Anesth Analg 2002;94:296-301
© 2002 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Sodium Nitroprusside Decreases Leukocyte Adhesion and Emigration After Hemorrhagic Shock
Masayuki Miyabe, MD*,
Kennichi Yanagi, MD
,
Norio Ohshima, PhD,
Shigehito Sato, MD
,
Taeko Fukuda, MD*, and
Hidenori Toyooka, MD*
*Department of Anesthesiology, Institute of Clinical Medicine, and Department of Biomedical Engineering, Institute of Basic Medical Science, University of Tsukuba, Tsukuba, Japan; and Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Japan
Address correspondence and reprint requests to Masayuki Miyabe, MD, Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan, 305-8576. Address e-mail to miyabe{at}igaku.md.tsukuba.ac.jp
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Abstract
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The adhesion of polymorphonuclear leukocytes to the capillary endothelium is one of the key events in the pathophysiology of hemorrhagic shock. We studied sodium nitroprusside (SNP) for its ability to modulate leukocyte-endothelial cell interactions induced by hemorrhagic shock and reinfusion of blood by using intravital microscopy of the rat mesentery. Administration of SNP at a dose of 0.1 µg · kg-1 · min-1 infusion neither significantly decreased mean arterial blood pressure nor significantly altered bleedout volumes in hemorrhagic rats, indicating that SNP at this dose did not modify the severity of the shock protocol. Resuscitation from 1 h of hemorrhagic shock (mean arterial blood pressure approximately 45 mm Hg) significantly increased the number of adherent and emigrated leukocytes in the rat mesenteric microcirculation. However, infusion of SNP, started 15 min before hemorrhage, and continued over the entire experimental period, markedly reduced the leukocyte adhesion after reinfusion and emigration during hemorrhagic shock and after reinfusion. We concluded that the nitric oxide donor SNP is effective at reducing the leukocyte-endothelial interaction after blood reinfusion after hemorrhagic shock in rats.
IMPLICATIONS: The IV infusion of 0.1 µg · kg-1 · min-1 of sodium nitroprusside, a dose that does not exert a significant vasodilator effect, reduces leukocyte adhesion and emigration after hemorrhagic shock.
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Introduction
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Hemorrhage can lead to therapy-resistant circulatory failure and multiple organ failure, which greatly contribute to the frequent mortality of critically ill patients (1). The adhesion of polymorphonuclear leukocytes (PMNs) to the capillary endothelium is one of the key events in the pathophysiology of hemorrhagic shock (2,3). The activation of PMNs then results in the release of oxygen-derived free radicals, lysosomal enzymes, or both. The relative contribution of PMNs becomes more apparent at later stages of hemorrhagic shock, and activation of PMNs may play a role in the transition of shock from the reversible to the irreversible phase (2–4). Nitric oxide (NO) is an endogenous inhibitor of the adherence of PMNs, and the basal NO release from L-arginine by the endothelium isoform of NO synthase (NOS) prevents leukocytes from adhering to the endothelium under physiologic conditions (5,6). However, some pathologic situations, such as coronary ischemia (7) or circulatory shock (8), result in an impairment of the biosynthesis and release of NO. It is therefore conceivable that enhanced NO concentration in the vicinity of the endothelium by NO donors might be useful during hemorrhagic shock.
There have been many studies demonstrating that NO donors or substrates enhance endothelial protection and reduce neutrophil adherence after ischemia-reperfusion and various types of shock. For example, it has been reported that the NO precursor L-arginine significantly enhances the survival of hemorrhagic rats (9) and that addition of exogenous NO via the NO donor S-nitroso-N-acetylpenicillamine (SNAP) exerts significant protective effects against hemorrhagic shock, including the maintenance of systemic blood pressure, preservation of vascular integrity, and attenuation of PMN accumulation in ischemic reperfused tissue (10). Further, we confirmed that SNAP administration during hemorrhagic shock reduced the mortality in dogs (11). Another study has shown that superfusion of rat mesenteric microvessels with the NO donor sodium nitroprusside (SNP) reduces microvascular dysfunction induced by ischemia and reperfusion (12). However, IV administration of SNP might be harmful during and after hemorrhagic shock, because SNP is a vasodilator and induces hypotension. The aim of this study was thus to examine whether IV SNP, in a dose that does not affect blood pressure, could reduce the leukocyte rolling, adhesion, and emigration that are thought to constitute the initial tissue damage during and after hemorrhagic shock (2,3). The dose of SNP, 0.1 µg · kg-1 · min-1, was chosen because it is a threshold vasodilator dose that decreased mean arterial pressure by <5% in preliminary experiments.
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Methods
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The study protocol was approved in accordance with the prescriptions for animal care and use by the University of Tsukuba. Twenty-eight male Wistar rats (Charles River, Kanagawa, Japan), weighing 350–450 g, were anesthetized by IM injection of pentobarbital sodium (100 mg/kg). A tracheostomy was performed, and the animals were mechanically ventilated to maintain an end-tidal CO2 value between 35 and 45 mm Hg throughout the experiment. A polyethylene catheter (PE-50) was inserted into the right common carotid artery for the measurement of mean arterial blood pressure (MABP) or to withdraw blood during hemorrhagic shock. Another polyethylene catheter was placed into the right external jugular vein for the administration of drug or vehicle. The abdominal cavity was opened via a midline laparotomy. A loop of the ileal mesentery was exteriorized through the midline incision, placed into a temperature-controlled, fluid-filled Plexiglas chamber, and transilluminated for observation of the mesenteric microcirculation via intravital microscopy.
The anesthetized animal was placed on the stage of an intravital microscope system (model BHWI; Olympus Optical Co., Tokyo, Japan). The ileum and mesentery were superfused throughout the experiment with warmed saline. The image was projected by a charge-coupled device video camera (model DXC-107A; Sony Co., Tokyo, Japan) onto a color high-resolution video monitor (model PVM-1445D; Sony Co.) by use of a recording lens (FK 3.3x; Olympus) and an objective lens (20x; Olympus). Red blood cell velocity was determined on-line by using a dual-sensor method as previously reported (13). This method gives the centerline erythrocyte velocity, which is digitally displayed on a meter and allows for the calculation of venular shear rates.
After a 20- to 30-min stabilization period, a 20- to 40-µm-diameter postcapillary venule was chosen for observation. The number of rolling, adhered, and emigrated leukocytes was determined off-line by playback analysis of the videotapes. The examiner of the videotapes was blinded to the groups. Leukocytes were considered to be rolling if they were moving at a velocity significantly slower than that of red blood cells. Leukocyte rolling was expressed as the number of cells moving past a designated point per minute. A leukocyte was judged to be adherent if it remained stationary for >30 s. Adherence was expressed as the number of leukocytes adhering to the endothelium per 100 µm of vessel length. Leukocyte emigration was expressed as the number per 100-µm length of venule. The diameter of postcapillary venule was measured on the television monitor. The wall shear rate was calculated as 
= 4 U/r, U = Vb/1.6, where is the wall shear rate, U is the mean blood velocity, Vb is the centerline erythrocyte velocity, and r is the internal radius of the venule.
Rats were subjected to hemorrhage by withdrawal of blood to allow MABP to be maintained at approximately 45 mm Hg. The decreased blood pressure was maintained for 1 h by withdrawal or injection of a small volume of blood into or out of the syringe. During hypotension, the shed blood was kept at room temperature in a heparinized (200 U) plastic syringe connected to the arterial cannula. After 60 min of hemorrhagic hypotension, the blood remaining in the syringe was reinfused over 5 min at a rate slow enough to prevent large increases in blood pressure. After reinfusion of shed blood, intravital observation was continued for 60 min.
The animals were divided into four experimental groups. In the Sham-Shock with Vehicle group (Sham Vehicle, n = 7), hemorrhagic shock was not induced, and normal saline was administered. In the Sham-Shock with SNP group (Sham SNP, n = 7), hemorrhagic shock was not induced, and SNP (0.1 µg · kg-1 · min-1) was administered. In the Vehicle group (n = 7), hemorrhagic shock was induced, and normal saline was administered at the rate of 4 mL · kg-1 · min-1. In the SNP-Treated group (SNP, n = 7), hemorrhagic shock was induced, and SNP (0.1 µg · kg-1 · min-1) was administered. SNP or its vehicle saline infusion was started 15 min before hemorrhagic shock or sham shock and continued over the entire experimental period at the rate of 4 mL · kg-1 · min-1. The dose of SNP was chosen because it was a threshold vasodilator dose that decreased mean arterial pressure by <5% in preliminary experiments. Rats were killed by an overdose of pentobarbital sodium when the intravital studies were completed. Video recordings were continuously made and analyzed at the following time points for quantification of leukocyte rolling, adherence, and emigration: B1 (baseline 1), B2 (baseline 2; 15 min after infusion of SNP or vehicle), H15 (at 15 min of hemorrhagic shock), H30 (30 min of hemorrhagic shock), H50 (50 min of hemorrhagic shock), R15 (15 min after reinfusion), R30 (30 min after reinfusion), R45 (45 min after reinfusion), and R60 (60 min after reinfusion).
All values for data listed in the text and figures are presented as means ± SEM. Data were compared by analysis of variance using post hoc analysis with the Scheffé F-test. Values of P < 0.05 were considered to indicate statistical significance in all cases.
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Results
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The volume of blood withdrawn to achieve hypotension did not differ significantly between the control and SNP groups (9 ± 1 and 8 ± 1 mL, respectively). Figure 1 illustrates the time course of MABP in the four experimental groups of rats. All groups of rats exhibited initial MABP values in the range of 90–120 mm Hg. In both the Sham-Vehicle and Sham SNP groups, MABP did not change significantly over the entire 135-min observation period. In both the Control and SNP groups, MABP was maintained at approximately 45 mm Hg throughout the 60-min hemorrhagic shock period (Fig. 1).
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Figure 1. Time course of mean arterial blood pressure (MAP) in the Sham-Shock with Vehicle group (Sham Vehicle, n = 7), Sham-Shock with Sodium Nitroprusside (SNP) group (Sham SNP, n = 7), Hemorrhagic Shock with Vehicle group (Vehicle, n = 7), and Hemorrhagic Shock with SNP group (SNP, n = 7). All values are mean ± SEM. B1 = baseline 1; B2 = baseline 2 (15 min after infusion of SNP or saline); H15 = 15 min of hemorrhagic shock; H30 = 30 min of hemorrhagic shock; H50 = 50 min of hemorrhagic shock; R15 = 15 min after reinfusion; R30 = 30 min after reinfusion; R45 = 45 min after reinfusion; R60 = 60 min after reinfusion. In both the Vehicle and SNP groups, MAP was maintained at approximately 45 mm Hg throughout the 60-min hemorrhagic shock period.
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Venular centerline erythrocyte velocity, diameter, and wall shear rates for the four experimental groups of rats are reported in Table 1. Venular velocity decreased significantly during hemorrhagic shock in the Control and SNP groups. In all four groups, the diameters during hemorrhagic shock and reinfusion were identical to but not significantly different from those at baseline. Shear rates in the mesenteric venules abruptly decreased to approximately 30% of the initially observed control values after hemorrhage. Thus, this hemorrhagic shock model was characterized by a marked hypoperfusion of the splanchnic microvasculature during the oligemic phase. Upon reinfusion of shed blood, however, the venular shear rates returned nearly to the baseline values.
The number of leukocytes rolling at 60 min after reinfusion in the Hemorrhagic Shock with Vehicle group was significantly larger than that in the Hemorrhagic Shock with SNP group (Fig. 2). The number of adherent leukocytes in the Hemorrhagic Shock with Vehicle group was significantly more than those in the other three groups at 45 and 60 min after reinfusion (Fig. 3). The number of emigrated leukocytes in this group was also more than those in the other three groups at 30 min of hemorrhage and thereafter (Fig. 4).
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Figure 2. The number of leukocytes rolling in rat mesenteric venule (mean ± SEM). The number of leukocytes rolling in the Vehicle group was significantly larger than those in the SNP group at 45 and 60 min after reinfusion. B1 = baseline 1; B2 = baseline 2 (15 min after infusion of SNP or saline); H15 = 15 min of hemorrhagic shock; H30 = 30 min of hemorrhagic shock; H50 = 50 min of hemorrhagic shock; R15 = 15 min after reinfusion; R30 = 30 min after reinfusion; R45 = 45 min after reinfusion; R60 = 60 min after reinfusion; SNP = sodium nitroprusside.
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Figure 3. The number of adherent leukocytes in rat mesenteric venule (mean ± SEM). The number of adherent leukocytes in the Vehicle group was significantly larger than those in the SNP group at 45 and 60 min after reinfusion. B1 = baseline 1; B2 = baseline 2 (15 min after infusion of SNP or saline); H15 = 15 min of hemorrhagic shock; H30 = 30 min of hemorrhagic shock; H50 = 50 min of hemorrhagic shock; R15 = 15 min after reinfusion; R30 = 30 min after reinfusion; R45 = 45 min after reinfusion; R60 = 60 min after reinfusion; SNP = sodium nitroprusside.
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Figure 4. The number of emigrated leukocytes in rat mesenteric venule (mean ± SEM). The number of emigrated leukocytes in the Vehicle group increased during hemorrhagic shock and reinfusion and was more than those in the other groups at 30 min of hemorrhage and thereafter. B1 = baseline 1; B2 = baseline 2 (15 min after infusion of SNP or saline); H15 = 15 min of hemorrhagic shock; H30 = 30 min of hemorrhagic shock; H50 = 50 min of hemorrhagic shock; R15 = 15 min after reinfusion; R30 = 30 min after reinfusion; R45 = 45 min after reinfusion; R60 = 60 min after reinfusion; SNP = sodium nitroprusside.
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Discussion
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The administration of SNP at a dose of 0.1 µg · kg-1 · min-1 infusion neither significantly decreased MABP nor significantly altered bleedout volumes in hemorrhagic rats, indicating that SNP at this dose did not modify the severity of the shock protocol. Resuscitation from one hour of hemorrhagic shock (MABP approximately 45 mm Hg) significantly increased the number of adherent and emigrated leukocytes in the rat mesenteric microcirculation. However, infusion of SNP, started 15 minutes before hemorrhage and continued over the entire experimental period, markedly reduced the leukocyte adhesion and emigration occurring during hemorrhagic shock and after reinfusion. Our findings partially support those of the previous reports, which have shown that NO is beneficial during ischemia and reperfusion. For example, the experimental administration of NO precursors, such as L-arginine (9,14), or NO donors (8,10,15) is beneficial in improving the survival rate of animals exhibiting hemorrhagic shock.
Previous studies have reported that IV infusion of NOS inhibitor (NOSI) induces leukocyte adhesion (5,6). Therefore, physiologic NO synthesis might be essential for maintaining the physiologic function of leukocytes. Because NO production is reduced during hemorrhagic shock (7,8), the administration of exogenous NO may protect against hemorrhagic shock and reperfusion injury. Superfusion of rat mesenteric microvessels with SNP reduces the leukocyte-endothelial interaction (12). However, there has been no report on the effect of IV NO donors on endothelial-leukocyte interactions after hemorrhage and reinfusion of blood using intravital microscopy. In this study, it was clearly demonstrated that a small dose of SNP decreased the interaction between leukocytes and the endothelium.
Several mechanisms by which NO donors decrease leukocyte-endothelial cell adhesion have been proposed. These include inactivation of superoxide (16), which stimulates adhesion molecule expression and leukocyte adherence (5) and prevents neutrophil activation and adhesion molecule expression, and enhancement of the wall shear rate (12).
Alterations in venular shear rate can exert a significant influence on leukocyte adhesion in postcapillary venules. Reductions in the venular shear rate tend to promote leukocyte adhesion, whereas increases in shear rate would be expected to decrease leukocyte adhesion. In this study, we noted that the MABP and the venular blood flow and wall shear rate did not differ between the Saline Control and SNP groups after reinfusion. It is therefore unlikely that the perturbations in local hemodynamics were a cause of the adhesion response after hemorrhage or reinfusion.
Another possible mechanism is the effect of NO donors on blood pH, because acidosis influences neutrophil integrin receptors in trauma patients (17). It is possible that the decrease of neutrophil adhesion and emigration in this study might be caused by increased blood pH by SNP infusion. However, in our previous study (11), the administration of an NO donor, SNAP, during hemorrhagic shock in dogs did not alter arterial blood pH compared with that in saline-administered controls. Furthermore, in this study venular blood flow and diameter did not change by SNP compared with that in saline-administered controls, and thus SNP might have had only a minimal effect on peripheral circulation and pH. However, because we did not measure blood pH in this study, we cannot exclude the possibility.
SNP is a nitrovasodilator that is metabolized by smooth muscle cells to its active metabolite, NO, and that dilates both arterioles and venules (18). In this experiment we administered SNP at the rate of 0.1 µg · kg-1 · min-1, which affected the microvessel minimally. The dose was chosen because, in preliminary experiments, it did not affect the MABP or the mesenteric venule diameter. Although this dose of SNP did not affect either blood pressure or the diameter of postcapillary venules, SNP may decrease blood pressure during hemorrhagic shock in humans. Further studies will therefore be needed before SNP can be applied clinically in cases of hemorrhagic shock.
NO has been implicated in the pathophysiology of hemorrhagic shock. However, the role of NO during hemorrhagic shock and after reperfusion is still controversial. Hemorrhagic shock leads to an inhibition of NO production by the calcium-dependent endothelial NOS, which may enhance the adhesion of leukocytes and platelets to the endothelial surface (19). In contrast, prolonged periods of hemorrhagic shock are associated with the induction of a calcium-independent isoform of NOS in a variety of organs and in the vascular smooth muscle (20–23). This formation of large quantities of NO by the inducible isoform of NOS contributes to the delayed vascular decompensation and to the hyporeactivity of the vasculature to vasoconstrictor drugs. Therefore, inhibition of NO overproduction after inducible NOS expression—as induced by a NOSI (24,25) or NO scavenger (26)—may have beneficial effects during or after hemorrhagic shock. In our study, SNP might have decreased the leukocyte-endothelial interaction by enhancing NO concentration in the vicinity of the endothelium. However, a small dose of NO donor can inhibit the activation of inducible NOS (27). It is also possible, therefore, that excessive NO production was inhibited by the small dose of SNP used here. In contrast, other reports have shown that NOSI administration in hemorrhagic shock provides no beneficial effects on hemodynamics and can even worsen gastric mucosal injury (28) or alter coronary circulation (29). Although both NO donors and NOSI might have benefits in treating hemorrhagic shock, the complete deficit of NO production, as well as the excessive release of NO, may induce hyporeactivity to vasopressor drugs and decompensation in hemorrhagic shock.
In summary, IV administration of a small dose of SNP, a dose that did not exert a significant vasodilator effect, reduced leukocyte-endothelium interaction during hemorrhage and after reinfusion.
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Acknowledgments
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Supported by Research for the Future Program Grant JSPS-RFTF96I00202 from the Japan Society for Promotion of Science and Grant-in-Aid 12671450 for Scientific Research from the Ministry of Education, Science, and Culture, Tokyo, Japan.
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Accepted for publication October 2, 2001.
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Abstract
Introduction
