Pentoxifylline Attenuates the Depressed Endothelial Cell Function and Vascular Muscle Contractility following Trauma and Hemorrhagic Shock

Abstract

Although pentoxifylline (PTX) produces various beneficial effects following adverse circulatory conditions, it is not known whether this agent attenuates the depressed vascular endothelial cell function [i.e., the reduced release of endothelium-derived nitric oxide (EDNO)] and smooth muscle contractility after trauma and hemorrhage. To study this, rats underwent a midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximal shed volume was returned in the form of lactated Ringer's solution. The animals were then resuscitated with 4 times the volume of maximal bleedout with lactated Ringer's solution, following which PTX (50 mg/kg body weight), or an equivalent volume of normal saline, was infused intravenously over 95 minutes. At 1.5 hours after resuscitation, the aorta was isolated and studied in vitro. Norepinephrine-induced vascular contraction and dose responses for acetylcholine (ACh), an endothelium-dependent vasodilator, were then determined. The results indicate that the decreased ACh-induced relaxation in hemorrhaged animals was restored with PTX treatment. Moreover, the increased ACh IC50 values (ACh concentration that causes half-maximum relaxation) after hemorrhage were reduced by PTX. In contrast, there was no significant difference in the relaxation induced by an endothelium-independent vasodilator, nitroglycerine, in the tested groups. Thus, PTX restores a hemorrhage-induced decrease in endothelium-derived nitricoxide production. In addition, the depressed smooth muscle contractile function was also attenuated by PTX treatment. Because PTX restored the depressed endothelial cell function and smooth muscle contractility, this agent appears to be a useful adjunct to fluid resuscitation for the management of trauma and hemorrhage.

Preservation of hepatic blood flow by direct peritoneal resuscitation improves survival and prevents hepatic inflammation following hemorrhagic shock

“…Reversing small intestinal vasoconstriction to prevent post-RES hypoperfusion has been achieved using agents including heparan sulfate, heparin, and pentoxifylline (10,41,43). We have focused on DPR to reverse the post-RES vasoconstriction in the ileum.…”

Effects of Dextran and Pentoxifylline on Hemorrhagic Shock-Induced P-Selectin Expression

“…A study using galactose clearance as an index of nutrient blood flow to liver demonstrated the improved restoration of blood flow to liver when pentoxifylline was administered during resuscitation of hemorrhagic shock [34]. Endothelium-dependent vascular relaxation and antagonist-induced vascular smooth muscle contractility (as indexes of endothelial function) have been shown to be preserved when pentoxifylline was used during resuscitation of hemorrhagic shock [35]. Pentoxifylline has been shown to reduce leukocyte adhesiveness to nylon wool columns, encountered after resuscitation of hemorrhagic shock [36].…”

Effect of lowering tumour necrosis factor-α on vascular endothelial function in Type II diabetes

“…Indeed, Lefer et al [35] reported that ACh-mediated endotheliumdependent relaxation of isolated aortic rings from cats, was impaired in the presence of TNFα. In addition, Wang et al demonstrated that the administration of TNFα to rats can induce endothelial dysfunction [25], that pentoxifylline reduces plasma TNFα [36], and that the impaired endothelial function associated with elevated TNFα [37] is improved by pentoxifylline [38]. Collectively, these studies suggest down-regulation of TNFα as a possible mechanism for the improvement in endothelial function observed with pentoxifylline.…”

“…In the study of incubated cat aortic rings, the effect of TNFα was dose-dependent and µg : ml −" , rather than pg : ml −" , concentrations were required to induce depression of endothelial function [35]. In addition, animal studies indicating that pentoxifylline can improve endothelial function were performed on a model of sepsis [38] which is associated with markedly enhanced TNFα production and much higher circulating levels [39] than studies have typically found in obese insulin-resistant subjects in whom TNFα is putatively derived from adipocytes [40].…”