A novel mechanism for cyclosporine: inhibition of myocardial ischemia and reperfusion injury in a heterotopic rabbit heart transplant model.
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.
Gatewood
L B
LB
University of Arizona, Department of Surgery, Tucson 85724, USA.
Larson
D F
DF
Bowers
M C
MC
Bond
S
S
Cardy
A
A
Sethi
G K
GK
Copeland
J G
JG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001826:Body Fluids / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000009:adverse effects* / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D013997:Time Factors; D016042:Transplantation, Heterotopic; D016277:Ventricular Function, Left / Q000187:drug effects
D002317:Cardiovascular Agents; D016572:Cyclosporine