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Cyclosporine A improves coronary artery function in rat cardiac allografts

University of British Columbia

BACKGROUND: A marked decline in the vascular myogenic response during the course of allograft rejection was previously shown in a rat model of heart transplantation. Two important contributory features are an iNOS-catalyzed, NO-mediated vasodilation and a loss of smooth muscle function. In this study, the effect of cyclosporine A immunosuppressive therapy on the alleviation of myogenic and endothelial cell dysfunction of coronary resistance arteries in allograft was examined using pressure myography. We hypothesized that cyclosporine therapy will improve coronary artery function in rat cardiac allografts. METHODS: Coronary septal arteries (internal diameter 200μm) were dissected from heterotopic abdominal heart isografts (Lewis-Lewis) and allografts (Fisher-Lewis) at days 4 and 21 post-transplantation and mounted on a pressure myograph. Pressureinduced vasoconstriction was measured in the absence and presence of an iNOS blocker (aminoguanidine [AG], 100 μM). Endothelium based (ACh induced) and endothelium independent (SNP induced) vasorelaxation was also tested in each group and compared. RESULTS: Myogenic response was reduced in allograft coronary arteries at day 21 posttransplantation in comparison with matched isografts (p<0.05). AG potentiated myogenic tone in allograft arteries but had no effect on untreated day-21 isografts indicating the presence of iNOS based relaxation only in allograft vessels. At day 4, however, myogenic tone was potentiated by AG in all CsA-treated groups suggesting that CsA might induce iNOS in these vessels. Depolarization-induced vasoconstriction was lower in day-21 allografts in comparison to isografts whereas at day 4, KC1 induced tone was similar in both groups. CsA therapy also improved depolarization-induced constriction in day-21 allografts as compared to the other untreated groups (p<0.05). Furthermore, CsA therapy improved endothelium based and endothelium independent vasorelaxation in allograft arteries at day-21 post-transplantation. CONCLUSIONS: The results of this study suggest that CsA immunosuppressive therapy has a significant effect in the alleviation of early endothelial and smooth muscle cell dysfunction in coronary allograft vascular disease. However, the results reflect a dual and counterbalancing effect of CsA, both increasing the activity of iNOS (reducing tone) at an early time point, while attenuating the extent of smooth muscle destruction at a later time point (augmenting tone).

Thesis/Dissertation

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2009-09-28

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http://hdl.handle.net/2429/13288

Pharmacology

University of British Columbia

UBCV

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