicardipine for Venous Grafts 95

FIRST 4 WEEKS

GROUP I NICARDIPINE (20mglkg)

GROUP 2 PLACEBO

GROUP 3 P PLACEBO

0 P E R A T I 0 N

AO

j BG

SECOND 4 WEEKS

NICARDIPINE (20mglkg)

NICARDIPINE (20mglkg)

PLACEBO

D,,

v

h , v

Fig. 1. Design of the study and the bypass technique employed on the rabbits. Ao: abdominal aorta; IVC: inferior vena cava; VBG: vein bypass graft.

(IVC) was ligated and divided at two levels, with the upper level 1 cm below the origin of the renal veins and the lower level 1 cm above the bifurcation point of the IVC. The proximal and distal ends of the intervening IVC segments were sutured in an end-to-side manner to the abdominal aorta with a continuous 8-0 microvascular monofilament polypropylene sterile suture (Prolene | Ethicon, Edinburgh, U.K.) to obtain an aortoaortic bypass. To increase flow through the bypass route, the abdominal aorta was ligated at approximately midlevel between the anastomosis sites.

Twelve rabbits died during the first postoperative hour, presumably owing to anesthetic complications and operative trauma. Comparison of the survival rates of separate groups using the X 2 test revealed no statistically relevant difference among them, and the study was continued with the remaining 30 rabbits. No other deaths occurred. During the following 4 weeks, groups 1 and 2 received nicardipine, and placebo was continued in group 3. The design of the study and the bypass technique employed are depicted in Figure 1.

The animals were fed standard rabbit chow. Nicardipine was given orally at a dose of 20 mg/kg body weight; to ensure its

ingestion, it was ground and mixed with 5 grams confectioners' sugar and 10 ml distilled water; the resulting mixture was drawn into an injector and slowly pushed through a polyethylene catheter of 10 cm length inserted between the incisive teeth to reach the oropharynx of the animal. Placebo consisted of 5 grams confectioners' sugar dissolved in 10 ml distilled water administered in the same manner.

At the end of the study the animals were sacrificed under anesthesia to permit removal of the bypass grafts, which were first evaluated under a dissection microscope. Observing an almost uniform wall structure in each graft along its respective length, biopsy specimens were taken at midlevel to obtain representative samples that were sent as coded specimens preserved in formalin to a pathologist blinded to the study design, who evaluated them with an oculary micrometer after hematoxylin-eosin staining. The wall thickness values mea- sured in micrometers (/xm) at 12 radiuses were averaged for each animal and reported in relation to their code numbers. The results were then decoded and analyzed with Student 's un- paired t-test. We reported the relations between the changes in venous structure, blood pressure, and lipid profile of Orycyto-

96 World J. Surg. Vol. 17, No. 1, Jan./Feb. 1993

Table 1. Experimental results in rabbits.

Characteristic Group 1 Group 2 Group 3

No. 14 14 14 Age (months) 10.2 -+ 0.3 9.9 -+ 1.0 10.1 _+ 0.3 Initial weight (grams) 1947.8 -+ 14.0 1960.0 -+ 11.9 1964.0 -+ 10.7 Final weight (grams) 1970.0 -+ 12.1 1986.1 -+ 10.2 1989.4 -4- 11.3 No. of deaths after 5 3 4

grafting Survival rate (%) 64 78 71

Results are given as the mean -+ SEM. p > 0.05 for all differences between groups.

Table 2. Characteristics of the autogenous vein bypass grafts at the end of the study.

Group 1 Group 2 Group 3 Site (/xm) (/xm) 0xm)

Intima 185.0 _+ 0.6* 194.0 -+ 1.4"* 254.7 _+ 5.7 Media 348.0 -+ 1.3" 364.2 -+ 2.3** 621.2 -+ 2.3

Results are given as the mean -+ SEM thickness of the intima or media.

*p -< 0.005 vs. group 2 andp -< 0.0005 vs. group 3; **p <- 0.0005 vs. group 3.

lagus cuniculus rabbits in response to nicardipine and a similar procedure, AVF [16]; because the descendants of those animals were used in this study, we did not reevaluate the relations mentioned. The results are given as the mean -+ SEM.

Results

No statistically relevant difference was encountered among the age averages, initial and final weights, and survival rates of the groups (Table 1). At the end of the study, the mean intimal and medial thickness values were significantly lower in groups 1 and 2 than in group 3. The mean intimal and medial thickness values of group 1 were also lower than those of group 2, and the differences carried statistical relevance (Table 2). Figures 2, 3, and 4 are light micrographs of graft biopsies obtained from the three groups to illustrate the differences among them with respect to the final wall thicknesses of the bypass grafts.

Discussion

Nicardipine has been identified as the most potent and long- lasting vasodilator among a series of 1,4-dihydropyridines [18, 19]. Its affinity for the dihydropyridine receptor linked to the calcium channel is greater than that of other dihydropyridines [20], and it is more vasculoselective and less cardioselective than most other CCBs [13, 20]. The tertiary amine structure in the ester side chain from position 3 of the dihydropyridine ring is unique to nicardipine [19, 20] and has been held responsible for its lipophilicity, intracellular sequestration, and membrane- stabilizing activity, with the latter possibly explaining its increased ability to protect cells from extracellular factors compared to other dihydropyridines [21-23]. Nicardipine has calcium overload-inhibiting properties as well [24].

The clinical relevance of these findings is reflected by the current interest in use of the drug to treat hypertension and

vascular disorders. Furthermore, it has been suggested that nicardipine may have clinical indications not associated with other CCBs [20]. Amenta and colleagues [25] showed decreased arterial hypertrophy in hypertensive rats and we showed decreased cardiac dimensions in hypertensive humans [!5] and decreased venous hyperplasia in the AVFs of normotensive rabbits following its use [16]; these data indicate regression of the structural changes associated with high wall tension in the arteries, heart, and veins, respectively, and lend support to the suggestion that nicardipine may have exceptional clinical util- ity. Because the success of an AVF for access to hemodialysis is limited by increased vascular resistance, thrombosis, wall thickening, stenosis, and failure [17], a sequence of events reminiscent of those leading to vein bypass graft occlusion, nicardipine could decrease luminal narrowing in vein bypass grafts as well as in AVFs.

The findings of the present study indicate'--that nicardipine does have a preventive effect on the intimal and medial hyperplasia in autogenous vein bypass grafts compared to placebo. This effect appears to be more pronounced in the media than in the intima, possibly due to the sensitivity of smooth muscle cells to even slight changes in calcium influx [26]; but further studies, including cell counts on samples of the intima and media following the use of nicardipine are needed to confirm a selective action, if any. The distribution of dihydropyridine receptors as well as their binding properties and the intensity of the postrecep- tor cellular changes they mediate could show important variations between the layers of the venous wall and contribute to the emergence of differing responses to nicardipine.

The lower mean intimal and medial thickness values of group 1 in contrast to those of group 2 imply that the use of nicardipine before grafting could substantially augment its protective effect. In the clinical situation, wall hyperplasia may occur months to Years after the vascular intervention, implying that the long- term use of nicardipine, starting during the preoperative period and continuing postoperatively, would be necessary to achieve a clinically relevant reduction in hyperplasia. Because a spon- taneous adaptation to arterialization in veins sufficient to prevent occlusion indefinitely is unusual, pharmacologic control of intimal hyperplasia seems mandatory [27]. Theoretically, the use of nicardipine would probably have to be continued so long as the graft remained, although there are data indicating a decline in endothelial and smooth muscle cell proliferation in vein grafts within 6 months after implantation [28]. Prior studies have revealed the safety and efficacy of nicardipine during long-term use [8]. The hypotensive effect of this drug is corre- lated with initial blood pressure, permitting its administration to normotensive subjects with coronary artery disease as well as to subjects with mild to moderate arterial hypertension [8, 9]. The duration of nicardipine therapy required to obtain a clinical reflection of its vascular hyperplasia-preventing effect and whether its chronic use would be followed by the development of tolerance to this beneficial effect remain to be determined.

We previously searched for correlations between the changes in the venous thickness values, systemic arterial blood pressures, and serum lipid profiles of Orycytolagus cuniculus rabbits in response to nicardipine and a similar procedure, the creation of AVFs, and found that the negative correlations between the decreases in systolic blood pressure and the increases in wall thickness lacked statistical relevance; more-

O. G6kqe: Nicardipine for Venous Grafts 97

Fig. 2. Light micrographic view of an exemplary vein graft biopsy obtained from group 1. (Hematoxylin-eosin. • Fig. 3. Light micrographic view of an exemplary vein graft biopsy obtained from group 2, showing increased intimal and medial hyperplasia compared to group 1. (Hematoxylin-eosin. x400.) Fig. 4. Light micrographic view of an exemplary vein graft biopsy obtained from group 3, revealing striking intimal and medial hyperplasia in contrast to groups 1 and 2. (Hematoxylin-eosin. •

over, the serum lipid profile was not significantly altered, indicating that the decrease in hyperplasia obtained with nicardipine is not a direct consequence of any changes in blood pressure or lipids [16]. In line with this view are the observations of El-Sanadiki and colleagues [29], who reported reduced intimal hyperplasia in vein bypass grafts in rabbits given verapamil at a dose that did not lower blood pressure, and of Zwolak and colleagues [28], who showed that hypercholesterolemia did not exert an incremental mitogenic stimulus on endothelial and smooth muscle cells.

Because arachidonic acid metabolites are implicated in cellular injury [30], the inhibitory action of nicardipine on arachidonic acid metabolism [31, 32] could have facilitated the beneficial effect observed in this study. Nicardipine also has a direct inhibitory effect on platelet aggregation [11]; thus it could decrease both the need for, and the degree of, platelet activation after grafting. Alterations in growth factor secretion or action should also be considered; the report of Nakao and associates [10] on inhibition of smooth muscle cell migration by nicardipine strengthens this possibility. The latter effect may be related to reduced arachidonic acid metabolism as well [33].

Other characteristics of the drug deserve mention within this context. It inhibits the formation of inositol phosphates in response to endothelin [34]. As injured endothelium tends to produce more endothelin [35], vasoconstriction could compli- cate injury in venous bypass grafts; nicardipine could modify such changes. Another aspect of endothelin is its mitogenic action on smooth muscle cells and fibroblasts [36], which could explain its probable involvement in the atherogenic process [37]. The preventive effect of nicardipine on vascular structural

alterations could be related to an inhibitory effect on the mitogenic action of endothelin. The similarity of the late changes in venous bypass grafts to arteriosclerotic changes [3, 28, 38] suggests that nicardipine could expectedly at tenuate the former, in analogy to its protective effect against the latter [39]. Decreased activation of membrane phosphoinosit ides by nicardipine could have further relevance to the prevention of graft occlusion, as the messengers that are produced following phos- phoinositide turnover affect the responses of platelets [40--42] and stimulate cell proliferation [43, 44].

We conclude that nicardipine has an important preventive effect on the proliferative changes in experimental autogenous vein bypass grafts. Most of the properties discussed above as possible explanations for this effect are probably common to all CCBs, but CCBs show remarkable variation with respect to the strength and preferential site of expression of their properties. Dihydropyridines constitute the most vascular-selective group of commonly used CCBs [45]; and among this group, nicardipine stands apart as an agent with a markedly high level and duration of vascular activity [18, 19]. Fur ther comparative studies on the effects of CCBs on venous resistance, vasoactive agents, platelet functions, and growth factors are needed to elucidate their relative merit in preventing vascular hyperplasia. We hope that our results will help increase the interest in this subject.

R6sum6

La nicardipine (N) est une enzyme de conversion r61ativement nouvelte capable d 'at t6nuer la prolif6ration n6faste des greffons

98 World J. Surg. Vol. 17, No. 1, Jan./Feb. 1993

veineux autog~nes. Dans cet te 6tude exp6rimentale , random- is6e et contr616e, on a 6valu6 l 'effet de la N sur les pontages aor toaor t iques proth6t iques pathologiques. Quarante-deux lapins mfiles, de l ' esp6ce Orycytolagus cuniculus, ont 6t6 random- isds en 3 groupes. Seul le groupe 1 a re~u de la N. alors que les deux autres groupes ont re~u du placebo pendant 4 semaines. Un pontage aor toaor t ique a ensuite 6t6 rdalis6 en utilisant la veine cave autog~ne. Pendant les quatre semaines SUlvantes. les groupes 1 et 2 ont re~u de la N. alors que |es lapins du groupe 3 ont continu6 de recevo i r du placebo. T o u s l e s animaux ont 6t6 sacrifids ~ la fin de l ' exp6r imenta t ion, les greffons ont 6t6 pr61ev6s et examin6s. L '6pa i s seur moyenne de l ' int ima et de la m6dia 6taient diminu6e dans les groupes 1 et 2 par rapport au groupe 3. at testant du pouvoi r de la N h r6duire l 'hyperplasie des greffons veineux. De m6me. l '6paisseur moyenne de l ' intima et de la m6dia dans le groupe 1 6tait r6duite par rapport aux groupes 2 et 3. Cet te diff6rence 6tait s tat ist iquement significa- tive. sugg6rant que l 'uti l isation de N avant de r6aliser un pontage avait un effet potential isateur. Les m6canismes 6v6n- tuel lement capables d ' exp l iquer l 'effet d ' inhibi t ion sur l 'hyperplasie sont 6voqu6s. afin de st imuler la recherche h l 'avenir .

Resumen

La nicardipina (N) es un bloqueador de calcio re la t ivamente nuevo con importantes propiedades que pueden resultar en la a tenuacion de los cambios adversos de tipo proliferativo que ocurren en los injertos con vena aut6gena. En el presente estudio exper imental , randomizado y controlado, se valor6 el efecto de la N sobre los hallazgos patol6gicos en injertos aorto-a6rt icos. Los conejos utilizados en el estudio fueron divididos en 3 grupos: el Grupo I recibi6 N. mientras los grupos 2 y 3 recibieron placebo por 4 semanas, despu6s de 1o cual se practic6 un injerto aor to-a6r t ico con segmento de vena cava inferior. En las 4 semanas siguientes, los grupos 1 y 2 recibieron N. mientras se cont inuaba la administraci6n de placebo al grupo 3. Los animales fueron sacrificados al final del estudio para r emover y valorar los injertos. E1 grosor promedio de la fntima y de la media en los grupos 1 y 2 fue menor q u e e n el grupo 3, lo cual es indicat ivo de que la N posee un efecto prevent ivo de significaci6n sobre los cambios hiperplgtsicos en los injertos de vena, en comparaci6n con el placebo. E1 grosor promedio de la /nt ima y de la media tambi6n fue menor en el grupo 1 q u e e n el grupo 2, y la diferencia tuvo significaci6n estad/stica, lo cual sugiere que el uso de N antes de injertar puede potenciar su efecto protector . En el presente artfculo se intenta relacionar el efecto p reven t ivo de la hiperplasia de la N con algunos mecan- ismos probables , con miras a es t imular m~is invest igaci6n sobre el tema.

References

1. Gundry, S.R., Jones, M., Ishihara, T., Ferrans, V.J.: Intraopera- tive trauma to human saphenous veins: scanning electron micro- scopic comparison of preparation techniques. Ann. Thorac. Surg. 20:40, 1980

2. Grondin, C.M., Campeau, L., Lesperance, J., Enjalbert, M., Bourassa, M.G.: Comparison of late changes in internal mammary artery and saphenous vein grafts in two consecutive series of patients 10 years after operation. Circulation 70(Suppl. 1):I-208, 1984

3. Bulkley, B.H., Hutchins, G.M.: "Accelerated atherosclerosis": a morphologic study of 97 saphenous vein coronary artery bypass grafts. Circulation 55:163, 1977

4. Boerboom, L.E., Bonchek, L.I., Kissebah, A.H., Werner, P.H., Pepper, J.R., Olinger, G.N., Korns, M.E., Garancis, J.D.: Effect of surgical trauma on tissue lipids in primate vein grafts: relation to plasma !ipids. Circulation 62:I-142, 1980

5. Malone, J.M., Kischer, C.W., Moore, W.S.: Changes in venous endothelial fibrinolytic activity and histology with in vitro venous distention and arterial implantation. Am. J. Surg. 142:178, 1981

6. Ross, R.: Factors influencing atherogenesis. In The Heart, Arteries and Veins, J.W. Hurst, editor. New York, McGraw-Hill, 1990, pp. 877-892

7. Holmsen, H.: Composition of platelets. In Hematology, W.J. Williams, E. Beutler, A.J., Erslev, M.A. Lichtman, editors. New York, McGraw-Hill, 1991, pp. 1182-1200

8. Sorkin, E.M., Clissold, S.P.: Nicardipine, a review of its pharma- codynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders. Drugs 33:296, 1987

9. Pepine, C.: Nicardipine, a new calcium channel blocker: role for vascular selectivity. Clin. Cardiol. 12:240, 1989

10. Nakao, J., Ito, H., Ooyama, T., Chang, W.C., Murota, S.: Calcium dependency of aortic smooth muscle cell migration induced by 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid: effects of A23187, nicardipine and trifluoperazine. Atherosclerosis 46:309, 1983

11. Greer, I.A., Walker, J.J., McLaren, M., Calder, A.A., Forbes, C.D.: Inhibition of whole blood platelet aggregation by nicardipine, and synergism with prostacyclin in-vitro. Thromb. Res. 41:509, 1986

12. Marzatico, F., Gaetani, P., Spanu, G., Buratti, E., Rodriguez y Baena, R.: Effects of nicardipine treatment on Na+-K + ATPase and lipid peroxidation after experimental subarachnoid haemorrhage. Acta Neurochir. (Wien) 108:128, 1991

13. Clarke, B., Grant, D., Patmore, L., Whiting, R.L.: Comparative calcium entry blocking-properties of nicardipine, nifedipine and PY-108068 on cardiac and vascular smooth muscle. Br. J. Pharma- col. 79:333P, 1983

14. Hansson, L.: Regression of structural alterations of hypertension with calcium antagonists--vascular hypertrophy. J. Hypertension 5(Suppl. 4):$71, 1987

15. G6k~e, ~., Oram, A., Kes, S., Oram, E., U~urlu, S.: Effects of nicardipine on left ventricular dimensions and hemodynamics in systemic hypertension. Am. J. Cardiol. 65:680, 1990

16. G6k~e, ~., G6k~e, 0. , Gfinel, S., H~iseyino~lu, K., U~ar, 0 . , Gfingen, Y.: Preventive effect of nicardipine on experimental venous intimal hyperplasia. In Abstracts of The International Surgical Week, Stockholm, August 25-31, 1991, p. 278

17. Lazarus, J.M., Hakim, R.M.: Medical aspects of hemodialysis. In The Kidney, B.M. Brenner, F.C. Rector Jr., editors. Philadelphia, Saunders, 1991, pp. 2223-2298

18. Murakami, M., Takahashi, K., Iwanami, M., Fujimoto, M., Shiba- numa, T., Kawai, R., Takenaka, T.: Belgian patent no. 811 324, 1974

19. Takenaka, T., Usuda, S., Nomura, T., Maeno, H., Sado, T.: Vasodilator profile of a new 1,4-dihydropyridine derivative, 2,6- dimethyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)]-ethyl ester 5-methyl ester hy- drochloride (YC-93). Arzneimittelforschung 26:2172, 1976

20. Whiting, R.L.: Animal pharmacology of nicardipine and its clinical relevance. Am. J. Cardiol. 59:3J, 1987

21. Michel, A.D., Whiting, R.L.: Cellular action of nicardipine. Am. J. Cardiol. 64:3H, 1989

22. Nakaya, H., Kanno, M.: Effects of nicardipine, a new dihydropyridine vasodilator, on coronary circulation and ischemia-induced conduction delay in dogs. Arzneimittelforschung 32:626, 1982

23. Alps, B.J., Calder, C., Wilson, A.: The beneficial effect of nicardipine compared with nifedipine and verapamil in limiting myocar- dial infarct size in baboons. Arzneimittelforschung 33:868, 1983

24. Tari, C., Fournier, N., Ducet, G., Crevat, A., Albengres, E., Urien, S., Tillement, J.P.: Comparative study of bepridil and nicardipine action on respiration and calcium transport in mito- chondria. Int. J. Clin. Pharmacol. Ther. Toxicol. 25:26, 1987

O. G6k~;e: Nicardipine for Venous Grafts 99

25. Amenta, F., Bronzetti, E., Ferrante, F.: Nicardipine and vascular hypertrophy. Am. Heart J. 122:324, 1991

26. Desilets, M., Driska, S.P., Baumgarten, C.M.: Current fluctuations and oscillations in smooth muscle cells from hog carotid artery: role of the sarcoplasmic reticulum. Circ. Res. 65:708, 1989

27. Clowes, A.W., Reidy, M.A.: Prevention of stenosis after vascular reconstruction: pharmacologic control of intimal hyperplasia--a review. J. Vasc. Surg. 13:885, 1991

28. Zwolak, R.M., Kirkman, T.R., Clowes, A.W.: Atherosclerosis in rabbit vein grafts. Arteriosclerosis 9:374, 1989

29. E1-Sanadiki, M.N., Cross, K.S., Murray, J.J., Schuman, R.W., Mikat, E., McCann, R.L., Hagen, P.O.: Reduction of intimal hyperplasia and enhanced reactivity of experimental vein bypass grafts with verapamil treatment. Ann. Surg. 212:87, 1990

30. Vane, J.R., Anggfird, E.E., Botting, R.M.: Regulatory functions of the vascular endothelium. N. Engl. J. Med. 323:27, 1990

31. Rodriguez y Baena, R., Gaetani, P., Marzatico, F., Benzi, G., Pacchiarini, L., Paoletti, P.: Effects of nicardipine on the ex vivo release of eicosanoids after experimental subarachnoid hemor- rhage. J. Neurosurg. 71:903, 1989

32. Tuca, J.O., Planas, J.M., Parellada, P.P.: Increase in PGE2 and TXA2 in the saliva of common migraine patients: action of calcium channel blockers. Headache 29:498, 1989

33. Nakao, J., Ito, H., Chang, W.C., Koshihara, Y., Murota, S.: Aortic smooth muscle cell migration caused by platelet-derived growth factor is mediated by lipoxygenase product(s) of arachidonic acid. Biochem. Biophys. Res. Commun. 112:866, 1983

34. Xuan, Y.T., Whorton, A.R., Watkins, W.D.: Inhibition by nicardipine of endothelin-mediated inositol phosphate formation and Ca 2+ mobilization in smooth muscle cell. Biochem. Biophys. Res. Commun. 160:758, 1989

35. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Koba- yashi, M., Mitsui, Y., Yazaki, Y., Goto, K., Masaki, T.: A novel

potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411, 1988

36. Badr, K.F., Murray, J.J., Breyer, M.D., Takahashi, K., Inagami, T., Harris, R.C.: Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney: elucidation of signal transduction pathways. J. Clin. Invest. 83:336, 1989

37. Lerman, A., Edwards, B.S., Hallett, J.W., Heublein, D.M., Sand- berg, S.M., Burnett, J.C.: Circulating and tissue endothelin immu- noreactivity in advanced atherosclerosis. N. Engl. J. Med. 325:997, 1991

38. Kohler, T.R., Kirkman, T.R., Gordon, D., Clowes, A.W.: Mech- anism of long-term degeneration of arterialized vein grafts. Am. J. Surg. 160:257, 1990

39. Willis, A.L., Nagel, B., Churchill, V., Whyte, M.A., Smith, D.L., Mahmud, I., Puppione, D.L.: Antiatherosclerotic effects of nicardipine and nifedipine in cholesterol-fed rabbits. Arteriosclerosis 5:250, 1985

40. Brass, L.F., Joseph, S.K.: A role for inositol triphosphate in intracellular Ca 2+ mobilization and granule secretion in platelets. J. Biol. Chem. 260:15172, 1985

41. Authi, K.S., Hornby, E.J., Evenden, B.j., Crawford, N.: Inositol 1,4,5-triphosphate (IP3) induced rapid formation of thromboxane B 2

in saponin-permeabilised human platelets: mechanism of IP3 action. FEBS Lett. 213:95, 1987

42. Holmsen, H.: Metabolism of platelets. In Hematology, W.J. Wil- liams, E. Beutler, A.J. Erslev, M.A. Lichtman, editors. New York, McGraw-Hill, 1991, pp. 1200-1233

43. Meyer, P.: Increased intracellular calcium: from hypertension to cancer. J. Hypertension 5(Suppl. 4):$3, 1987

44. Macara, I.G.: Oncogenes, ions and phospholipids. Am. J. Physiol. 248:C3, 1985

45. Cummings, D.M., Amadio, P., Jr., Nelson, L., Mancini Fitzgerald, J.: The role of calcium channel blockers in the treatment of essential hypertension. Arch. Intern. Med. 151:250, 1991

Invited Commentary

Bren t T. Al len , M.D.

Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Intimal hyperplasia is a major obstacle to the long-term patency of bypass grafts in the coronary and peripheral arterial trees. Arterial lesions due to intimal hyperplasia and atherosclerotic disease have a similar morphologic appearance and are thought to be caused by the vessel's response to mechanical, hemody- namic, or biochemical injury [1, 2]. Several calcium channel blockers have been shown to inhibit atherosclerotic lesions in animals and more recently in man; therefore the hypothesis that nicardipine may reduce intimal hyperplasia in vein grafts pro- posed in this article by G6k~e et al. is a logical one [3]. The authors have made three important observations in their rabbit model: (1) oral nicardipine reduces vena caval wall thickening after aortic grafting; (2) the effect of nicardipine is more prominent in the media than the intima; and (3) the administration of nicardipine for 4 weeks preoperatively and continued postoperatively significantly enhances the reduction of venous wall thickening when compared to postoperative administration alone.

The authors note that evaluation with a dissecting microscope indicated a uniform appearance of the vessel wall along

the graft's length. Therefore vein graft measurements were made on biopsies taken from the midportion of the venous grafts. In contrast, other investigators have found intimal hyperplasia to be more prominent at the anastomoses, and perianastomotic stenoses are a more common cause of graft occlusion than intimal hyperplasia in the midgraft [4]. The uniform appearance of the grafts in this study may have been due to their short length or the duration of implantation. Further investigations are necessary to determine if the reduction in intimal hyperplasia by nicardipine occurs in the entire graft including the perianastomotic areas and if this effect will translate into improved long-term patency.

Table 2 from this manuscript indicates that the intimal thickness was reduced more than 20% and the medial thickness by more than 40% in nicardipine-treated animals (groups 1 and 2) when compared to controls. The significance of this obser- vation lies in the fact that the smooth muscle cell is the predominant cell type in the media. Additionally, animal studies by Clowes and Reidy indicate that smooth muscle cells are the primary cellular component in intimal hyperplasia produced by balloon catheter injury [5]. G6k~e et al. suggest that the apparent inhibition of smooth muscle cell proliferation in this study may be secondary to nicardipine's influence on calcium influx. They postulate that nicardipine's reported vascular selectivity may make it more efficacious in intimal hyperplasia than other calcium channel blockers. However, the necessity for vascular selectivity is uncertain, as other calcium channel blockers when used in association with aspirin and dipyri-

preventive effect of nicardipine on hyperplastic changes in venous bypass grafts

Documents