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Cardiovascular Research 1999 43(1):173-182; doi:10.1016/S0008-6363(99)00073-5
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Copyright © 1999, European Society of Cardiology

Role of autacoids in cardiovascular collapse in anaphylactic shock in anesthetized dogs

S. Minka,b,c,*, A. Beckere, S. Sharmaa,b, H. Unruhf, K. Dukeb,c and W. Kepronb,c,d

aSection of Critical Care, University of Manitoba, Winnipeg, MB, Canada
bSection of Respiratory Disease, University of Manitoba, Winnipeg, MB, Canada
cDepartment of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
dSection of Allergy and Immunology, University of Manitoba, Winnipeg, MB, Canada
eDepartment of Pediatrics, University of Manitoba, Winnipeg, MB, Canada
fSection of Thoracic Surgery, University of Manitoba, Winnipeg, MB, Canada

* Corresponding author. Tel.: +1-204-787-2914; fax: +1-204-787-4826 minksn{at}cc.umanitoba.ca

Received 21 September 1998; accepted 11 January 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
Objective: In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins (prost), and leukotrienes (leuk) on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. Methods: In randomized design, we investigated whether blockade of histamine H1, H2, and H3 receptors or inhibition of the cyclooxygenase (cyclo) and lipoxygenase pathways (lipox) prevented AS in ragweed sensitized dogs. Seven dogs were studied under pentobarbital anesthesia in which the treatment studies were approximately 2 weeks apart. Results: During H1 receptor blockade, the decreases in blood pressure and cardiac output otherwise observed in AS were attenuated (P<0.05) and the release of prost, thromboxanes, and leuk were reduced as compared with nontreatment studies. Cyclo inhibition also attenuated cardiovascular collapse and mediator release in AS, but the other treatments showed no effects. Conclusion: H1 receptor blockade and cyclo may attenuate cardiovascular shock in AS. These agents inhibit autacoid release from mast cells in addition to any specific receptor blocking and pathway inhibition effects.

KEYWORDS Vasculature; Pathophysiology; Shock; Hemodynamics; Immunology; Prostaglandins; Pulmonary circulation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 
In anaphylaxis, circulatory shock results when mediators with vasoactive properties are released from basophils and mast cells during allergen challenge [1–3]. Of the mediators released, the autacoids which include histamine, prostaglandins, and leukotrienes have assumed important etiological roles in contributing to cardiovascular collapse in anaphylactic shock [1,4–6].

Histamine may act through H1, H2, and H3 receptors to promote shock during allergen challenge [5,7–10]. H1 receptors mediate chronotropic effects, coronary vasoconstriction, and cardiac depression [5,11], while H2-receptor agonists produce coronary and systemic vasodilation as well as increases in heart rate and ventricular contractility [11]. Recently, histamine H3 receptors have been identified on presynaptic terminals of sympathetic effector nerves that innervate the heart and systemic vasculature [7,9]. These receptors have been found to inhibit endogenous norepinephrine release [7] which would be expected to enhance the degree of shock during challenge. However, the contribution of the H3 receptor to hypotension in anaphylaxis has not been studied.

The eicosanoids which include the prostaglandins and leukotrienes are derived from arachidonic acid [4,12–14]. Cyclooxygenase pathway products, such as PGI2, PGE1 and PGA1 cause systemic vasodilation and positive inotropy [14], whereas other products such as thromboxane A2 and PGD2 are vasoconstrictors and cause cardiac systolic dysfunction either by direct or indirect effects [14]. Alternatively, the lipoxygenase pathway yields mainly systemic vasoconstrictors of which LTD4, LTC4, and LTE4 are the active constituents of the slow-reacting substance of anaphylaxis [4]. These agents have been purported to cause cardiac depression in many experimental preparations [4]. Finally, although platelet activating factor (PAF) is grouped among the autacoids and may contribute to cardiovascular collapse in anaphylactic shock [15], PAF appears to cause damage by modulation of other classes of mediators, and not by a primary process [12].

In the literature, the relative effects of the autacoids on causing cardiovascular collapse in anaphylaxis, and the roles of receptor blocking agents and pathway inhibitors on preventing this collapse are unclear. In some studies, histamine H1 blockers have shown to prevent allergic reactions, but not in others [16,17]. Different findings in the literature may reflect dissimilar preparations in which variable doses of allergen have been administered to produce shock [4,5,15–17]. In the present study, we investigated the roles of H1, H2, and H3 receptor blockers as well as cyclooxygenase and lipoxygenase pathway inhibitors in preventing cardiovascular collapse in a canine model in which the same animal was repeatedly studied under identical doses of allergen challenge.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 Acknowledgments
 References
 
2.1 Anaphylaxis model
This experiment was approved by the University Animal Care Committee and this investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85-23, revised 1996). Our canine model of ragweed anaphylaxis has previously been described. Briefly, newborn dogs received allergen (0.5 mg ragweed pollen extract mixed with 30 mg Al(OH)3 intraperitoneally within 24 h of birth) [18–21]. Injections were repeated at weekly intervals for 8 weeks, at biweekly intervals for {approx}30 weeks, and then at monthly intervals. This sensitizing regimen results in mean IgE anti-ragweed antibody titers of >256 dilutions by passive cutaneous anaphylaxis, while nonsensitized littermate controls show no IgE titers by this test [19,20]. The animals were examined at {approx}1 year of age.

2.2 Protocol
Cardiac hemodynamics were examined in seven dogs. Each dog was studied on seven occasions in which the interval between studies was approximately 2–3 weeks. This interval was chosen because the anaphylactic response is fairly reproducible when challenges are repeated over this time period [21]. The first and last studies were control studies in which no drugs were administered, and were used to assess whether a change in ragweed sensitivity occurred during the study period.

The order of the five treatments was randomized among the dogs. In the H1 blocker study (StudyH1 blocker), the animals were challenged following pretreatment with chlorpheniramine maleate (10 mg/kg) [17]; in the H2 blocker study (StudyH2 blocker), the animals were challenged following pretreatment with ranitidine HCl (20 mg/kg) [19]; in the H3 blocker study (StudyH3 blocker), the animals were challenged following pretreatment with thioperamide maleate (1 mg/kg) [9]; when the cyclooxygenase pathway was inhibited (Studycyclo), the animals were challenged following pretreatment with indomethacin (2 mg/kg) [22]; and when the lipoxygenase pathway was inhibited (Studylipox), the 5-lipoxygenase activating protein (FLAP) antagonist MK-0591 was administered [23].

Except for MK-0591, the inhibitors were administered intravenously over a 20-min period and the doses denoted were based on previously reported findings. MK-0591 was administered initially as a 2 mg/kg IV bolus and then as 8 µg/kg/min constant intravenous infusion for the remainder of the experiment. MK-0591 was kindly supplied by Dr. A.W. Ford-Hutchinson of Merck, Frosst, Canada [23].

In the initial control study, during which each dog was anesthetized (see further below), we determined the intravenous dose of allergen required to reduce mean systemic blood pressure (MAP) by {approx}50% from that found pre-shock. This same dose was then used for the remaining studies.

In the control studies, hemodynamics (see below) were determined at baseline, post placebo, and shock. Approximately 45 min after the preparation was completed during which the animal was stable, baseline (i.e preshock) measurements were determined. Then, measurements were repeated 1 h post baseline. For the first 20 min of this 1 h period, normal saline (250 ml) was administered to simulate drug administration, after which there was a 40-min period of rest. Then intravenous ragweed was administered through a central intravenous line (shock condition). These measurements were obtained at the point of lowest mean arterial pressure (MAP) when a plateau in MAP had occurred. As determined in previous studies, this plateau lasts for {approx}10–15 min [18,21].

In five studies, drugs were administered in which after baseline measurements were determined, medication was administered over a 20-min period in 250 ml normal saline solution (except for MK-0591 which was administered as above). After an additional 40-min wait, measurements were repeated, Then, the dose of ragweed was given.

Moreover, to examine the effect of time on our hemodynamic measurements, we performed a separate sham shock protocol (n=7) in which hemodynamic variables were obtained under conditions of the different blocking agents when only the diluent for the ragweed allergen (normal saline) was given after the respective drugs were administered. Measurements were obtained at baseline, drug administration, and sham-anaphylaxis.

Thus, for each of the seven studies (initial control, final control, and the five studies that involved drug administration, hemodynamic measurements were obtained in three conditions: (1) baseline, (2) drug/placebo administration, and (3) during shock.

2.3 Animal preparation and measurements
The animals were anesthetized with pentobarbital anesthesia (30 mg/kg) [24,25]; the trachea was intubated with an endotracheal tube, and the lungs were mechanically ventilated (tidal volume: 12 ml/kg). Respiratory rate was adjusted to maintain pH at approximately 7.3 to 7.4. Supplemental oxygen was given to maintain arterial PO2>100 mmHg. Hemodynamic measurements were obtained at end-expiration, so that respiratory variation did not contribute to the results.

Procedures were performed under sterile conditions during which the animals were anesthetized as described above on each occasion. Vascular catheters were acutely implanted by percutaneous techniques. MAP was measured with a polyethylene catheter inserted into the femoral artery. Through the right jugular vein, a thermodilution Swan–Ganz catheter was advanced into the pulmonary artery to measure mean pulmonary arterial pressure (mPpa), mean pulmonary capillary wedge pressure (mPwp), and cardiac output (CO). Through the left jugular vein, another Swan–Ganz catheter was advanced into the right atrium for injecting cold saline boluses used in the CO determination and for measurement of mean right atrial pressure (mPra). The balloon on the catheter was deflated once the right atrial catheter was properly positioned. Moreover, two Swan–Ganz catheters were used since some of animals were small, and if only one Swan–Ganz catheter were used, the injection port used in the determination of cardiac outputs was often too proximally located to give accurate results. In addition, a polyethylene catheter was placed into one femoral vein to administer intravenous normal saline solution and the drug treatments (see below). Normal saline solution was given at the beginning of the experiment (if necessary), to attain a baseline mPwp of {approx}7–9 mmHg. No other fluids were administered during the study. All of the fluid-filled catheters that were used for vascular pressure measurements were connected to transducers (Cobe, CO, USA), and the zero reference point taken was the level of the left atrium. The left atrium was determined as the lower one-third distance between the spine and sternum based on previous experiments [26]. Transducer outputs and all signals were displayed on an eight-channel recorder (Astra-Med, W. Warrick, RI, USA).

Stroke-volume (SV) was calculated from CO divided by heart rate (HR). Pulmonary vascular resistance (PVR) was calculated from [(Ppa–Pwp)/CO], and systemic vascular resistance (SVR) was calculated from [(BP–Pra)/CO]. Following conclusion of the experiment, vascular accesses were removed and hemostasis was obtained. The animal was given prophylactic antibiotics (cloxacillin 10 mg/kg i.v., and gentamicin 2 mg/kg) and returned to its cage for recovery.

During each condition, immediately after hemodynamic measurements were determined, arterial samples were obtained for blood gas and mediator analyses. Plasma concentrations of mediators were measured by radioimmunoassay techniques. For all mediators, samples were obtained in duplicate and stored at –70°C until analyzed. Histamine immunoanalysis (Immunotech Inter, Cedex, France) was performed by competition between modified histamine in the sample with iodinated histamine tracer binding to the antibody coated on tubes [27]. Plasma concentrations of 6-keto-prostaglandin F1{alpha} (stable breakdown product of prostacyclin), thromboxane B2 (TXB2, stable breakdown production of thromboxane A2), and LTE4 were also measured by radioimmunoassay techniques [NEN Res, Boston, MA, USA; NEK-008, NEK 007, and NEK-043] [22]; these assays can detect plasma concentrations down to approximately 5 pg/0.1 ml, 50 pg/0.1 ml, and 8.3 pg/0.1 ml, respectively. For each mediator, the standard curves were generated in which a known amount of the tracer was placed into an aliquot of pooled canine plasma.

In the leukotriene assay, since in vitro conversion of LTC4 and LTD4 to LTE4 occurs spontaneously, measurements of all leukotrienes were obtained after enzymatic conversion (by {gamma}-glutamyl transpeptidase and microsomal leucine aminopeptidase) to LTE4, which is then extracted by C18 Sep-Pak binding and elution as described by Heavey et al. [28].

2.4 Statistical analyses
To assess for significant differences between studies, a two-way ANOVA for repeated measures was used (Northwest Analytical, Portland, OR, USA). In this ANOVA, factor A was taken to be study (i.e., initial control, final control, and the five studies involving drug administration), and factor B was taken to be condition (i.e. either baseline, drug/placebo administration, or shock). Interaction between the two factors was assessed in which significance in the interaction term suggests that a given variable was different in the seven studies between the conditions [29]. If a significant interaction was present, then a Student–Newman–Keul’s (SNK) multiple comparison test was used to determine where treatment differences occurred. During shock, our sample size was of 90% power to detect a MAP difference between the initial control study and treatment study of 25 mmHg, a CO difference of 1 l/m, a SV difference of 7 ml, and an approximate doubling of the mediators.

Furthermore, to also test for differences between studies, we compared the absolute change between the drug/placebo condition and the shock condition among the seven studies by repeated- measures one-way ANOVA and SNK. The rationale was that although the preshock conditions (i.e. baseline and drug/placebo) were not different between studies by ANOVA, there may have been small differences between the different drug studies, albeit non-significant ones, at the time of treatment that became additive with the shock effect. This may render values after shock different without differentiating the effects of treatment versus the shock response.

Moreover, in both statistical analyses, we were primarily interested in the effect of the drug treatment in comparison with the control anaphylactic response. We therefore concentrated our statistical analyses on the drug vs. the control studies and not on the differences between the five drug studies examined. Both statistical analyses (i.e. ANOVA interaction and the change between drug/placebo and shock) gave consistent results in the findings that are reported.

Finally, to assess significant differences within studies, when there was no interaction between the seven studies, we used the two-way repeated measures ANOVA and SNK in which the changes in the B factor were compared. On the other hand, when interaction was present in the 2-way ANOVA, a one-way repeated measures (ANOVA1R) and SNK were used to examine the changes between conditions in a specific study. Results are reported as mean (±1 S.E.).


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 Acknowledgments
 References
 
The mean dose of allergen given was 2.3±0.5 mg. This dose was kept constant in all of the studies.

Figs. 1 and 2Go and Table 1 show the measured variables. In the control studies, as compared with preshock, MAP decreased during shock by {approx}50%. This decrease was not different between the control studies. CO showed similar decreases of 50% between baseline and shock, and the changes observed in SV and mPwp paralleled those in CO. Between preshock and shock, PVR increased (Table 1), while HR showed no change. On the other hand, whereas SVR increased during shock in the initial control study, this increase did not reach statistical significance in the final control study.


Figure 1
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  		Fig. 1 Mean arterial pressure, cardiac output, stroke volume, and pulmonary capillary wedge pressure are shown in the different studies at baseline, treatment, and shock. By one way ANOVA for repeated measures and SNK multiple comparison test, all variables measured within a study except for CO and SV in StudyH1 blocker decreased during shock vs. preshock conditions. Between group analysis included two-way ANOVA for two repeated measures as well as one way repeated measures ANOVA in which the change between the drug/placebo condition and shock condition was compared among the studies. Both methods gave similar results. {dagger}P<0.05 during shock vs. initial and final control studies.

 

Figure 2
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  		Fig. 2 Heart rates and systemic vascular resistances are shown in the different studies at baseline, drug administration, and shock. *P<0.05 shock vs. preshock within a study; !P<0.05 vs. all other studies; &P<0.05 during shock vs. cyclooxygenase inhibition and initial control studies (see legend to Fig. 1 for statistics).

 

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  		Table 1 Pulmonary hemodynamics in the different studies (mean±S.E.)a

 
In the five drug studies, the treatments administered alone did not change hemodynamics. In three of the five drug studies, StudyH2 blocker, StudyH3 blocker, and Studylipox, the treatments did not modify the response to shock with respect to MAP, CO, mPwp, SV, mPra, PVR, and mPpa (see Figs. 1 and 2Go and Table 1). Only H1 blocker and cyclo-oxygenase inhibition changed the hemodynamic response somewhat. In these two studies, there were smaller declines in MAP, BP, CO, and SV than those found in the control studies, although mPwp declined to a similar extent in all studies. Moreover, in all studies except for the H3 blocker study, HR were unchanged between conditions. In the H3 blocker study, HR increased with treatment and remained higher than values found in the other studies during shock. In the H1, H2, and H3 blocker studies, SVR measured during shock were lower as compared with the initial control study and cyclooxygenase inhibition study, although results did not reach statistical significance as compared with the final control study.

In the sham shock study (n=7), there were no changes in hemodynamics over the course of the experiment, and MAP measured 158±17 at baseline, 167±15 mmHg during drug administration alone, and 165±10 mmHg during sham anaphylaxis.

The different mediator responses observed are shown in Fig. 3. Baseline concentrations of mediators were unchanged between studies. The different drug treatments did not affect any of the baseline mediator concentrations, except in Studycyclo where TXB2 was reduced compared with the baseline value. In Studycyclo, the concentrations of all classes of mediators were reduced during challenge as compared with the control studies. In StudyH1 blocker, the concentrations of prostaglandins, thromboxanes, and leukotrienes were reduced, while the release of histamine was unchanged. In Studylipox, the increase in LTE4 observed during challenge was eliminated.


Figure 3
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  		Fig. 3 Mediators are shown in the different studies at baseline, treatment, and shock. *P<.05 shock vs. preshock within a study; ?P<.05 vs. baseline within a study. !P<.05 during shock vs. all other studies; {dagger}P<.05 during shock vs. initial and final control studies (see legend to Fig. 1 for statistics).

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
Acknowledgments
 References
 
The primary objective of this study was to determine the role of the autacoids in producing cardiovascular collapse in anaphylaxis, and the extent to which receptor blocking agents and pathway inhibitors may be useful in preventing this collapse. The results showed that H1 receptor blockade and cyclooxygenase inhibition attenuated the decreases in MAP, CO, and SV found in anaphylactic shock as compared with the control studies.

In StudyH1 blocker, H1 blockade prevented the release of mediators, except for histamine which increased to a variable extent during challenge. Other investigators [30–32] have shown that antihistamines may inhibit the ultrastructural changes of mast- cell release in sensitized individuals. Ting et al. [32] found that when the antihistamine hydroxyzine was given orally for three days, there was an inhibitory effect on antigen-induced histamine release in ragweed sensitized individuals who were challenged by intradermal skin reaction. They suggested that hydroxyzine exerted a direct protective action against mast cell activation. In StudyH1 blocker, we found that histamine H1 receptor blockade preferentially inhibited the release of lipid derived, newly generated mediators during allergen challenge (see Fig. 3), while histamine release per se was not systematically reduced. These results suggest that mast cell release of newly generated mediators is more sensitive to the effect of H1 receptor blockade than is the release of histamine.

In StudyH1 blocker, although a reduction in the release of lipid derived mediators was associated with an improvement in hemodynamics, there was probably a receptor blocking effect on cardiovascular system. As shown in Fig. 1, mPwp fell during challenge and this decrease was similar to that found in the other studies. Yet, CO in the H1 blocker study was higher than values found in the control studies. Since left ventricular (LV) diastolic compliance is unchanged during ragweed challenge in this model [18], the higher CO and SV found in the H1 blocker study indicates an improvement in LV emptying rather than an increase in LV preload. Guo et al. [8] showed that with histamine H2 blockade, a negative inotropic effect of histamine was unmasked and concluded that cardiac depression was mediated by H1 receptors. Thus, a reversal of cardiac depression by histamine H1 receptor blockade could account for the higher CO and SV observed during anaphylaxis in our model.

Experimentally, the question of whether antihistamines are useful in anaphylactic shock remains controversial. In an Ascaris suum canine model of anaphylaxis, Silverman et al. [17] could not show an effect of H1 receptor blockade on cardiovascular collapse during allergen challenge, even though the dose of chlorpheniramine maleate was exactly the same in the two studies. This lack of an effect of H1 receptor blockade on hemodynamics was attributed to either high local tissue levels of histamine that could not be blocked by the dose of antihistamine given, or to the fact that other mediators were more important than histamine in the production of shock. However, our results indicated that the antihistamine chlorpheniramine had two positive effects in this model. Not only did it block the peripheral effect of histamine, but also inhibited the release of other autacoids that may contribute to shock in anaphylaxis.

In StudyH2 blocker, H2 receptor blockade might be expected to cause a depression in LV function as compared with the control studies. In the condition in which an H2 receptor antagonist is administered, the number of H2 receptors for binding of histamine would be reduced. Since more of the histamine released during shock would be available to bind with histamine H1 receptors, this may cause more pronounced LV depression during allergen challenge. However, this was not the case, since MAP, CO and SV measured in the H2 blocker study were not lower than control values. In the study of Silverman et al. [17], a similar lack of an effect of H2 receptor blockade on hemodynamics was observed. The explanation for the lack of a depressant effect with H2 receptor blockade may be related to the relative binding characteristics of the H1 and H2 antagonists to their respective receptors. In human pectinate muscles, Guo et al. [8] reported that under conditions of high histamine concentrations, the blockade of H2 receptors by cimetidine was completely reversed, while the blockade of H1 receptors by pyrilamine maleate still remained. In the present study, the local concentrations of histamine released were probably large enough to overcome any H2 receptor blockade produced by ranitidine, so that no further depression in hemodynamics was observed.

In the H3 blocker study, thioperamide maleate was administered to block the effect of histamine on inhibition of sympathetic adrenergic release during allergen challenge. McLeod et al. [9] showed that activation of peripheral H3 receptor by the agonist R-{alpha}-methylhistamine (RAMH) caused a lowering of basal MAP, heart rate, and SVR in many animal models which may reflect a decrease in noradrenaline release from sympathetic effector nerves which innervated the cardiovascular system. In the present study, we hypothesized that H3 receptor signalling might be important in the pathophysiology of anaphylactic shock in our model. We gave a slightly higher dose of thioperamide than that given by Mcleod et al. [9]. We expected that during H3 receptor blockade, SVR would be relatively increased, and the fall in MAP and CO would be reduced as compared with the control studies. Although HR increased with H3 receptor blockade, there was no effect on SVR or cardiac output during challenge. This may indicate lack of sufficient blockade or a limited role for histamine H3 receptor activation in anaphylaxis.

In Studycyclo, the reduction in CO observed during shock was attenuated as compared with the control studies. Although mPwp was not significantly different between studies, individual data revealed that Pwp measured with indomethacin was higher in most experiments (5/7) compared with control shock values. Thus, a relative increase in LV filling during anaphylaxis may have maintained more normal CO and SV. The explanation for generally higher Pwp with indomethacin may indicate general inhibition of mast cell release in response to allergen challenge. This finding is different from that reported by Liebeg et al. [33] in the isolated guinea pig heart where in spite of treatment with indomethacin, histamine increased during allergen administration. On the other hand, administration of indomethacin attenuated the bronchoconstrictor response to aerosolized allergen in a canine model [34]. In other animal models, cyclooxygenase pretreatment blocks the acute systemic manifestations of bolus endotoxemia which also works through a rapid release of preformed mediators [35]. Thus, our results showed that indomethacin pretreatment lessened the hemodynamic collapse ordinarily found during shock. This appeared to reflect global inhibition of mediator release during allergen challenge.

With lipoxygenase pathway inhibition, the increase in LTE4 usually found during ragweed administration was completely abolished (see Fig. 3). However, leukotriene inhibition did not affect hemodynamics during shock. Even though leukotrienes have been shown to be an important contributor to cardiovascular dysfunction in other models of anaphylaxis [4], there was little effect of this lipoxygenase synthesis inhibitor on the modulation of hemodynamics in canine anaphylaxis.

In terms of this ragweed model, an increase in SVR was observed during challenge, whereas SVR appears to decrease during anaphylaxis in humans [3]. Nevertheless, most hemodynamic data recorded in human anaphylaxis have been obtained after fluid resuscitation. In a previous study, it was shown that SVR also decreased when fluid resuscitation was performed [18]. It is important to recognize that SVR is a calculated variable, and not measured directly. It is possible therefore, for SVR to rise if, for example, the CO falls more than and disproportionate to the fall in MAP. This may account for the discrepancies in SVR found between the initial and final control studies, and makes the finding observed in SVR in the different drug studies difficult to interpret.

Furthermore, none of the treatments affected PVR preshock. In other studies, indomethacin pretreatment has shown an increase in PVR in otherwise healthy canine lung [36]. Nevertheless, in a previous study [21], we examined partitioned PVR during ragweed shock in this model. In that study, we also did not find that indomethacin increased PVR preshock in this model. This may indicate a loss of pulmonary vascular sensitivity to indomethacin that develops in our ragweed model.

In the present experiment, hemodynamics were examined while the animals were anesthetized. It would not be possible to study these animals in the conscious condition. Of the anesthetic agents available, all agents would affect some aspect of the anaphylactic shock in our model, and since pentobarbital anesthesia is often used in investigating hemodynamics in allergic models [17,37], this anesthesia was administered in the present study. A previous study has shown that plasma concentrations of pentobarbital would remain within a relatively constant range over the course of the experimental interval [25]. In the present experiment, since all control and treatment studies were performed on different occasions with identical anesthesia, there would be constancy of anesthesia effect between studies.

Nevertheless, pentobarbital anesthesia is known to increase HR and blood pressure which may be related to the vagolytic effect of the agent, although baroreceptor reflex effects cannot be excluded [25,38,39]. In addition, in the present study, HR did not increase during anaphylaxis. In human anaphylaxis, Smith et al. [40] showed similar findings in their study on insect sting hypersensitivity and venom rechallenge. Thus, the pattern of heart rate response found in our model was similar to that observed in human disease. Nevertheless, since it is not possible to exclude an effect of anesthesia on our results, it is recognized that the conclusions of this study must be cautiously applied to the human condition.

Among the many mediators that are released in anaphylaxis, histamine, leukotrienes, and prostaglandins have assumed an important role in causing the cardiovascular collapse observed. We recognize that many other mediators are released during challenge that may also contribute to this process [12,15]. Based on the findings in the literature, we concentrated on those mediators that were likely to be important in mediating cardiovascular collapse in anaphylaxis. For instance, platelet activating factor (PAF) is grouped with the autacoids [12], but appears to cause damage by modulation of other classes of mediators, and not by a primary process. Furthermore, it is necessary to note that the present study looks at pretreatment with various drugs in anaphylaxis, and that the results might not be applicable to treatment of anaphylaxis after onset of shock. Also, it is recognized that the application of animal models to the human condition must be interpreted cautiously.

In summary, the present results showed that there were no effects of leukotriene inhibition or histamine H2 and H3 receptor blockade on altering cardiovascular collapse during shock. In contrast, cyclooxygenase inhibition diminished cardiovascular collapse and resulted in a global inhibition of mediator release. In StudyH1 blocker, H1 receptor blockade also caused an attenuation of the hemodynamic changes found during shock. Importantly, this was both due to a peripheral effect of the antihistamine as well as an inhibition of the release of mediators. Although the effectiveness of antihistamines in preventing anaphylactic shock has been questioned [17], the present study would provide further experimental rationale for the prophylactic administration of H1 receptor antihistamines in situations in which anaphylaxis may occur in the clinical setting.

Time for primary review 22 days.


   Acknowledgments
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
References
 
Supported by Heart and Stroke Foundation of Manitoba.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 Acknowledgments
 References
 

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