Vascular endothelial growth factor attenuates trauma-induced injury in rats.

Endothelial dysfunction and loss of nitric oxide (NO) is an integral part of the initiation and maintenance of the inflammatory process such as that occurring in traumatic shock, and is considered responsible for much of the trauma induced microvascular injury. We investigated the effects of a vascular endothelial growth factor (VEGF) in a rat model of traumatic shock. Pentobarbital-anaesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension and a 93% mortality rate with a mean survival time of 108+/-10 min in 14 rats. Accompanying these effects was a significant degree of endothelial dysfunction and a markedly elevated intestinal myeloperoxidase (MPO) activity. Treatment with 125 microg kg(-1) VEGF administered intravenously 18 h pre-trauma, increased survival rate to 67% (P<0.01), and prolonged survival time to 252+/-24 min in 12 rats (P<0.01). VEGF also significantly preserved the endothelium-dependent relaxation to ACh indicating a preservation of endothelium-derived NO. Our results indicate that endothelial dysfunction with its accompanying loss of NO plays an important role in tissue injury associated with trauma, and that preservation of NO is beneficial in traumatic shock. The mechanisms of the protective effect of VEGF in trauma involves preservation of eNOS function and diminished neutrophil accumulation resulting in reduced neutrophil-mediated tissue injury. British Journal of Pharmacology (2000) 129, 71 - 76

Cardioprotective effects of abciximab (ReoPro) in an isolated perfused rat heart model of ischemia and reperfusion.

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury, due in large part to endothelial dysfunction, upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. We studied the effects of abciximab (ReoPro), an anti-IIb/IIIa antibody, which has been shown to attenuate platelet interactions, in a neutrophil-platelet mediated isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of abciximab (6.5 micrograms/kg) 10 min prior to the perfusion of the PMN + platelet perfused I/R heart improved post-reperfusion coronary flow and preserved post-reperfusion left ventricular developed pressure (LVDP) and +dP/dt max as indices of cardiac contractile function. Abciximab-treated hearts reperfused in the presence of PMNs and platelets preserved all indices of cardiac contractile function. I/R heart perfused with PMNs and platelets produced a profound injury to the hearts which was attenuated with the treatment of abciximab. In addition, abciximab significantly reduced PMN accumulation in the ischemic myocardium from 38 +/- 1 PMNs/mm2 in untreated hearts to 7 +/- 1 in rats given abciximab. Similar results were obtained with PMN perfused I/R rat hearts without platelets. These results provide evidence that abciximab is a potent and effective cardioprotective agent that inhibits leukocyte-endothelial cell interactions as well as platelet-endothelial cell interaction and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion. Therefore, IIb/IIIa may be important in attenuating both platelet and neutrophil-mediated myocardial dysfunction.