Aprotinin Decreases Ischemic Damage During Coronary Revascularization

Lazar, Harold L.; Bao, Yusheng; Tanzillo, Leslie; O'Gara, Paul; Reardon, Deborah; Price, David C.; Crowley, Richard; Cabral, Howard

doi:10.1111/j.1540-8191.2005.00136.x

Cited by 15 publications

(10 citation statements)

References 35 publications

(37 reference statements)

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“…The cardioprotection exerted by aprotinin in this study was characterized by a 50% reduction in necrotic myocardium and by a marked attenuation of plasma CK activity compared to treatment with vehicle alone. These findings are in keeping with previous data from a number of animal models ( Pruefer et al , 2002 ; Khan et al , 2004 ; Lazar et al , 2005 ). Our data are novel in that they demonstrate cardioprotection using parallel techniques and these show that firstly, the effects of aprotinin are dose‐dependent (with no significant effect using ‘low‐dose’ aprotinin) and, secondly, that aprotinin is effective when given at the end of the ischaemic period (thus, indicating an effect on reperfusion injury).…”

Section: Discussionsupporting

confidence: 91%

Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury

Carter

Buerke

et al. 2008

British J Pharmacology

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Background and purpose: Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen-derived radicals and proteases causing damage. Experimental approach: We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI þ R). Aprotinin (10 000 Ukg À1 ) or its vehicle were injected 5 min prior to the start of reperfusion. Key results: Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11 ± 2.7% necrosis as percentage of area at risk after aprotinin; 24 ± 3.1% after vehicle; Po0.05) and plasma creatine kinase activity (12.2±1.5 and 17.3±2.3 IU g À1 protein in aprotinin and vehicle groups, respectively, Po0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin-treated animals compared to vehicle (Po0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI þ R and this was significantly reduced by aprotinin therapy (44 ± 15 vs 102 ± 2 PMN mm 2 in aprotinin vs vehicle-treated animals, Po0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil-endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI þ R. Conclusions and implications: Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI þ R.The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.

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Section: Discussionsupporting

confidence: 91%

Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury

Carter

Buerke

et al. 2008

British J Pharmacology

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“…Aprotinin is a naturally occurring broad spectrum protease inhibitor obtained from bovine lung. Notwithstanding recent debate over its use sparked by 2 recent articles reporting an association with renal failure and other complications, 2,3 aprotinin has found widespread use in cardiac surgery for its benefits in reducing perioperative bleeding, 4 myocardial ischemia, 5 and cerebral events. 6 Animal studies have revealed a variety of effects including cardioprotection, reduced endothelial dysfunction and leukocyte migration.…”

mentioning

confidence: 99%

Effects of Aprotinin on Gene Expression and Protein Synthesis After Ischemia and Reperfusion in Rats

Buerke

Pruefer²,

Sankat³

et al. 2007

Circulation

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Background-Reperfusion injury of ischemic myocardium has been attributed to neutrophil infiltration, inflammatory activation and cardiac necrosis/apoptosis. Serine protease inhibition with aprotinin is cardioprotective, but the mechanism is unknown. Methods and Results-We studied aprotinin in a rat model of myocardial ischemia for 20 minutes and reperfusion for 20 minutes, 8 hours or 24 hours. Aprotinin (20 000 IU/kg) given 5 minutes before reperfusion significantly reduced leukocyte accumulation (PϽ0.01), myocardial injury (determined by CK depletion, PϽ0.01) and myocyte apoptosis (PϽ0.05) compared with vehicle treated rats. Differential gene expression analysis showed myocardial ischemia plus reperfusion increased expression of proinflammatory genes like P-selectin, E-selectin, intercellular adhesion molecule, tumor necrosis factor-␣, tumor necrosis factor-␣ receptor, interleukin-6, monocyte chemoattractant protein-1, p53, and Fas (CD59). Aprotinin before reperfusion suppressed expression of these inflammatory genes. Finally, differential protein expression analysis demonstrated increased intercellular adhesion molecule-1, tumor necrosis factor-␣, and p53 after myocardial ischemia plus reperfusion, and this effect was diminished by aprotinin. Conclusions-We demonstrated myocardial ischemia plus reperfusion induced leukocyte accumulation, inflammation, gene expression, protein expression and finally tissue injury and showed aprotinin limiting reperfusion injury through each of these stages, even after 24 hours of reperfusion. This effect seems partly attributable to suppression of proinflammatory genes and leukocyte accumulation. This work casts further light on the complex signaling of ischemia and reperfusion.

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“…Aprotinin is suggested to reduce capillary leakage and is of interest as it is already used in cardiac surgery to inhibit hyperfibrinolysis. In patients undergoing cardiac surgery, aprotinin is thought to decrease pulmonary edema [30]. In experimental CPB, aprotinin reduced myocardial edema and fluid requirements [31].…”

Section: Discussionmentioning

confidence: 99%

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass

Dekker

Leeuwen

Meurs

et al. 2021

ICMx

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Background Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. Methods Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. Results CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10–16) to 6 (2–10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67–599) to 129 (31–292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7–15) vs. 6 (2–10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35–313) vs. 129 (31–292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. Conclusions Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

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Aprotinin Decreases Ischemic Damage During Coronary Revascularization

Abstract: Aprotinin limits ischemic injury during acute coronary revascularization by decreasing ventricular arrhythmias and lung edema, preserving endothelial function, and minimizing myocardial necrosis.

Cited by 15 publications

References 35 publications

Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury

Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury

Effects of Aprotinin on Gene Expression and Protein Synthesis After Ischemia and Reperfusion in Rats

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass

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