Interference of the PAF-acether antagonist BN 52021 with passive anaphylaxis in the guinea-pig

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INTERFERENCE OF THE PAF-ACETHER ANTAGONIST BN 52021 WITH ENDOTOXlN-INDUCED HYPOTENSION IN THE GUINEA-PIG

S. Adnot, J. Lefor t , P. Braquet* and B.B. Vargaft ig

Unit6 des Venins Unit6 associ6e I n s t i t u t Pasteur

INSERF n ° 285 25, rue du Dr. Roux

F - 75015 Paris - France

* I n s t i t u t Henri Beaufour 17, Avenue Descartes

F - 92350 Le Plessis Robinson - France

Abstract

Because of the potential role of PAF-acether in the pathogenesis of endotoxin shock, we examined the preventive and curat ive ef fects of BN 52021, a new PAF-acether antagonist in guinea-pig challenged with S. Typhimurium endotoxin. A biphasic reduction of mean a r te r ia l pressure was e l i c i t ed by i . v . endotoxin (300 wg/kg) in control animals, with a rapid drop of blood pressure (maximal decrease within 10 min), par t ia l recovery at 20 min and a second gradual decrease af ter 30 min. Treatment with BN 52021 injected 15 min pr io r to endotoxin reduced the i n i t i a l rapid drop ef blood pressure from 38.5 ± 5 mmHg in vehicle-treated controls (n = 15) to 17 ± 3 mmHg (p < 0.01) in animals treated with i mg/kg BN 52021(n = 10) and to 9.5 ± 8 mmHg (p < 0.01) in guinea-pigs treated with 6 mg/kg BN 52021 (n = 5). The early hypotensive phase was associated with severe thrombocytopenia-leukopenia; only the thrombocytopenia was reduced by BN 52021. The prolonged secondary phase of hypotension was reduced by BN 52021 pretreatment whereas a small increase of hematocrit persisted. The two phases of the a r te r ia l pressure p ro f i le during endotoxic shock were not observed in animals previously made thrombopenic by rabbi t an t i - p l a te le t serum and only the late hypotensive phase persisted. This late hypotension induced by endotcxin in thrombopenic animals was suppressed by BN 52021 pretreatment suggesting that BN 52021 may act via a platelet-independent mechanism. The intravenous in ject ion of BN 52021 during the prolonged secondary phase of shock was followed by an immediate increase of the depressed blood pressure. This increase ef blood pressure was dose-dependent, maximum at 6 mg/kg BN 52021, and observed in normal and thrombopenic animals. The interference of BN 52021 with endotoxin shock may be related to i t s PAF-acether antaconist properties and suggests that PAF-acether is an impertant par t ic ipant in endotoxic shock.

DECEMBER 1986 VOL. 32 NO. 6 791

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Introduction

The pathogenesis of tissue injury following endotoxemia involves different humoral and cellular systems. As pointed out by Morrisson and Ulevitch (I) " I t is in many cases the host response to the gram-negative organism, rather than the organism i tse l f , which poses the ultimate threat to host tissues". Evidence for the interaction of serum complement and coagulation systems with endotoxin shock has been provided (2,3), whereas the release of chemical mediators, histamine, kinins, serotonin and arachidonate metabolites was demonstrated for the early phase of shock (2-6). PAF-acether (1-O-hexadecyl-2-acetYl-sn-glycero-3-phosphocholine) is a pharmacologically active phospholipid which displays a variety of effects l ikely to occur in endotoxemia such as systemic hypotension, pulmonary hypertension, increased vasopermeability, leukocyte and platelet activation (7-12 ; review in ref. 13). Recently, evidence has also been provided in favour of the participation of PAF-acether in anaphylaxis and in septic shock (14,15).

O

O O HO 1° 9 ~ t21"1

H 1 t H

i BN52021 OH OH H

Ftg 1 Chemical structure of the paf-acether antagomst BN 52021

The discovery of PAF-acether antagonists may help in evaluating the role of PAF-acether in endotoxic shock. Until now, two chemically distinct PAF-acether antagonists, CV 3988 and kadsurenone have been shown to reduce the early hypotensive phase of endotoxic shock (12, 16). BN 52021 (Fig. I) is a selective PAF-acether antagonist (17-19) which prevents the hypotension and extravasation induced by i .v . PAF administration in rats (19). BN 52021 was also shown to interfere with passive anaphylaxis in the guinea-pig (18) and with shock induced in rats by the injection of immune aggregates (19).This study was undertaken to determine i f BN 52021 interferes with hypotension and with the hematologic changes of shock triggered

792 DECEMBER 1986 VOL. 32 NO. 6

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in guinea-pig by the i . v . administration of Salmonella typhimurium endotoxin.

Methods

Animals and monitorin 9. Hart!ey guinea-pigs of either sex (300-500 g) were anesthetized

with sodium pentobarbitone (30 mg/kg, i . p . ) . A cannula was inserted into the trachea and positive pressure vent i lat ion was insured with room air by a Palmer miniature respiratory pump at 60 breaths/min and a t idal volume of 6 ml/kg. Spontaneous breathing was prevented with pancuronium (4 mg/kg i . v . ) . These vent i lat ion conditions, determined in a few preliminary experiments by measurement of arter ia l gas tensions in order to maintain a normal PaO 2 (100 mmHg) and a PaCO 2 within 30-35 mmHg, were kept constent during each experiment. The airway pressure was monitored through a polyethylene catheter inserted into the airway c i rcu i t , and connected to a pressure transducer (Gould P23Db). The systemic blood pressure was continuously monitored by a pressure transducer through a polyethylene catheter placed in the carotid artery and recorded on a Beckman physiograph. A jugular catheter was inserted for the intravenous infusion of drugs, heparinized saline being used to flush the catheters. When required, a 150 ul blood sample was removed from the carotid artery catheter for analysis. White blood cell (WBC) and platelet counts were performed with a Coulter Counter ZBI and hematocrit was determined from centrifuged microhematocrit tubes.

Experimental protocol. After surgery, a one hour period was le f t to establish a

steady-state blood pressure. A base-line period was defined as a 30 min period during which the blood pressure and the bronchial resistance to inf lat ion did not vary more than i0 %. Experiments were conducted or paired animals, one being pretreated with BN 52021 injected intravenously and the other treated with the solvent. Ten animals received I ~g/kg and f ive others 6 mg/kg BN 52021, followed within 15 min by 0.3 mg/kg of Salmonella typhimurium endotoxin as a bolus inject ion. This dose was chosen because i t induced a marked hypotensien as determined in preliminary experiments, ard enabled the animals to survive for al l the study duration. The changes in mean systemic blood pressure and peak pressure airways insuff lat ion (Pi) were then continuously recorded for 90 min. Five min pr ior to endotoxin challenge, a blood sample was removed from the carotid artery catheter and was used for blood content determinations. This procedure was repeated at 6, I0, 30 and 60 min after endotoxin administration. Upon completion of each experiment, the lungs were removed and weighed immediately (wet weight), then dried in an oven at 60 ° C unt i l a steady (dry) weight was obtained. Wet/dry lung weight ratios were used as an index of excess lung water (20). In a second series of experiments, BN 52021 was given intravenously 60 min after the endotoxin had been injected.


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Plate let depletion. Eight animals were depleted from c i rcu la t ing p late lets by the

administrat ion of 0.5 ml/kg of rabbi t an t i - p la te le t serum (APS) obtained as previously described (21), which resulted in the reduction of the number of c i rcu la t ing p late lets by 90-95 % within one hour. This procedure did not modify a r te r ia l blood pressure.

S ta t i s t i ca l analysis. Analysis of variance (ANOVA) was used to compare each of the

post-endotoxin infusion values with the baseline values and to compare the individual differences between control group and groups treated with BN 52021. Student's group unpaired tests were performed for individual comparison points in the experiments with thrombopenic animals. The values in the tex t and f igures are mean ± SEM. A p value of less than 0.05 was considered s ign i f i can t .

Materials. Salmonella typhimurium lipopolysaccharide (Difco Labs, Detro i t ,

MI, lo t number 357235) was dissolved in I ml s t e r i l e , pyrogen free 9 % NaCl solut ion immediately before the in jec t ion. BN 52021 (9H-I, 7a-(Expoxymethano)-IH, 6aH-cyclopenta [c ] fu ro [2 , 3 - b ] f u r o - [ 3 ' , 2 ' , : 3 , 4 ] cvclopenta[1, 2-d] furan-5,9,12-(4H)- t r ione, 3-tert-butylhexahydro- 4, 4b- l l - t r ihydroxy-8-methy l ) from IHB-IPSEN, Le Plessis-Robinson, France was dissolved in dimethysulfoxide at a concentration of 70 mg per ml and was then di luted in isotonic serum chloride at a f ina l concentration of 5 mg per ml.

Results

Effects of endotoxin. Al l animals responded to endotoxin with a biphasic change in

mean a r te r ia l pressure. As shown in Fig. 2, a f ter an i n i t i a l rapid drop in blood pressure, averaging 38.5 ± 5 mmHg at I0 min, a par t ia l recovery occurred within 20 min and was followed by a gradual decrease reaching 41.5 ± 5 mmHg at 90 min. The maximum drop in blood pressure was 42.5 ± 5 mmHg during ~he ~ i r s t phase cf hypotension and 44.5 ± 4 mmHg during the second phase. Early hypotension was accompanied by an 81% ± 7 % drop in the number of c i rcu la t ing p late lets I0 min af ter endotoxin and by a paral le l 74 % ± decrease in the number of WBC (Table I ) . The p la te le t counts then par t ly recovered to only a 28 ± 5 % fa l l measured at 60 min, the WBC counts remaining low. The hematocrit increased very s l i g h t l y a f ter endotoxin in ject ion from 42.5 ± 2 % under basal conditions to 44 ± 2 % at 60 min (p < 0.02). There was only a s l i gh t modif ication of the peak inspi ratory pressure, since i t increased from 8 to 9.3 cmH20 (p < 0.01) immediately a f ter endotoxin administrat ion up to 9.8 cmH20 at 60 min (p < 0.01). Two control animals died during the study from hypotension, one during the f i r s t period of shock and one at 90 min. The wet/dry weight lung ra t io at death or at 90 min was 4.92 ± 0.25 (n = 7).


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90 ~ENDOTOXINT T

~ 8o

~ 7 0

6 o

5 o 1 1 I I i I I I

10 20 30 40 50 60 70 80 90

T IME (mm) H VEHICLE TREATED ~n = 15) tX-I~BN 52021, lmg/kg, v (n = 10~ Jr---ZkgN S20~ 16mg/kg i v (n = s)

Interference of BN 52021 with endotoxin-induced hypotenslon.The evolutive prof i le of mean arterlal pressure following 0.3 mg/kg S. typhimurium i .v . injection is shown in the upper part of the figure (n = 15) for the animals recelving vehicle ( • ) and in the lower part for the animals pretreated with I mg/kg ( A ; n = 10) and wlth 6 mg/kg BN 52021 ( • ; n = 5). Individual values were compared by ~NOVA signlficant differences between control and BN 52021-treated animals for al l the time intervals between three and ten mln after endotoxin injection, as well as from 70 to 90 min.

.... i

TIME (min) 6 I0 30 60

PLATELET COUNTS (% fall)

CONTROL BN52021 (l mg/kg) BN52021 (6 mg/kg)

WBC COUNTS (% fall)

CONTROL BN52021 (I mg/kg) BN52021 (6 mg/kg)

69 ± 5 81 ± 7 46 ± 5 28 ± 5 50 ± 6" 52 ± 3** 42 +_ 5 25 ± 4 40 ± 24* 48 ± 18 W* 28 ± 19 }7 ± 15

66 + 3 74 ± 3 68 ± 3 64 ± 3 51 ± 6 65 -+ 4 63 ± 4 59 ± 6 42 ± 10"* 66 -+ 3 66 -+ 5 58 ± 12

- • - • . . . . . . . . . . . . . . . . . . . . . . . . ~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I WBC COUNTS (% fall)

I CONTROL 45 ± 9 57 ± 9 *~ 57 ± |5 61 ± 13 I BN52021 (I mg/kg) 34 ± 7 61 ± 6 62 + 7 66 ± 8

, p l < 0.05 ~ * p - < ' O . 0 2 T a b l e I ~ r e n c e of BN 52021 with the disappearance of circulatlng platelets and whlte blood cells (W B C) in animals given S. twphimurium endotoxin. The reduction in platelets and W B C counts, expressed in percent fa l l ~om basal values, were measured at 6, 10, 30 and 60 min after endotoxin a~in is t ra t ion. Non thrombopenic animals treated wlth 1 mg/kg BN 52021 (n = 10) and 6 mg/kg BN 52021 (n = 5) were compared to vehicle-treated animals (n = 15) by ANOVA. (*) p < 0.05, (**) p < 0.02, The percent fa l l of W B C counts in control thrombopenic animals was c~pared to control non thrombopenic anlmals by the unpaired t - test (T, p < 0.05).


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BN 52021 administered before endotoxin. As calculated from the data used in Fig. 2, the in i t ia l rapid

drop in blood pressure measured ten min after endotoxin injection decreased from 38.5 ± 5 mmHg in control animals (n = 15) to 17 ± 3 mmHg (p < 0.01), and to 9.5 ± 8 mmHg (p < 0.01) in those treated with I mg/kg BN 52021 (n = 10) and 6 mg/kg BN 52021 (n = 5) respectively. However, when measuring the maximal drop in blood pressure recorded at any time during the f i r s t 10 min of shock, a drop of 42.5 ± 5 mmHg was found in control animals as compared to 24 ± 3 mmHg (p < 0.05) with I mg/kg BN 52021 and to 22.5 ± 4 mmHg (p < 0.01) with 6 mg/kg BN 52021. The dose-dependent effect of BN 52021 thus disappeared i f the maximal drop in blood pressure was used as a cr i ter ia. A partial but significant decrease in the reduction of the platelet counts was also observed with BN 52021, from 81% ± 7 % in control animals to 52 % ± 3 % (p < 0.02) and 48 % ± 18 % (p < 0.02) with I mg/kg and 6 mg/kg BN 52021, respect ively (Table I ) . Furthermore, the leukopenia rate was reduced by BN 52021 at 6 mg/kg (Table I ) .

The mere gradual secondary decrease in blood pressure recorded from 30 to 90 min af ter endotoxin was also reduced by BN 52021 (Fig. 2). The maximal decrease in mean blood pressure observed in control animals averaged 44.5 ± 4 mmHg as compared to 24 ± 7 mmHg (p < 0.02) in the 1 mg/kg BN 52021 treated group and to 22.5 ± 11 mmHg (p < 0.05) in the 6 mg/kg BN 52021 treated group. The increase in hematocrit was also observed in the BN 52021 treated group, from 42.5 ± 2 % in basal conditions to 45 ± 2 % (p < 0.05) at 60 min and did not d i f f e r from that seen in control animals. Accordingly, wet/dry lung weight rat ios measured 90 min af ter endotoxin in ject ion were s imi lar in control and BN 52021 treated animals. The wet/dry lung weight ra t io for the BN 52021-treated animals (6 mg/kg) sacr i f iced 90 min a f ter endotoxin was 4.77 ± 0.44 (n = 7).

BN 52021 applied to thrombopenic animals. When erdotoxin was injected in animals made thrombopenic with

rabbit an t i - p l a te le t serum, blood pressure gradually decreased and the character is t ic p ro f i le of the two phase endotoxin-induced hypotension was rot seen any more. The values of a r te r ia l blood pressure observed in p la te le t depleted and in control non-thrombopenic animals beyond 30 min af ter endotoxin administrat ion were ident ica l , whereas a s ign i f i can t reduction of leukopenia was noted, from 74 ± 3 % fa l l in control to 57 ± 9 % fa l l in thrombopenic animals (p < 0.05) (Fig. 3). I t is noteworthy that the leukocyte counts in control and an t i - p l a te le t serum-treated animals were 6950 ± 900 mm ~ and 5900 ± 850/mm 3, respect ively (NS). When l mg/kg BN 52021 was administered to the thrombopenic animals, the endotoxin-induced hypotension was ~o~p}er~}v prevented, whereas the decrease in white blood cell counts and the increase in hematocrit persisted (Table I) .


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T~_~N DOTOXIN * • ~ 80 L T ~ 2 - ~ (n=4)

~ so

z [ I I i i A i L I I =E

0 I 0 20 30 40 50 eo 70 80 90

T iME (min)

VEHICLE - TREATED (n = 4)

z~----~BN 52021, 1 m g / k g t.v. ( n=4 )

Fiq. 3 Evolutive prof i le of mean arterial pressure in thrombopenic animals injected wlth the endotoxin, and treated (~) or not treated ( e ) with 1 mg/kg BN 52021. The unpaired group t- test was used for indlvidual points (*) p ( 0.05.

.It E

J

3O

2O

10

n = 4

0

(veh tc le )

n = 6

T n = 6

1 6

BN 52021 ( m g / k g )

* p < O . 0 5

* * p < O . 0 1

Dose-dependent increase in mean arterial pressure induced by BN 52021 during the late shock. The animals were given either vehlcle or BN 52021 {I and 6 mg/kg) 60 min after

endotoxln challenge. Values represent the difference between blood pressure recorded 15 min after BN 52021.


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BN 52021 administered during the late phase of shock. Intravenous administration of BN 52021 as a bolus 60 min after

the endotoxin injection was followed by an immediate dose-dependent increase in blood pressure, which amounted to 9 ± 2 mmHg p < 0.05) and 31 ± 8 mmHg (p < 0.01) mmHg when BN 52021 was given at I mg/kg and 6 mg/kg, respectively (Fig. 4). Under these conditions the arter ia l pressure recovered fu l l y after 6 mg/kg BN 52021. This change in blood pressure was observed whether the animals were thrombopenic or not.

Discussion

The effects of BN 52021, a new PAF-acether antagonist (17) were studied in guinea-pigs injected with S. typhimurium endotoxin, par t icu lar ly with respect to hypotension. In a previous study, BN 52021 has been demonstrated to reduce or even te abolish the le tha l i t y due to S. enter i t id is in rats (22). In this study, the animals experienced a biphasic change in blood pressure after endotoxin administration, ( i ) an early rapid drop in blood pressure associated with platelet and leukocyte disappearance from the circulat ion, ( i i ) a prolonged secondary hypotensive phase developed along with a moderate increase in hematocrit, ref lect ing extravasation. The effects of S. typhimurium endotoxin on the arter ia l blood pressure were thus similar to those described for other species (21, 23-25). Different mechanisms have been involved in the pathophysiology of the two phases and the irvolvement of PAF-acether can be discussed with respect to the effects of BN 52021 on both.

When BN 52021 was given prior to endotoxin inject ion, a signi f icant reduction of the immediate hypotension and of acute thrombocytopenia was observed. The effects of BN 52021 on blood pressure recorded at i0 min appeared to be dose-dependent (Fig. 2) whereas when the maximum drop was evaluated, dose-dependency disappeared. The early hypotensive phase may involve platelet part icipat ion. The relationship between immediate hypotension and platelet disappearance has ~Iready been demonstrated in C3-depleted animals (23) and in our experiments, the i n i t i a l rapid change in blood pressure due to endotoxin was indeed reduced in animals made thrombepenic with rabbit ant i -p late let serum. Thus, platelets may be at least par t ia l l y involved in the f i r s t phase of shock of our experimental model and BN 52021, a selective inh ib i tor of PAF-acether-induced platelet aggregation (26-28), completely reduced the immediate hypotension and par t ia l l y the platelet consumption. A signi f icant contribution of platelets to host response to endotoxemia has been suggested by studies showing correlation between thrombocytopenia and survival after endotoxemia (29). Thrombocytopenia is now considered as an indirect effect of host factors generated in response to endotoxin (30). This may be one reason why BN 52021 affected both systemic hypotension and thrombocytopenia, which could be relevant to a direct antagonism of


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endogenous PAF-acether. However, i t should be noted that even when the f i r s t phase of hypotension was abrogated in the 6 mg/kg BN 52021 treated group, a substantial decrease of platelet count s t i l l persisted.

The f i r s t phase of shock was also accompanied by leukocyte disappearance from the circulat ion which was not s ign i f icant ly reduced by BN 52021. However, leukopenia was s igni f icant ly lower (57 ± 9 %) in thrombopenic animals as compared to non thrombopenic ones (74 ± 3 % ; p < 0.05), suggesting that platelets may contribute te leukopenia.

The secondary phase of shock was also modified by BN 52021. This late steady-state phase of shock is usually characterized by low vascular resistance and intense extravasation. The evidence for increased vascular permeability tc f lu id and protein in the late steady-state phase of endotoxin shock has been provided by several studies (31, 32). PAF-acether by i t se l f can induce increased microvascular permeability (8, 33) and i t may be an important mediator of the permeability changes which occur in gram-negative shock as well as during the infusion of immune aggregates (15, 19). In a model of hypotension induced by immunoglobulin aggregates, BN 52021 has been shown to be as effective in preventing hypotension and extravasation as in antagonizing the effects of PAF-acether (19).

The hematrocrit increased 30 to 90 min after the endotoxin challenge. Even though s igni f icant ly higher blood pressure values were observed in the BN 52021-treated group as compared to untreated animals, hemoconcentration and extravascular lung water (as assessed by the dry/weight lung rat io) were identical in both groups. This indicates that the effect of BN 52021 on the late phase shock are unrelated to inhibi t ion of the disturbed vascular permeability, par t icu lar ly since in thrombopenic animals, the effectiveness of BN 52021 in reducing the gradual endotoxin-induced hypotension contrasted with the persistapce of hemoconcentratior.

One interesting point arising from our study is that, contrary to our i n i t i a l expectations that endotoxin wou ld tr igger bronchoconstriction in the guinea-pig, whose bronchopulmorary sens i t iv i ty is very marked, pract ical ly no modification of bronchial resistance to inf lat ion was observed. This might be used as evidence against the part icipation of PAF-acether in our model, but in unpublished experiments we observed that infusions of 3-11 ng/kg per min of PAF-acether to guinea-pigs have marked effects on cell counts and blood pressure, whereas bronchial resistance to inf lat ion was pot modified.

The i . v . injection of EN 52021 during the prolonged secondary phase of shock was followed by an immediate reversal of the depressed blood pressure also when thrombopenic animals were used. This curative effect was dose-dependent, did not require renewed injections of BN 52021 to be maintained and was not followed by an improvement of thrombocytopenia or neutropenia.


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As a conclusion, the effectiveness of BN 52021 in correct ing the endotexin induced hypotension contrasted with the apparent refractor iness of neutropenia. I t is not clear whether the interference of BN 52021 with endotoxic shock is a d i rect consequence of the PAF-acether antagonist properties of th is molecule. However, the fact that three chemically d i s t i n c t molecules which share an anti-PAF a c t i v i t y , Kadsurenone, CV 3988, and BN 52021 can reduce and reverse the hypotension of endotoxic shock should j u s t i f y fur ther studies on the involvement of PAF-acether in the physiopathology of endotoxin and other forms of shock.

References

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Editor: J.R. Fletcher Received: 5-27-86 Accepted: 10-31-86


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Interference of the PAF-acether antagonist BN 52021 with passive anaphylaxis in the guinea-pig