Calpain inhibition decreases endothelin-1 levels and pulmonary hypertension after cardiopulmonary bypass with deep hypothermic circulatory arrest.
OBJECTIVE
Cardiopulmonary bypass in infants and children can result in cardiopulmonary dysfunction through ischemia and reperfusion injury. Pulmonary hypertension and injury are particularly common and morbid complications of neonatal cardiac surgery. Inhibition of calpain, a cysteine protease, has been shown to inhibit reperfusion injury in adult organ systems. The hypothesis is that calpain inhibition can alleviate the cardiopulmonary dysfunction seen in immature animals following ischemia and reperfusion with cardiopulmonary bypass.


METHODS
Animal case study.


METHODS
Medical laboratory.


METHODS
Crossbred piglets (5-7 kg).


METHODS
Piglets were cooled with cardiopulmonary bypass to 18 degrees C followed by deep hypothermic circulatory arrest for 120 mins. Animals were rewarmed to 38 degrees C on cardiopulmonary bypass and maintained for 120 mins. Six animals were administered calpain inhibitor (Z-Leu-Leu-Tyr-fluoromethyl ketone; 1 mg/kg, intravenously) 60 mins before cardiopulmonary bypass. Nine animals were administered saline as a control. Plasma endothelin-1, pulmonary and hemodynamic function, and markers of leukocyte activity and injury were measured.


RESULTS
Calpain inhibition prevented the increased pulmonary vascular resistance seen in control animals (95.7 +/- 39.4 vs. 325.3 +/- 83.6 dyne.sec/cm, respectively, 120 mins after cardiopulmonary bypass and deep hypothermic circulatory arrest, p = .05). The attenuation in pulmonary vascular resistance was associated with a blunted plasma endothelin-1 response (4.91 +/- 1.72 pg/mL with calpain inhibition vs. 10.66 +/- 6.21 pg/mL in controls, p < .05). Pulmonary function after cardiopulmonary bypass was better maintained after calpain inhibition compared with controls: Po2/Fio2 ratio (507.2 +/- 46.5 vs. 344.7 +/- 140.5, respectively, p < .05) and alveolar-arterial gradient (40.0 +/- 17.2 vs. 128.1 +/- 85.2 mm Hg, respectively, p < .05). Systemic oxygen delivery was higher after calpain inhibition compared with controls (759 +/- 171 vs. 277 +/- 46 mL/min, respectively, p < .001). In addition, endothelial nitric oxide synthase activity in lung tissue was maintained with calpain inhibition.


CONCLUSIONS
The reduction in plasma endothelin-1 and maintenance of lung endothelial nitric oxide levels after cardiopulmonary bypass and deep hypothermic circulatory arrest with calpain inhibition were associated with reduced pulmonary vascular resistance. Improved gas exchange and higher systemic oxygen delivery suggest that calpain inhibition may be advantageous for reducing postoperative cardiopulmonary dysfunction commonly associated with pediatric heart surgery and cardiopulmonary bypass.
Duffy
Jodie Y
JY
Pediatric Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Schwartz
Steven M
SM
Lyons
Jefferson M
JM
Bell
Jason H
JH
Wagner
Connie J
CJ
Zingarelli
Basilia
B
Pearl
Jeffrey M
JM
D000818:Animals; D000831:Animals, Newborn; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D007036:Hypothermia, Induced; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects
D019332:Endothelin-1; D002154:Calpain