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Anesth Analg 1999;89:218
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

The Effects of Cimetidine, Ranitidine, and Famotidine on Human Neutrophil Functions

Katsuya Mikawa, MD*, Hirohiko Akamatsu, MD{dagger}, Kahoru Nishina, MD*, Makoto Shiga, MD*, Nobuhiro Maekawa, MD*, Hidefumi Obara, MD*, and Yukie Niwa, MD{ddagger}

*Department of Anaesthesiology and Intensive Care Unit, Kobe University School of Medicine, Kobe; {dagger}Department of Dermatology, Kansai Medical College, Moriguchi, Osaka; and {ddagger}Niwa Institute for Immunology, Kochi, Japan

Address correspondence and reprint requests to K. Mikawa, MD, Department of Anaesthesiology and Intensive Care Unit, Kobe University School of Medicine, Kusunoki-cho 7, Chuo-ku, Kobe 650-0017, Japan.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Neutrophil functions, which play an important role in the antibacterial host defense system, are inhibited by various anesthetics and surgical procedures. Histamine H2-receptor antagonists are perioperatively used as a prophylaxis against acid aspiration syndrome or stress ulceration. We examined the effect of cimetidine, ranitidine, and famotidine, at clinically relevant concentrations and at 10 and 100 times this concentration, on several aspects of human neutrophil function using an in vitro system. The three H2-receptor antagonists did not impair neutrophils' chemotaxis or phagocytosis. Cimetidine and famotidine inhibited superoxide (O2-) and hydrogen peroxide (H2O2) production of the neutrophils in a dose-dependent manner, although the inhibitory effects were minimal. In contrast, ranitidine failed to change O2- or H2O2 production of neutrophils. The three H2-receptor antagonists did not scavenge these reactive oxygen species generated by the xanthine-xanthine oxidase system. The increase in intracellular calcium concentrations in neutrophils by a stimulant were dose-dependently attenuated with cimetidine or famotidine. This decreasing effect of the drugs on [Ca2+]i in neutrophils may represent one of mechanisms responsible for inhibition of reactive oxygen species generation.

Implications: Neutrophils play a pivotal role in the antibacterial host defense system and tissue injury. We found that cimetidine and famotidine slightly reduced the O2- or H2O2 production of neutrophils in a dose-dependent manner, although ranitidine failed to do so. At least ranitidine does not seem to have any deleterious effect on neutrophil function, which is clearly an important consideration in its use in severely ill patients.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
It is well recognized that anesthetic and surgical procedures inhibit several functions of neutrophils (1), which play a crucial role in the antibacterial host-defense mechanism as a component of nonspecific cell-mediated immunity (2). Histamine H2-receptor antagonists such as cimetidine, ranitidine, and famotidine are widely used for prophylaxis against the aspiration of gastric content syndrome (3). These drugs are also given to patients undergoing major surgery (e.g., cardiovascular surgery, neurosurgery, organ transplantation) to prevent stress ulceration (4). Critically ill patients in the intensive care unit (ICU) often receive H2-receptor antagonists for the same purpose (4). These patients are potentially immunocompromised. Histamine compromised suppresses human neutrophil superoxide (O2-) production via H2-receptors on neutrophils (5–7). Cimetidine and famotidine antagonize the histamine-induced inhibition of neutrophil function (5–7). Although several articles are available regarding the effects of the H2-receptor antagonists per se on the production of reactive oxygen species (ROS) by neutrophils, these studies have yielded conflicting results (7–10). Hydrogen peroxide (H2O2) is considered to be an important oxygen derivative and is of major concern because of its more potent oxidative activity to kill microorganisms or to injure host tissues (11). However, only one group has addressed the effects of cimetidine on this oxygen-toxic metabolite. Most studies have not specified the types of oxygen metabolites because chemiluminescence is used to assess ROS production. Chemotaxis and phagocytosis are among the most important neutrophil functions. There is disagreement among researchers concerning the effects of H2-receptor antagonists on these neutrophil functions (12–14). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is responsible for the production of O2-, exists in the membrane of neutrophils (2). Cimetidine is so highly lipid-soluble that it may accumulate in the lipid membranes, leading to alteration of the membranes' physical properties. This may change conformation of the membrane-bound enzyme, consequently impairing O2- generation. It is conceivable that cimetidine reduces ROS production through this mechanism. However, there are no comparative studies concerning the effects of these representative H2-receptor antagonists on the neutrophil function. We investigated the effects of cimetidine, ranitidine, and famotidine on neutrophil chemotaxis, phagocytosis, and the production of O2- and H2O2. We also examined whether these drugs can scavenge excess ROS generated using a cell-free system. Furthermore, to elucidate the mechanism underlying the effects on neutrophil functions, if observed, we determined intracellular calcium ion concentrations ([Ca2+]i) in neutrophils.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Neutrophils were isolated from heparinized venous blood from 12 healthy volunteers after receiving institutional approval and informed consent. After centrifugation of the blood over a Ficoll-Hypaque® gradient (Pharmacia, Uppsala, Sweden), the plasma-containing upper layer, mononuclear cell layer, and remaining cell pellet were removed separately. The plasma was freed of platelets by centrifugation (1400g for 10 min). The cell pellet containing neutrophils and erythrocytes was washed with saline solution and resuspended in plasma containing dextran 170 at a final concentration of 1%. The neutrophils were recovered after sedimentation at unit gravity, and the few contaminating erythrocytes were lysed by treatment of the preparation with 0.876% NH4Cl. The neutrophils were then resuspended in media appropriate for their subsequent use: Rosewell Park Memorial Institute (RPMI) 1640 medium for chemotaxis assay, Krebs-Ringer phosphate (KRP) buffer for phagocytosis assay, and KRP buffer containing glucose (5 mM) and gelatin (1 mg/mL) for the assay of O2- generation.

Neutrophil viability after incubation with these drugs was determined by using the trypan blue exclusion test. When >5% of the neutrophils were stained with trypan blue, their function was considered to have been impaired, and the results were discarded.

Cimetidine, ranitidine, or famotidine (Sigma Chemical Company, St. Louis, MO) did not contain any preservative and was diluted with 0.1% (at final concentration) dimethyl sulfoxide (DMSO). One of the three H2-receptor antagonists (0.1 or 0.2 mL except chemotaxis assay) was placed in the measuring cuvette to a total volume of 1 or 2 mL, giving the following final concentrations of the three H2-receptor antagonists: cimetidine 0, 1, 10, and 100 µg/mL; ranitidine 0, 0.1, 1, and 10 µg/mL; and famotidine 0, 0.02, 0.2, and 2 µg/mL. However, for chemotaxis assay, 20 µL of each H2-receptor antagonist was added to the upper compartment of a Boyden chamber to a total volume of 0.2 mL. These concentrations corresponded to 1, 10, and 100 times clinical plasma concentrations (15).

Neutrophil chemotaxis was determined by using a modified Boyden chamber (16). A siliconized or nonsiliconized glass tube (4.5 mm in diameter, 12.0 mm long) was used as the upper compartment of the chamber. The bottom surface was attached to a nonsiliconized polycarbonate filter (3.0-µm pore; Bio-Rad Laboratories, Hercules, CA) using Eukit (O. Kindler, Freiburg, Germany), a mounting reagent. A vial 4.5 mm in diameter and 4.8 mm in length was used as a lower compartment of the Boyden chamber. The neutrophils (0.2 x 106 cells/0.2 mL of total volume) containing 70 µL of neutrophil medium (RPMI 1640 medium) with each concentration of the H2-receptor antagonists were placed into the upper compartment of the chamber, and N-formyl-L-methionyl-L-leucil-L-phenylalanine (FMLP) 10-7 M, a potent synthetic chemoattractive peptide, was placed into the lower compartment (total volume 0.2 mL). The chamber was incubated at 37°C for 45 min in an atmosphere of 5% CO2. The number of cells reaching the bottom surface of the filter was expressed as the average number of cells per field after counting five fields for each filter.

Emulsions of paraffin oil containing Oil Red O were prepared using normal human serum (16). The emulsion was incubated with an equal volume of normal human serum at 37°C for 30 min for opsonization. Neutrophils (2 x 107 cells/0.9 mL of KRP), which had been preincubated for 5 min with each concentration of the H2-receptor antagonists, were added to 0.1 mL of the opsonized emulsion. The mixture was incubated for 5 min at 37°C, then 9 mL of ice-cold KRP was added to the solution to stop the reaction. The cells were washed three times with ice-cold KRP to remove the paraffin oil droplets that had not been ingested. Paraffin oil containing Oil Red O was extracted from the cells using a method described elsewhere (16), using chloroform and methanol (vol/vol 1:2). The optical density of the chloroform layer was determined at wavelengths of 525 nm. The mean optical density of Oil Red O extracted from 2 x 107 neutrophils incubated with opsonized paraffin oil droplets was 0.029 ± 0.0021 (average ± SD of five experiments), and microscopic examination revealed that most neutrophils were heavily loaded with oil droplets. However, after incubation of nonopsonized paraffin oil droplets and neutrophils, the optical density was <0.007. Only a few neutrophils were observed to be loaded under the microscope. These findings confirmed that most of the extracted Oil Red O represented droplets ingested by the neutrophils.

For O2– formation, 1 x 106 neutrophils were preincubated at 37°C for 10 min with 1 mg/mL opsonized zymosan (Sigma) and various concentrations of the H2-receptor antagonists; 0.1 mM ferricytochrome-C (type III of the same lot, >95% of oxidized form; Sigma) was then added. The neutrophils were incubated for another 30 min. Immediately after sedimentation of the neutrophils and opsonized zymosan by centrifugation, 0.1 mL of the supernatant was assayed for reduced cytochrome C by measuring the absorbance at 550 nm in 2 mL of 100 mM potassium phosphate buffer (pH 7.8) containing 0.1 mM EDTA (pH 7.8) (16). The results were converted to nmol of reduced cytochrome C, using {Delta}E550 nm = 2.1 x 104 M/cm (16).

H2O2 generation was measured by quantifying a decrease in fluorescence intensity of scopoletin (Sigma) due to its peroxidase-mediated oxidation by H2O2 (16). After the incubation of 2.5 x 106 neutrophils for 10 min at room temperature in KRP containing 5 mM glucose and 0.1 mg/mL gelatin in the presence of each concentration of the H2-receptor antagonists and 1 mg/mL opsonized zymosan, 0.1 mL of 50 mM scopoletin in KRP and 0.05 mL of 1 mg/mL horseradish peroxidase (type II; Sigma) in phosphate-buffered saline were added. The rate of decrease in fluorescence intensity of scopoletin was quantified using a fluorescence spectrophotometer (Hitachi, Tokyo, Japan) within 30 min. The H2O2 concentration was calculated assuming that 1 mol H2O2 oxidizes 1 mol scopoletin (16).

O2- and H2O2 were also generated by reacting hypoxanthine with xanthine oxidase. Instead of neutrophils and opsonized zymosan, 0.1 mM hypoxanthine, 1.25 mM EDTA, and one of the three H2-receptor antagonists were mixed in a total volume of 2 mL (125 mM phosphate buffer). This reaction mixture was incubated for 2 min at 37°C. Approximately 0.006 U/mL dialysed xanthine oxidase was added to the mixture to start the reaction. The O2- and H2O2 generated by the cell-free system was measured by using the same method used in the neutrophils system.

The fura-loaded, FMLP-stimulated increase in [Ca2+]i was assessed according to a method described in the literature with some modifications (16). Fura-2 A/M (at a final concentration of 1 µM) was added to the purified neutrophil suspension in 0.1 mM CaCl2 containing KRP and incubated for 30 min at 37°C in a cuvette with mild shaking. After incubation, the fura-2–loaded cells were washed twice with KRP and were resuspended in KRP at a concentration of 107 cells/mL. Each H2-receptor antagonist at the indicated concentration was then added and incubated for a further 5 min (total volume 2 mL). Fifteen milliliters of 10-6 M FMLP was added to 1.5 mL of this mixture to measure fura-2 fluorescence using a Hitachi F-4000 fluorescence spectrophotometer, with the excitation wavelength alternated every 4 s from 340 nm to 380 nm, and with the emission wavelength set at 510 nm. The neutrophil suspension was maintained at 37°C with constant stirring throughout the measurement. Calcium concentrations were determined from the ratio of fura-2 fluorescence intensities at excitations of 340 and 380 nm (16). The data were processed with a computer fitted to the Hitachi F-4000 fluorescence spectrophotometer, and estimated [Ca2+]i levels were recorded sequentially. Calcium concentration was expressed by the following formula:


where R is the ratio of F340 nm to F380 nm, Kd is the K value of Ca2+ and fura-2, Rmax is sufficient fura-2 bound to Ca2+ in the presence of 10% Triton X-100 (30 µL), Rmin is the minimal amount of fura-2 bound to Ca2+ in the presence of 100 mM EGTA (pH 9.3), and b is the ratio of F380 nm in the absence of Ca2+ to F380 nm in the presence of Ca2+.

Data are expressed as mean ± SD (n = 12 volunteers). Results are expressed as a percentage of the control (in the absence of the H2-receptor antagonists). We assayed any measurement (chemotaxis, phagocytosis, ROS, and Ca2+) in triplicate using neutrophils isolated from each volunteer. Raw data were analyzed for statistical significance by using the Friedman rank test, followed by Dunnett's test for post hoc comparisons. P < 0.05 was deemed significant. The sample size of the current study was sufficient to detect large differences (d = (µ1 - µ2)/s = 0.7–1.0) in variables at a significance level of 0.05, although the power of the study is relatively weak (power = 1 - b = 0.5–0.7).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Table 1 shows absolute values in the control (absence of the H2-receptor antagonists) of any variable. None of the three H2-receptor antagonists modulated chemotaxis and phagocytosis of neutrophil (Figure 1). Cimetidine and famotidine exerted a dose-dependent inhibitory effect on production of O2- and H2O2 by human neutrophils (Figure 2, A and C, respectively). The clinically relevant concentration of cimetidine (1 µg/mL) impaired ROS production, although famotidine failed to do so at clinical plasma concentrations. In contrast, ranitidine did not inhibit ROS generation by neutrophils (Figure 2B). The three H2-receptor antagonists also failed to affect the ROS generated in the xanthine-xanthine oxidase system (Figure 2, D–F). These findings indicate that cimetidine and famotidine did not scavenge the ROS generated, but rather impaired the ability of neutrophils to produce ROS. The increase of [Ca2+]i in the neutrophils stimulated by FMLP was attenuated with cimetidine or famotidine in a dose-dependent fashion (Figure 3).


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  		Table 1. Absolute Values in the Control (Absence) of the Three H2-Receptor Antagonists (After Stimulation)
 


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  		Figure 1. Effects of H2-receptor antagonists on neutrophils' chemotaxis and phagocytosis. Data (mean ± SD) are expressed as a percentage of the control (in the absence of H2-receptor antagonists = 0.1% dimethyl sulfoxide alone). *P < 0.05 versus control.

 


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  		Figure 2. Effects of H2-receptor antagonists on reactive oxygen species (ROS) production by neutrophils or the xanthine-xanthine oxidase system. Data (mean ± SD) are expressed as a percentage of the control (in the absence of H2-receptor antagonists = 0.1% dimethyl sulfoxide alone). *P < 0.05 versus control.

 


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  		Figure 3. Effect of H2-receptor antagonists on intracellular calcium ion concentrations in neutrophils stimulated by N-formyl-L-methionyl-L-leucil-L-phenylalanine. Data (mean ± SD) are expressed as a percentage of the control (in the absence of H2-receptor antagonists except = 0.1% dimethyl sulfoxide alone). *P < 0.05 versus control.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We showed that cimetidine (at clinically relevant concentrations) slightly suppressed the ROS production of neutrophils, although it failed to scavenge the ROS generated in a cell-free system. However, these results disagree with a previous report (5) in which cimetidine was shown to have no effect on FMLP-induced neutrophil O2- production by itself. The inability of cimetidine to quench O2- and H2O2 is consistent with research by Lapenna et al. (17) but in conflict with observations by Zimmerman et al. (8). Because neutrophils are important components of the immunological defense system that protects the host from invading bacteria (2), inhibition of this neutrophil function could reduce a patient's ability to fight infection. This may be more serious if cimetidine is continuously infused into patients with infection or sepsis or into those in whom infection is likely to occur (e.g., an immunocompromised host), particularly in the ICU. Cimetidine predisposes critically ill patients to developing a variety of infectious diseases (18). In addition to facilitating bacterial overgrowth mediated by a decrease in gastric acidity, impairment of ROS production with cimetidine may have been responsible for these dangerous complications. In our study, famotidine also reduced the ROS production by neutrophils in a dose-dependent fashion. However, it is plausible that this effect of famotidine has few clinical implications because clinically relevant concentrations of the drug failed to impair the neutrophil function. In contrast, no dose of ranitidine affected the neutrophil function.

However, the ROS produced excessively by neutrophils may play a pivotal role in pathogenesis of the host autoinjury leading to multiple organ dysfunction syndrome associated with systemic inflammatory response (19). In several animal experimental studies, cimetidine successfully ameliorated acute respiratory distress syndrome (20) and burn wound edema (21), both of which may involve activated neutrophil pathophysiology. The ability of cimetidine to decrease the neutrophil function may be a favorable characteristic. Our findings suggest that we may be able to use ranitidine in patients with infection or sepsis without great caution, but we cannot expect the drug to be prophylactic against host autoinjury whose pathogenesis includes activation of neutrophils. However, a previous clinical study demonstrated that treatment with IV ranitidine in patients who underwent major abdominal surgery reduced chemiluminescence response of their neutrophils to opsonized zymosan, although insignificantly (22). This different finding in clinical settings may be due to multiple factors that are present in the circulation or tissue. The factors include stress, hormonal changes, cytokines, and previous medications, all of which can alter neutrophil functions. Furthermore, using neutrophils from patients with sepsis or multiple organ dysfunction syndrome may have produced different results because neutrophil functions are probably modulated by such influential factors in these seriously ill patients. Carey et al. (24) found that cimetidine reverses histamine-induced inhibition of neutrophil O2- production to levels similar to those in pigs receiving Pseudomonas organisms, which suggests potential enhancement of microvascular injury in sepsis. However, in the current study, we used neutrophils obtained from healthy adult volunteers to assess the fundamental effects of the H2-receptor antagonists. Our goals also included comparison of the effects of cimetidine, ranitidine, and famotidine on neutrophil function using the same protocol.

An increase in the [Ca2+]i of neutrophils is one of the important pathways by which extracellular stimuli such as FMLP are transmitted to activate NADPH oxidase in the cell membrane (2). We also showed that cimetidine or famotidine attenuates the increase of [Ca2+]i in neutrophils stimulated with FMLP. Our findings may be supported by the observation that cimetidine and famotidine diminish the histamine-induced increase in cytosolic calcium concentrations in HL-60 promyelocytes (24). Although the precise mechanism underlying the suppressive effect of cimetidine or famotidine on ROS production remains to be elucidated, attenuation of the increase in [Ca2+]i stimulated by the chemotaxin may at least contribute to inhibition of the neutrophil function. An increase of [Ca2+]i in response to chemotaxin (e.g., FMLP) also plays a pivotal role in neutrophil chemotaxis (2). In the current study, although cimetidine and famotidine inhibited the [Ca2+]i response to FMLP in neutrophils, the two H2-receptor antagonists failed to impair chemotaxis. We are unable to give a satisfactory explanation for this discrepancy. Cimetidine and famotidine may act directly on effector systems (e.g., actin, myosin) or an energy source (e.g., gycolysis) involved in chemotaxis, rather than on intracellular signal transduction, which consists of receptors and their second messengers. Conflicting in vitro data on the effects of the H2-receptor antagonists on neutrophil chemotaxis have been also reported (12,14,25). Cimetidine per se has no effect on neutrophils' chemotaxis but can reverse histamine-induced inhibition of chemotaxis (12). This finding seems to coincide with our results. In contrast, cimetidine (2 mg/kg) reduces neutrophil migration into the mouse peritoneal cavity induced by staphylococcal enterotoxin type A (14). In conflict with our observation, famotidine (10 mg/kg) diminishes recruitment and adhesion of neutrophils to implanted biomaterials in mice (25).

Cimetidine and famotidine's high lipid solubility (octanol/water partition coefficient at pH 7 is 1.5) makes them likely to accumulate in lipid membranes, leading to an alteration of their physical properties. The resultant changes in conformation of the membrane-bound enzymes may be another mechanism underlying the inhibitory effect of cimetidine on ROS production. In contrast, ranitidine, which is highly water-soluble (chloroform/water partition coefficient at pH 7 is 0.33), had no effects on neutrophil function. Furthermore, ranitidine and famotidine are approximately 10 times more potent than cimetidine as an H2-receptor antagonist. These data suggest that the inhibitory effect of cimetidine on ROS production is ascribed to mechanisms unrelated to antagonism against H2-receptors.

In conclusion, we showed that clinically relevant concentrations of cimetidine inhibited O2- and H2O2 production by neutrophils without scavenging the ROS generated in a cell-free system. However, we must emphasize that the observed effects of the H2-receptor antagonist were quite minimal. Suppression of the increase in [Ca2+]i of neutrophils in response to a stimulus may be at least partly responsible for the inhibition of neutrophil function by cimetidine. In contrast, ranitidine failed to reduce ROS production.


   Acknowledgments
 
This work was supported in part by departmental funds.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 13, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press