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Published on: December 5, 2017
The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats
Cecilia M Shing1, Robert G Fassett, Lindsay Brown
1School of Human Life Sciences, University of Tasmania, Launceston, Australia. cecilia.shing@utas.edu.au
Abstract:
Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week-old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus-treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.
Insights
Calcineurin and mammalian target of rapamycin (mTOR) inhibitors like cyclosporine A, sirolimus, and tacrolimus can cause vascular dysfunction and endothelial dysfunction in rats. Everolimus did not impair aortic function in this study.
Area of Science:
- Cardiovascular Pharmacology
- Immunopharmacology
- Translational Medicine
Background:
- Immunosuppressants are crucial for preventing organ transplant rejection.
- However, these drugs are linked to an increased risk of cardiovascular disease.
- The specific impact of calcineurin and mammalian target of rapamycin (mTOR) inhibitors on vascular health requires further elucidation.
Purpose of the Study:
- To investigate the effects of different immunosuppressants on vascular endothelial and smooth muscle function.
- To assess the impact of calcineurin inhibitors (cyclosporine A, tacrolimus) and mTOR inhibitors (sirolimus, everolimus) on inflammation and oxidative stress.
- To compare the vascular effects of these immunosuppressants in a rat model.
Main Methods:
- Adult male Wistar rats received daily administration of cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus, or placebo for 10 days.
- Ex vivo assessment of aortic vascular endothelial and smooth muscle function using organ baths.
- Measurement of plasma inflammatory markers (interleukin-1β, tumor necrosis factor-α) and antioxidant status (catalase, total antioxidant capacity).
Main Results:
- Sirolimus significantly increased maximal aortic contraction compared to cyclosporine, everolimus, and placebo groups.
- Cyclosporine A and tacrolimus impaired endothelial-dependent relaxation, while tacrolimus also impaired endothelial-independent relaxation.
- Sirolimus treatment was associated with reduced pro-inflammatory cytokines (IL-1β, TNF-α) and enhanced antioxidant markers.
- Everolimus did not compromise aortic endothelial or smooth muscle function at the tested doses.
- Vascular dysfunction was observed with cyclosporine A, sirolimus, and tacrolimus, but not everolimus.
Conclusions:
- Different immunosuppressants exert varying effects on vascular function in rats.
- Cyclosporine A, sirolimus, and tacrolimus induced vascular dysfunction, whereas everolimus showed a neutral effect on aortic function.
- These findings highlight the importance of considering specific immunosuppressant agents when evaluating cardiovascular risk in patients.
