A novel mechanism for cyclosporine: Inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model

L. B. Gatewood, Douglas F Larson, M. C. Bowers, S. Bond, A. Cardy, G. K. Sethi, J. G. Copeland

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. Methods: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. Results: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. Conclusions: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.

Original languageEnglish (US)
Pages (from-to)936-947
Number of pages12
JournalJournal of Heart and Lung Transplantation
Volume15
Issue number9
StatePublished - 1996

Fingerprint

Myocardial Reperfusion Injury
Reperfusion Injury
Cyclosporine
Myocardial Ischemia
Rabbits
Transplants
Reperfusion
Heart Transplantation
Blood Pressure
Immunosuppressive Agents
Ischemia
Wounds and Injuries
Heart Failure
Transplantation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

Cite this

A novel mechanism for cyclosporine : Inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model. / Gatewood, L. B.; Larson, Douglas F; Bowers, M. C.; Bond, S.; Cardy, A.; Sethi, G. K.; Copeland, J. G.

In: Journal of Heart and Lung Transplantation, Vol. 15, No. 9, 1996, p. 936-947.

Research output: Contribution to journalArticle

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abstract = "Background: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. Methods: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. Results: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. Conclusions: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.",
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T2 - Inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model

AU - Gatewood, L. B.

AU - Larson, Douglas F

AU - Bowers, M. C.

AU - Bond, S.

AU - Cardy, A.

AU - Sethi, G. K.

AU - Copeland, J. G.

PY - 1996

Y1 - 1996

N2 - Background: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. Methods: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. Results: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. Conclusions: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.

AB - Background: Advances in myocardial preservation techniques and immunosuppressive drug therapy have resulted in heart transplantation as an acceptable treatment for end-stage heart failure. However, excessive periods of global myocardial ischemia followed by reperfusion can progress to irreversible graft injury. It has been reported that cyclosporine A (in addition to its well-characterized immunosuppressive actions) can blunt certain features of ischemia and reperfusion injury. This study was performed to examine the ability of cyclosporine A to attenuate such injury in a model of heart transplantation. Methods: Twenty rabbit heterotopic transplants were divided into four study groups: (1) 30-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts; (3) 4-hour ischemic control hearts; and (4) 4-hour ischemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both the donor and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. Results: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a significant (p < 0.01) leftward shift in the left ventricular end-diastolic pressure versus left ventricular volume curve compared with the 30-minute ischemic control hearts. This finding represents higher end-diastolic pressures and incomplete diastolic relaxation caused by ischemia and reperfusion. Cyclosporine A administration to the donor and recipient rabbits resulted in a significant improvement (p < 0.01) in diastolic relaxation (shift in the left ventricular end-diastolic pressure versus left ventricular volume curve back to the right) compared with 4-hour ischemic control hearts. Cyclosporine A-treated hearts also showed significant improvements in the rate of diastolic pressure fall (p < 0.05) and tau (the isovolumetric pressure decay constant) (p < 0.01) compared with ischemic control hearts. Conclusions: These results indicate that single doses of cyclosporine A to both the donor and recipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possible mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.

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