Reperfusion

Inhibits Elevated Splanchnic Prostanoid

Production After

Hemorrhagic Shock

STUART 1. MYERS, M.D., F.A.C.S., BETTY J. TAYLOR, B.S, and MARIA STANISLAWSKA

The effect of reperfusion following hemorrhagic shock on splanchnic prostanoid release was studied. Anesthetized male rats were bled to a mean arterial blood pressure of 30 mmHg for 30 minutes and either killed or treated with shed blood for 60 minutes and then killed. The superior mesenteric arterial bed was cannulated and perfused in vitro with oxygenated Krebs. Collected venous effluent (up to 180 minutes) was analyzed for 6-keto-PGFI, (PGI2 metabolite), PGE2, PGF2, and thromboxane B2 by radioimmunoassay in shock, shock plus reperfusion, and sham groups. The major prostanoid released was 6-ketoPGFIa and was three times higher in the shock group compared to the sham group (p < 0.05). Reperfusion of shed blood abolished the increase in 6-keto-PGFi1 found in the shock group (p < 0.05). These data show that the attempt of the rat splanchnic bed to compensate for hemorrhagic shock by increasing release of PG12 (potent vasodilator) was abolished during reperfusion of blood.

T n HE GASTROINTESTINAL TRACT has been described as the motor organ in the production of multiple-organ failure. This hypothesis describes alterations in the gastrointestinal mucosal barrier following hemorrhagic shock and resuscitation. Disruption of the mucosal barrier allows bacterial translocation and systemic release of bacterial toxins. These bacterial products contribute to multiple-organ failure and subsequent death.'" The factors that alter splanchnic blood flow during acute hemorrhagic shock and subsequent resuscitation are not known. Splanchnic vascular prostanoids (PGs) are locally produced paracrine substances that are thought to be one of several factors contributing to regulation of splanchnic vascular flow.5 These factors include age, sex, dietary lipids, sympathetic tone, ischemia, hormones, and shock.5 22 These factors can act as stimuli for the release of either This project was funded by NIH Grant 38529. Address reprint requests to Stuart I. Myers, M.D., Department of Surgery, University of Texas, Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9031. Accepted for publication November 4, 1989.

From the Department of Surgery, University of Texas Medical School at Houston, Houston, Texas

vasodilator or vasoconstrictor PGs. The resulting balance of potent vasoactive PGs represents one important factor that contributes to the overall vascular tone of the splanchnic vascular bed. Recently we compared splanchnic PG release in acute hemorrhagic shock to sham-operated controls in vitro in the rat. In this study rats were subjected to hemorrhagic shock without reperfusion of shed blood to determine specifically if the splanchnic bed can compensate for decreased flow secondary to the shock by release of vasodilator prostanoids. Hemorrhagic shock markedly increased the release of PGI2 (potent vasodilator) but not thromboxane B2 (TxB2), PGE2, or PGF2< when compared to sham-operated controls.'3 This study examines the hypothesis that the capability of the splanchnic vascular bed to compensate for shock by release of PGI2 is inhibited by reperfusion of the shed blood. This study will use the technique of in vitro perfusion of the rat superior mesenteric artery with its viscera in continuity (splanchnic vessels and small intestine [SV + SI]). This technique allows accurate determination of alterations in endogenous prostanoid release from the superior mesenteric arterial bed without contamination with exogenous sources. Materials and Methods Preparation of Shock Rat Model Male Sprague-Dawley rats weighing approximately 300 g were used for all studies. Regulations of The University of Texas Medical School at Houston for the care and use of animal subjects were followed rigidly. All animals were fasted overnight and anesthetized by methoxyflurane inhalation. The necks and groins were shaved and washed with providine iodine and 70% ethanol. The right com-

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REPERFUSION INHIBITS RAT SPLANCHNIC PGI2

mon carotid artery and the right femoral artery were cannulated with PE-50 and PE-20 polyethylene cannulas, respectively. The carotid artery catheter was attached to a pressure transducer (Deseret Model 8000) and connected to a Keithley 500 system (Keithley AMM 1) and interfaced to an IBM PC/XT computer. Arterial pressure and pulse were monitored continuously and stored throughout the study period using this equipment. Animals received 50 units of heparin and hypovolemic shock was induced in all animals by withdrawing a sufficient volume of blood to reduce the mean arterial pressure to 30 mmHg (acute hemorrhagic shock group, SK). This level of shock was maintained for 30 minutes by withdrawing or infusing shed blood as required. The animals of the SK group were killed at this time. The animals in the SK + R group (acute shock plus perfusion) were treated with the shed blood, allowed to recover for 60 minutes, and then killed. Instrumented but nonshocked animals served as controls for both groups (SK + SM, SK + R + SM).

Preparation of Rat Isolated Mesenteric Perfusion The technique of rat isolated splanchnic perfusion was described previously by our laboratory and is a modification of the technique described by McGregor. 13,23-25 A midline laparotomy was performed after the abdomen was washed with providine iodine. The superior mesenteric artery was isolated, rapidly cannulated with PE-50 tubing, and removed with its terminal splanchnic vessels and end organ (intestine, SV + SI). The ends of the bowel were cannulated and vented outside the warming apparatus to avoid distention. The SV + SI was perfused at 3 mL/minute using a Cole-Parmer peristaltic pump (ColeParmer Instrument Co., Chicago, IL) with oxygenated (PO2 460 ± 10 mmHg) Krebs-Henseleit buffer pH 7.4 at 37 C. The perfusion pressure was monitored constantly via a side arm of the arterial cannula using a Statham pressure transducer (Grass Instruments, Quincy, MA). The splanchnic venous effluent was collected after 15, 30, 60, 90, 120, 150, and 180 minutes of perfusion in the SK, SK + SM, SK + R, and SK + R + SM groups. Each sample was collected, placed in siliconized microcentrifuge tubes, and immediately frozen at -40 C until assayed. Radioimmunoassays for 6-keto-PGF,a (stable metabolite of PGI2), thromboxane B2 (stable metabolite of thromboxane A2, TxB2), PGF2a, and PGE2 were performed within a 2-week period of each experiment. Cyclooxygenase inhibition by indomethacin was used as a control to confirm the specificity of the radioimmunoassay in the shock group. We have previously shown that indomethacin treatment decreased basal splanchnic prostanoids by approximately 70%.25 In the current study indomethacin (20 ,g/mL) was added to the perfusate in the shock group by a separate infusion line and samples were collected as described above.

689

Radioimmunoassay Radioimmunoassays were performed as previously described. 13'25 6-keto-PGF,a, thromboxane B2 (TxB2), PGF2a, and PGE2 were measured from the unextracted effluent perfusate by radioimmunoassay. The assay reaction occurred in a volume of 300 uL consisting of 100 gL each of sample (or standard), radiolabeled tracer ligand, and specific antisera, all incubated at 27 C for 2 hours. Bound and free fractions of ligand were separated by adding 500 ,L dextran-coated charcoal (DCC, see below) followed by centrifugation at lOOOg (2400 rpm) for 20 minutes. The supernatant containing the antibody-bound component then was decanted. Five milliliters of Aquasol (NEN Research Products, Boston, MA) was added and beta emissions were counted on an LKB Rack Beta 1217 scintillation counter (LKB Instruments, Inc., Gaithersburg, MD). All samples and standards were assayed in duplicate. The assay buffer, used to dilute the antisera, radiolabeled ligands, and in preparing DCC consisted of 50 mmol/L (millimolar) TRIS pH 7.5 (Trizma base and HCI, Sigma Chemical Co., St. Louis, MO) with 0.1% biologic grade gelatin (porcine, bloom number = 300; Aldrich, Milwaukee, WI) and 0.01% sodium azide (Sigma). Dextran-coated charcoal was 7 mg Norite-A activated carbon (Aldrich) and 0.360 mg Dextran (T-70, Aldrich) per milliliter of assay buffer. Unlabeled PGE2, 6-keto-PGF,l, PGF2a, and TxB2 (Sigma) were kept refrigerated at 100 ng/mL in assay buffer (TRIS). For each assay serial dilutions in Krebs buffer were made for seven standards ranging from 2.7 to 2000 pg/100 uL. Tritiated standards (Amersham Co., Arlington Heights, IL) of 0.1 mCi/mL had specific activities of 157 Ci/mmole 6-keto PGF10, 178 Ci/mole TxB2, 179 Ci/mole PGF2a, and 184 Ci/mmole PGE2. Antisera was obtained in lyophilized form from Dr. Lawrence Levine, Department of Biochemistry, Brandeis University (TxB2 and 6-keto PGFIa) and Advanced Magnetics (Cambridge, MA) (PGE2, PGF2a). Dilutions in assay buffer of 1:12,000, 1:18,000, 1:5,000, 1:6000 for 6-ketoPGF,,, TxB2, PGE2, and PGF2a, respectively, were used to obtain 40% to 60% binding of a zero standard 'blank.' Cross-reactivity of antisera from Dr. Levine has been published: for 6-keto PGFIa, less than 1% to PGF2a, PGD2, TxB2, and 13,14-H2-PGE2;. for TxB2 antisera, less than 1% PGF2a, PGD2, 6-keto PGF2a, 13,14-H2-PGE2, and 6keto PGF,a 26; cross-reactivity of PGE2 and PGF2a antisera given by Advanced Magnetic for PGE2 was 50% to PGE,, 6% to PGA2, 3% to PGA,, 1.3% to PGF2a, less than 1% to TxB2 and 6-keto PGF,a; for PGF2a, 100% to PGFi,a, 1.1% to PGE,, 1.1% to 6-keto-PGF,a, 0.5% to TxB2, 0.3% to PGE2, less than 0. 1% to PGD2, less than 0. 1% to PGA2, less than 0.1 % to PGA,, less than 0.1 % to PGB,, less than

690

MYERS, TAYLOR, AND STANISLAWSKA

0.1% to PGB2, less than 0. 1% to 13, 14-Dihydro- 1 5-ketoPGF2a, and less than 0.1% to 6-keto-PGE,. All samples and standards were measured in duplicate. The standard curve was constructed using the smoothspline function (RIA computer package SecuRIA, Packard, Downers Grove, IL). Unbound, unabsorbed tracer (referred to as 'nonspecific binding') was quantified in tubes containing only labeled ligand and DCC. Interassay and intra-assay variation was 7% to 9% for 6-keto-PGFi,a, PGF2a, and TxB2, while variation was 14% to 15% for PGE2. Sensitivity, the amount of unlabeled standard causing 10% reduction from maximal binding of the blank, was approximately 8 pg. (This was equivalent to 240 pg/minute at the flow rate of 3 mL/minute used in these experiments.

Statistical Analysis Data is reported as mean ± SEM (ng/min) for all groups. One-way analysis of variance and analysis by Duncan's post hoc test were used for all groups, except where indicated in Table 1. Differences in mean values were considered significant at a p value for type I error of less than 0.05. Results As previously reported the perfused SV + SI from the SK + SM group released 6-keto-PGF,a, PGE2, PGF2a, and TxB2 at all time periods measured. Prostanoid release was maximal at 15 and 30 minutes of perfusion and decreased to a stable baseline at 60 minutes of perfusion until the 180-minute time of perfusion when prostanoid release again increased (Figs. 1 to 4, Table 1). 6-ketoPGFi,a was the major prostanoid released in the SK + SM

Ann. Surg. * December 1990

group and was 3.5 to 6 times higher than the other PGs at 15 and 30 minutes of perfusion (Fig. 1, Table 1). Prostanoid release was increased two or more times in the SK group compared to the SK + SM group at all time periods studied (Figs. 1 to 4, Table 1), as previously described.'3 6-keto-PGFIa release was increased significantly in the SK group at 15 and 30 minutes of perfusion (Fig. 1, Table 1). Cyclooxygenase inhibition by indomethacin (20 ,ug/mL; Sigma) decreased SK released of 6-ketoPGFi,a, TxB2, and PGF2a by 60% to 70% at 15 and 30 minutes of perfusion, whereas PGE2 release was decreased by only 15% to 33% (Table 1). The indomethacin data suggests that acute shock increased release of 6-ketoPGFi,a and to a lesser extent TxB2 and PGF2a release and not PGE2The SK + R + SM group released prostanoids at all time periods and was similar to the SK + SM group (Figs. 1 to 4). 6-keto-PGFia was the major PG released and was two or more times higher than the other PGs (Figs. 1 to 4). Treatment ofthe SK animals with shed blood followed by recovery for 60 minutes completely abolished the general increase in prostanoid release described in the SK group. In fact 6-keto-PGF,a release was decreased four times in the SK + R group when compared to the SK group (Fig. 1, Table 1). Perfusion pressure was not altered in the SK or SK + R groups when compared to the sham groups.

Conclusions The gastrointestinal tract has been hypothesized to play a major role in the evolution of the clinical syndrome of multiple-organ failure. This hypothesis encompasses the notion that clinical hemorrhagic shock and resuscitation

TABLE 1. The Effect of Acute Hemorrhagic Shock (SK) and Acute Shock + Perfusion (SK + R) on Rat Splanchnic Prostanoid Release

Group/Time 15 Minutes SK + SM SK SK + SM + R SK+R SK + Indo 30 Minutes SK+SM SK SK+SM+R SK+R SK + Indo *

N

6-keto*

TxB2t

PGE2

PGF2ca

8 10 8 6 4

7.6 ± 1.6 19.0 ± 4.0§ 6.6 ±1.1 4.5 ±0.5§ 8.4 ± 2.4¶

1.2 ± 0.21" 3.5 ± 1.6** 1.7 ± 0.21"

2.1 ± 0.4"1

1.0 ± 0.3

2.1 ± 0.21" 4.5 ± 1.2** 3.8 ± 0.3 3.4±0.4 3.0 ± 0.6

5.3 ± 2.2** 2.3 ± 0.3 1.9±0.1 1.6 ± 0.4

8 10 8 6 4

4.0± 1.0 11.0 ± 2.8 3.5±0.6

0.7±0.1 1.1 ± 0.4** 1.0±0.1 0.9±0.1 0.4 ± 0.1

1.1 ±0.2 2.1 ± 0.5** 2.6±0.4 1.8±0.3 0.8 ± 0.5

1.4±0.3 2.7 ± 0.7** 1.7±0.1 1.3±0.1 0.7 ± 0.2#

2.0±0.2§ 3.2 ± 0.71

6-keto, 6-keto-PGFI,,.

t TxB2, thromboxane B2. t Significant at p < 0.05 compared to SK + SM in same group and time. § Significant at p < 0.05 compared to SK in same group and time. 11 Significant at p < 0.05 compared to SK + SM or SK + SM + R

1.8±0.2

6-keto. 1I Significant at p < 0.05 compared to SK 6-keto (Student's unpaired t test). # Significant at p < 0.05 compared to SK PGF2a,, (Student's unpaired t test). ** Significant at p < 0.05 compared to SK 6-keto.

and cecal ligation, and puncture as models of shock. Hemorrhage, splanchnic artery occlusion, and cardiac tamponade are other etiologies of shock developed to delineate this question. The studies performed since the discovery of PGI2, a potent vasodilator, and thromboxane A2, a potent vasoconstrictor, have implicated an increased release of TxB2 with mortality rates after experimental shock in animals.""'5 Inhibition of increased serum TxB2 levels with thromboxane synthetase inhibitors, cyclooxygenase inhibitors, and alterations in essential fatty acids decreased the number of shock-induced deaths. These studies have left several important questions unanswered. What is the source of enhanced prostanoid synthesis and

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REPERFUSION INHIBITS RAT SPLANCHNIC PGI2

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Minutes of Perfusion FIG. 1. Comparison of 6-keto-PGFI,X output from the perfused male rat splanchnic vessels and small intestine (SV + SI) in (A) acute hemorrhagic shock (SK) and sham groups (SK + SM) and (B) SK plus reperfusion (SK + R) and sham groups (SK + R + SM). All animals were perfused for 180 minutes. Values are given as mean ± SEM. (A) n = 10 SK, n = 8 SK + SM; * indicates p < 0.05 compared to SK + SM. (B) n = 6 SK + R, n = 8 SK + R + SM; ** indicates p < 0.05 compared to SK + R + SM.

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lead to a decrease in splanchnic blood flow. Decreased splanchnic flow affects the metabolically more active intestinal mucosa than the muscularis. Mucosal injury leads to a breakdown of the mucosal barrier to enteric bacteria, which then 'translocate' to the liver, regional lymph nodes, and so on. Release of toxic bacterial products affects normal physiologic function of the liver, lungs, kidneys, and heart and leads to progressive multiple-organ failure and subsequent death of the patient.'" The factors that regulate alterations in splanchnic flow in this scenario are not known. Elevations in serum levels of all prostanoids have been described following several types of experimental shock. 3 22 Most ofthese studies have used endotoxin shock, sepsis

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Minutes of Perfusion FIG. 2. Comparison of thromboxane B2 output from the perfused male rat splanchnic vessels and small intestine (SV + SI) in (A) acute hemorrhagic shock (SK) and sham groups (SK + SM) and (B) SK plus reperfusion (SK + R) and sham groups (SK + R + SM). All animals were perfused for 180 minutes. Values are given as mean ± SEM. (A) n = 10 SK, n 8SK + SM. (B) n 6SK + R, n 8SK + R + SM. =

=

=

692

Ann. Surg. * December 1990

MYERS, TAYLOR, AND STANISLAWSKA

release following shock? Does PGI2 play a role in alterations in vascular flow during shock? The data from this study supports our previous work that examined alterations in splanchnic prostanoid release after acute hemorrhagic shock. This preliminary study showed that treatment ofthe rats with acute hemorrhagic shock increased prostanoid release with the most substantial increase in 6-keto-PGFIa (PGI2) when compared to sham-operated controls.13 We attributed the marked increase in SK 6-keto-PGFIa (PGI2, a potent vasodilator) release as a compensatory mechanism of the rat splanchnic vascular bed to early acute shock and hypovolemia to maintain splanchnic flow. Previous data from our lab-

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FIG. 4. Comparison of PGF2. output from the perfused male rat splanchnic vessels and small intestine (SV + SI) in (A) acute hemorrhagic shock (SK) and sham groups (SK + SM) and (B) SK plus reperfusion (SK + R) and sham groups (SK + R + SM). All animals were perfused for 180 minutes. Values are given as mean ± SEM. (A) n = 10 SK, n = 8 SK + SM; (B) n = 6 SK + R, n = 8 SK + R + SM..

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FnG. 3. Comparison of PGE2 output from the perfused male rat splanchnic vessels and small intestine (SV + SI) in (A) acute he morrhagic shock (SK) and sham groups (SK + SM) and (B) SK plus reperfusion (SK + R) and sham groups (SK + R + SM). All animals %were perfused for 180 minutes. Values are given as mean ± SEM. (A) n SK + SM; (B) n =6SK + R, n = 8SK + R + SM.

oratory also demonstrated the splanchnic visceral bed (intestine) and not the splanchnic vessels as the site of synthesis of 90% of TxB2 and PGE2 released and 60% to 80% of the 6-keto-PGFI,a released in our model.25 In the context of these data, we suggest that the attempt at compensation for decreased splanchnic visceral blood flow by increasing PGI2 release is located within the intestine itself. In the present study, reperfusion of the shed blood after acute hemorrhage totally abolished the rise in prostanoid levels described in the SK group. These data suggest that reperfusion inhibits the attempt by the splanchnic visceral =8 lsbed to compensate for acute hemorrhage rSK,s byo increasing =

synthesis

and release of

P?GI2.

Vol. 212 * No.6

REPERIFUSION INHIBITS RAT SPLANCHNIC PGI2

We believe that one of the factors responsible for reperfusion inhibition of increased prostanoid release following acute hemorrhage may be related to the production of lipid peroxides or oxygen-derived free radicals. Oxygenderived free radicals and lipid peroxides have been described as one type of mediator of tissue injury following ischemia. The hypothesis implicating oxygen-derived free radicals in tissue injury describes conversion of xanthine dehydrogenase to the superoxide-producing oxidase. Xanthine oxidase catalyses production of accumulated hypoxanthine (ATP metabolite) and oxygen to xanthine and superoxide radicals.27-30 The superoxide radicals are believed to alter cell viability by peroxidation of lipid components. Lipid peroxides have been shown to inhibit cyclooxygenase and more specifically prostacyclin synthetase.3' We hypothesize that oxygen free radicals or other lipid peroxides formed during ischemia are introduced into the splanchnic visceral bed during reperfusion. These toxic metabolites alter splanchnic PGI2 biosynthesis and release, abolishing the attempt of the splanchnic visceral bed to maintain blood flow following acute hemorrhagic shock.

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Reperfusion inhibits elevated splanchnic prostanoid production after hemorrhagic shock.

The effect of reperfusion following hemorrhagic shock on splanchnic prostanoid release was studied. Anesthetized male rats were bled to a mean arteria...
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