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Hypertension after cardiac transplantation: pathophysiology and management
1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA.
Insights
Cyclosporine A causes hypertension after heart transplants by inhibiting calcineurin, a mechanism shared with FK506 but not rapamycin. This highlights calcineurin as a key target for managing drug-induced side effects.
Area of Science:
- Nephrology
- Immunology
- Cardiology
Background:
- Cyclosporine A is a vital immunosuppressant post-heart transplant.
- Hypertension is a significant side effect of cyclosporine A therapy.
- The molecular mechanisms underlying cyclosporine A's dual actions require elucidation.
Purpose of the Study:
- To review the pathophysiology and management of cyclosporine A-induced hypertension.
- To explore the hypothesis that calcineurin inhibition mediates both immunosuppressive and hypertensive effects of cyclosporine A.
- To compare the toxicity profiles of cyclosporine A, FK506, and rapamycin.
Main Methods:
- Literature review of current knowledge on cyclosporine A-induced hypertension.
- Examination of experimental evidence at the whole animal and cellular levels.
- Analysis of data from multicenter clinical trials.
Main Results:
- Calcineurin is identified as the common cellular target for cyclosporine A and FK506.
- Cyclosporine A and FK506 share similar toxicity profiles, including hypertension.
- Rapamycin, which does not affect calcineurin, shows a different toxicity profile.
Conclusions:
- Calcineurin inhibition is hypothesized to mediate cyclosporine A-induced hypertension and toxicity.
- FK506 mimics cyclosporine A's hypertensive and toxic effects, supporting the calcineurin hypothesis.
- Further research is needed to understand rapamycin's clinical toxicity.
Abstract:
This article reviews the current state of knowledge concerning cyclosporine A-induced hypertension after heart transplantation, its pathophysiology and management. The hypothesis is presented that a common molecular mechanism mediates both the immunosuppressive and the hypertensive actions of cyclosporine. The calcium-calmodulin dependent phosphatase, calcineurin, is the common cellular target mediating the salient immunosuppressive effects of both cyclosporine A and FK506. Calcineurin is even more plentiful in nonlymphoid tissues such as the nervous system, muscle, and kidney. Because these are the main target sites for cyclosporine A-induced toxicity, it has been hypothesized recently that inhibition of calcineurin mediates cyclosporine A-induced toxicity. This hypothesis is supported by increasing experimental evidence, at both the whole animal and cellular levels, indicating that the toxicity profile of cyclosporine A is duplicated by FK506 but not by rapamycin, a structural analog of FK506 which is a potent immunosuppressive agent but has no effect on calcineurin. Recent multicenter trials demonstrate that in the clinical setting the hypertensive and other side effects of cyclosporine A are duplicated by FK506. The clinical toxicity of rapamycin is as yet unknown.