Print this pageToradol Effects On Post-Operative IntimaHyperplasia In a Rat Carotid Endarterectomy Model
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Venkat R. Kalapatapu, MD1, Leighton Satterfield, BS1, Aliza T. Brown, PhD1, Hongjiang Chen, MD1, Nuran Ercal, PhD2, Tulin O. Price, BS2, Jie Gao1, Khalil Ibrahim1, Mohammed M. Moursi, MD1.
1Central Ark Vet Healthcare Sys; U of Ark for Medical Sciences, Little Rock, AR, USA, 2University of Missouri-Rolla, Rolla, MO, USA.
Background: Carotid endarterectomy (CEA) and more recently carotid artery stenting are the treatments of choice for atherosclerotic disease of the extracranial carotid arteries as well as for stroke prevention. Restenosis after carotid manipulation can occur in nearly 30% of patients with a percentage of these patients becoming symptomatic with transient ischemic attacks or stroke. Early restenosis is primarily due to neointimal hyperplasia, characterized by smooth muscle cell (SMC) activation, proliferation and migration with the eventual deposition of extracellular matrix into the injured luminal surface. Arterial injury is immediately followed by platelet adhesion at the site of injury, a process that requires the interaction of subendothelial von Willebrand factor with the platelet GP1b receptor. Platelet aggregation and activation is believed to be the initiating event after vascular injury resulting in a cascade of events that eventually lead to intimal hyperplasia and luminal narrowing. A complex local inflammatory process in response to vascular injury is also becoming increasingly recognized as a potential contributor to restenosis. Associated with this inflammatory process is the pathological process of oxidative stress due to oxygen radicals. Oxidative stress has been implicated in the progression of intimal hyperplasia. Ketorolac tromethamine (Toradol®), a nonsteroidal anti-inflammatory drug is a potent cyclooxygenase inhibitor that decreases platelet aggregation and is widely used clinically both for its anti-inflammatory and analgesic properties. Due to the lack of data on Toradol and intimal hyperplasia and its anti- platelet and anti-inflammatory properties, we hypothesized that Toradol in a CEA model would decrease intimal hyperplasia formation. Furthermore, we also speculated that oxidative stress would be decreased with Toradol administration due to its inhibition of the cyclooxygenase pathway.
Methods: An open rat CEA model was utilized in combination with daily oral Toradol for examination of intimal hyperplasia. Endarterectomy involved exposure of the right common carotid artery with direct removal of the intima followed by primary closure. Twenty-nine rats underwent CEA and were divided into three treatment groups as follows: 1] control N=10, 2] 7.5 mg/kg/day (PO) Toradol N=9, or 3] 10 mg/kg/day (PO) Toradol N=10. Toradol treatment began two days prior to CEA and continued for two weeks. Two weeks following endarterectomy, carotid arteries were fixed, harvested and examined for the degree of intimal hyperplasia (presented as percent luminal stenosis). Serum was collected at the time of harvest and measured for oxidative stress expressed as levels of the antioxidant glutathionine (GSH) and malondialdehyde (MDA), an indicator of lipid peroxidation. Platelet activity was also measured as the degree of platelet binding to fibrinogen coated beads and reported as platelet binding units (PRU).
Results: Toradol at both treatment doses required a slightly longer application of pressure at the arteriotomy line in order to achieve hemostasis however; there was no significant bleeding in either Toradol group compared to the control group. When evaluating platelet activity, as measured by PRU, both 7.5 and 10 mg/kg doses of Toradol were effective versus control (0.9±0.14 and 1.6±0.24 vs. 2.6±0.51 PRU, respectively P=0.001 and P=0.04). No significant difference was noted between 7.5 and 10 mg/kg doses of Toradol with respect to platelet activity. Both the 7.5 and 10 mg/kg doses of Toradol were effective at lowering oxidative stress as indicated by lowered levels of MDA (0.52±0.03 and 0.56±0.05 vs. 0.74±0.05 µM MDA, respectively P=0.004 and P=0.01). GSH levels were significantly higher in the control group as compared to both the 7.5 and 10 mg/kg doses of Toradol (22.8 µM vs. 12.3±2.8 and 12.3±2.1 GSH, respectively P=0.01 and P=0.009) indicating the de novo antioxidant response against increased oxidative stress. Toradol at 10 mg/kg was effective at lowering intimal hyperplasia versus controls (30.8±11.5 vs. 68.3±11.7 % luminal stenosis, P=0.03, respectively), this represents a 54% reduction in luminal stenosis. The 7.5 mg/kg Toradol group showed a marked but not statistically significant reduction in intimal hyperplasia compared to the control group (39.5±11.9 vs. 68.3±11.7 % luminal stenosis, P=0.09).
Discussion: While many elements of the etiological development of intimal hyperplasia are known, much is still not understood about this process. Our open CEA rat model has been useful in studying different clinically relevant agents that may prove to have an inhibitory effect on intimal hyperplasia development. This study focused on the anti-platelet, anti-inflammatory and anti-oxidative stress effects of a commonly administered drug, Toradol. The use of Toradol in this rat CEA model, at 10 mg/kg significantly decreased oxidative stress, lipid peroxidation, platelet activity and intimal hyperplasia. Until this endarterectomy rodent study no other published work has specifically examined the use of Toradol in the prevention of intimal hyperplasia development. The study suggests that an inhibition of platelet aggregation at the endarterectomy site as measured by platelet activity can result in a significant reduction in intimal hyperplasia. The effects of Toradol on oxidative stress demonstrated by decreased lipid peroxidation shown by MDA levels suggests that the inflammatory and oxidative stress processes associated with intimal hyperplasia are reduced and this inhibition contributes to a reduction in restenosis. The exact contribution of each of these systems is still unclear. However, given the mechanism of action of Toradol as an inhibitor of cyclooxygenase it is likely that a combination of these effects are contributing to the greater than 50% reduction in luminal narrowing after CEA in this rat model.
Conclusion: Toradol given daily beginning two days prior to CEA and two weeks post procedure was effective at significantly reducing intimal hyperplasia development in the rat without any increase in bleeding. While the mechanism of action of this reduction is not completely understood one possible explanation may be through the inhibition of reactive oxygen species production. Given that Toradol is a commonly used agent in our patient population it may prove to have some benefit in preventing intimal hyperplasia development, which continues to be a vexing problem in vascular surgery.
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