No abstract

Although ATP-MgCl2 enhances the recovery of renal function after ischemia and reperfusion, it is not known whether this agent has any beneficial effects on renal microcirculation and function in a nonheparinized model of trauma and severe hemorrhage. To study this, a midline laparotomy was performed (i.e., trauma induced) and the rats were bled to and maintained at a mean arterial pressure of 40 mmHg (1 mmHg = 133.32 Pa) until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate (RL) solution. Animals were then resuscitated with 4 times the volume of the shed blood in the form of RL. ATP-MgCl2, 50 mumol/kg body weight, or an equivalent volume of saline, was infused intravenously during and following resuscitation. Renal microcirculation was examined by using colloidal carbon infusion and laser Doppler flow-metry. Glomerular filtration rate (GFR) was assessed with [3H]inulin clearance and cardiac output (CO) was determined by dye dilution technique. The results indicate that the depressed renal microcirculation following hemorrhage and resuscitation was restored by ATP-MgCl2 treatment. GFR was significantly higher in ATP-MgCl2-treated than saline-treated rats. ATP-MgCl2 also increased urine output, restored the decreased CO, and prevented the occurrence of renal edema after hemorrhage and resuscitation. Thus, ATP-MgCl2 appears to be a useful adjunct to crystalloid resuscitation following trauma and severe hemorrhagic shock even in the absence of blood resuscitation.

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.

Pentoxifylline appears to be a useful adjunct for maintaining hepatocellular function and improving cardiac performance during the early hyperdynamic stages of polymicrobial sepsis.

Since administration of PEG-(rsTNF-R1)2 maintains vascular endothelial cell structure and function, it can be concluded that TNF plays a pivotal role in producing endothelial dysfunction during sepsis. Thus, pharmacologic agents that inhibit TNF biologic activity and/or its production may be useful for protecting endothelial cells during sepsis.