Suppression of Acute Rejection Prevents Graft Arteriosclerosis After Allogeneic Aorta Transplantation in the Rat

Geerling, Rob A.; Bruin, Ron W. F. de; Scheringa, Marcel; Bonthuis, Fred; Jeekel, J; IJzermans, Jan N.M.; Marquet, R. L.

doi:10.1097/00007890-199412000-00021

Cited by 21 publications

(8 citation statements)

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“…The inhibiting effect of ketanserin on BN platelet aggregation did not coincide with significant inhibition of the arteriosclerotic response in the WAG-BN aorta transplantation model, however. Similarly, in isografts, a greater sensitivity of BN platelets did not result in more pronounced arteriosclerotic lesions in BN rats than in WAG rats (20). On the other hand, intimal thickening was significantly reduced in the BN-WAG model, in which no effect of ketanserin on collagen-induced platelet aggregation could be detected.…”

Section: Discussionmentioning

confidence: 74%

“…In a previous study, we observed an increase in intimal thickness in the BN-WAG and WAG-BN aortic transplantation models as well as in BN and WAG aortic autotransplants (20). In the WAG-BN model, the process of intimal thickening was so rapid that severe lesions had already developed 4 weeks posttransplantation.…”

Section: Experimental Designmentioning

confidence: 70%

“…The significant reduction in intimal proliferation induced by ketanserin in the BN-WAG aortic model suggests that the stimulating effects of platelet-derived serotonin on the mitogenesis of VSMC might be of relatively greater importance in the BN-WAG model than in the WAG-BN model, possibly owing to differences in mononuclear cell infiltration in the two rat strain combinations (20). More severe cellular rejection in the WAG-BN combination may indicate a minor role of serotonin in the overall arteriosclerotic stimulation after aorta transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…In previous immunohistologic studies of graft arteriosclerosis in aortic allografts, we observed pre-dominantly actin-positive VSMC in late intimal lesions. Furthermore, we observed more severe arteriosclerotic alterations in the WAG-Brown Norway (BN) rat strain combination than in the reverse combination (20). Because of our results showing that the BN has a stronger blood-clotting tendency than the WAG rat, in the present study we examined the role of platelet aggregation in the development of posttransplant arteriosclerotic lesions.…”

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confidence: 94%

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Ketanserin Reduces Graft Arteriosclerosis After Allogeneic Aorta Transplantation in Rats

Geerling

Bruin²,

Scheringa³

et al. 1996

Journal of Cardiovascular Pharmacology

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The serotonin-2 receptor antagonist ketanserin has been suggested to diminish arteriosclerotic development by its effect on platelet function and on vascular smooth muscle cells. We investigated the ability of ketanserin in reducing immune-mediated arteriosclerosis using the BN-WAG and WAG-BN rat aortic transplantation models. Ketanserin (10 mg/kg/day) administered in drinking water significantly reduced posttransplant arteriosclerotic thickening of the intima in the BN-WAG rat model to 102 +/- 23 mu m as compared with 171 +/- 60 mu m in untreated BN-WAG allografts 8 weeks posttransplantation (p < 0.05). In the opposite WAG-BN combination, at 4 weeks posttransplantation, no significant reduction in intimal thickening was attained (112 +/- 42 vs. 152 +/- 49 mu m). Platelet aggregation to increasing amounts of collagen did not show a correlation between the effect of ketanserin on platelet function and reduction in intimal thickening. Ketanserin had no effect on systolic blood pressure or mononuclear cell infiltration. We conclude that ketanserin reduces graft arteriosclerosis by a mechanism other than by inhibition of platelet function, decrease in blood pressure, or immunosuppression. Because of this antiarteriosclerotic effect, ketanserin therapy might be beneficial to the long-term survival of vascular allografts.

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Section: Discussionmentioning

confidence: 74%

Section: Experimental Designmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

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Ketanserin Reduces Graft Arteriosclerosis After Allogeneic Aorta Transplantation in Rats

Geerling

Bruin²,

Scheringa³

et al. 1996

Journal of Cardiovascular Pharmacology

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“…Rapamycin has also been shown to be effective in other allograft models. In the rat aortic allograft model, a dose of 3 mg/kg three times per week effectively prevented both acute rejection and graft arteriopathy and was as effective as high‐dose cyclosporin therapy 35 . Not only has rapamycin been shown to reduce allograft vasculopathy, but reversal has also been demonstrated.…”

Section: Cardiac Transplantationmentioning

confidence: 96%

Rapamycin in cardiovascular medicine

Ruygrok

Muller

Serruys

2003

Internal Medicine Journal

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The cellular action of rapamycin (sirolimus), a natural fermentation product produced by Streptomyces hygroscopicus, is mediated by binding to the FK506 binding protein. By inhibiting a kinase known as the target of rapamycin, it restricts the proliferation of smooth-muscle cells by blocking cell-cycle progression at the G1/S transition. The finding that rapamycin possesses both anti-proliferative and antimigratory activity suggests that it could contribute to the control of arterial re-narrowing after percutaneous intervention and control the vascular manifestations of chronic rejection in transplanted hearts. The first clinical trials of implantation of rapamycin- coated stents in obstructive coronary artery lesions have been reported and, in selected patient groups, it appears that the restenosis process has been abolished. Studies are underway to establish the benefits of rapamycin-coated stents in day-to-day interventional practice, including small vessels, long lesions and patients with multivessel disease. With the addition of novel antiplatelet agents and delivery systems, it is possible that the two major limitations of percutaneous coronary intervention - restenosis and stent thrombosis - will be overcome. Cardiac graft loss due to intimal hyperplasia and accelerated atherosclerosis remains the major limitation to long-term survival following cardiac transplantation. Animal studies of rapamycin have suggested that this process can be reduced or abolished. Human studies of the efficacy of rapamycin in preventing both acute rejection and allograft arterial disease are in progress. Concerns regarding toxicity, carcinogenicity, delayed healing and endothelialization remain. As with any new agent or technology, we must remain vigilant to late adverse side-effects.

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Improved surgical technique for the establishment of a murine model of aortic transplantation

et al. 1998

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Aortic allotransplantation is a reliable procedure to study the evolvement of chronic rejection in mice. The progressive nature of this process in mice is characterized by diffuse and concentric myointimal proliferation which is inevitably associated with variable degrees of luminal constriction. These vascular changes are comparable to those that are witnessed in organ allografts undergoing chronic rejection in humans, underscoring its utility as a model of choice for the study of the development of this lesion. Whilst improved surgical technique has resulted in markedly enhanced graft survival, the results are far from being acceptable. Realizing this limitation, we embarked on developing a modified technique for aortic transplantation which would allow for improved graft survival in mice. A bypass conduit was created by end-to-side anastomosis of a segment of the donor's thoracic aorta into the infrarenal portion of the recipient's abdominal aorta. Using this technique, the graft survival was >98% with evidence in allotransplanted aorta of morphological changes pathognomonic of chronic rejection. On the contrary, no histopathological anomalies were discerned in aortic grafts transplanted across syngeneic animals. This modified surgical approach ameliorates the unacceptably high graft loss associated with earlier techniques, further extending the utility of this model as a tool to study the molecular and cellular mechanisms rudiment to the evolvement of chronic rejection.

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Suppression of Acute Rejection Prevents Graft Arteriosclerosis After Allogeneic Aorta Transplantation in the Rat

Cited by 21 publications

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Ketanserin Reduces Graft Arteriosclerosis After Allogeneic Aorta Transplantation in Rats

Ketanserin Reduces Graft Arteriosclerosis After Allogeneic Aorta Transplantation in Rats

Rapamycin in cardiovascular medicine

Improved surgical technique for the establishment of a murine model of aortic transplantation

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