Modulate Systemic Anaphylaxis: Et Al., 1973; Wells, Eyre & Lumsden, 1973)

364

Short communications and diethylcarbamazine (which are known to antagonize kinins, slow reacting sub- stance-A and prostaglandins) do so almost Histamine H2-receptors completely (Wells & Eyre, 1972; Eyre modulate systemic anaphylaxis: et al., 1973; Wells, Eyre & Lumsden, 1973). This suggested to us that kinins a dual cardiovascular action and pharmacologically-active lipids might of histamine in calves be of greater significance in bovine anaphylaxis than the amines, histamine P. EYRE AND P. or 5-hydroxytryptamine. Another ex- W. WELLS* planation for the low anti-anaphylactic potency of mepyramine in calves appeared Pharmzacology Laboratory, Department of possible however. It seemed feasible that Biomedical Sciences, University of Guelph, histamine H2-receptors might play a role Guelph, Ontario, Canada in bovine anaphylactic shock. Thus the present study was undertaken to determine Depressor changes in carotid blood pres- the effects of burimamide on mepyramine- sure caused by histamine or anaphylaxis in resistant systemic depressor responses to calves, were incompletely blocked by the H,- histamine and anaphylaxis in calves. receptor antagonist mepyramine. Burim- amide, the selective histamine H2-receptor Methods.-Twenty male Jersey and antagonist, potentiated the depressor actions Guernsey calves one to two months of of histamine and anaphylaxis. Potentiated age, weighing 30-70 kg were sensitized depressor responses were inhibited by with whole horse serum and Freund's mepyramine. Observations are consistent complete adjuvant (Eyre & Lewis, 1972; with histamine stimulating both H,- and Eyre, Lewis & Wells, 1973). Blood H,-receptors to cause respectively vaso- pressures were measured in the common dilatation and vasoconstriction. carotid and pulmonary artery under pento- Mepyramine has been classified as a barbitone anaesthesia as previously histamine-Hl-receptor antagonist (Ash & described (Lewis & Eyre, 1972 ; Eyre, Schild, 1966) and it is recognized that et al., 1973 ; Wells, et al., 1973). All drug this agent does not antagonize all the administrations were made into a actions of histamine. Mepyramine does cannulated tarsal vein. not inhibit the effect of histamine on Animals were divided into gastric secretion (Ashford, Heller & Smart, four groups 1949), of four and two groups of two. In group rat uterus (Dutta, 1949) sheep 1, after an 'equilibration' period of bronchus (Eyre, 1969), cat trachea approximately 15 min, histamine, 5- (Maengwyn-Davies, 1968) and a component of cat hydroxytryptamine and acetyl ,8-methyl blood pressure (Black, choline (methacholine) were administered Duncan, Durant, Ganellin & Parsons, randomly at several dose levels in four 1972). Mepyramine-resistant histamine calves in order to receptors are defined as H2-receptors establish three-point (Black et al., dose-response curves for each agonist. 1972). A new agent, burim- Horse serum (0-2 ml kg-') was then amide, antagonizes H2-receptor-mediated administered intravenously to induce effects of histamine on gastric secretion anaphylaxis. (Black et al., 1972; Wyllie, Hesselbo & Black, 1972), sheep bronchial and cat The four calves of group 2 were tracheal relaxations (Eyre, 1973) and cat similarly treated except that dose-response blood pressure (Black et al., 1972). curves for histamine, 5-hydroxytryptamine and methacholine were re-established 15 Despite the reported elevation of min after administration of histamine concentration in the plasma of mepyramine calves maleate, 5 x 5-6 mol kg-' as a single injec- during anaphylactic shock (Eyre, tion. The effectivenescs of mepyramine was Lewis & Wells, 1973), mepyramine does estimated by measuring the dose-ratio not effectively control anaphylaxis in this of species; each agonist: i.e. the ratio of doses of whereas sodium meclofenamate agonist giving equal carotid depressor * Present address: Animal Diseases Re- responses in the presence and absence of search Association, Moredun Institute, Edin- antagonist (Gaddum, Hameed, Hathway burgh EH17 7JH, Scotland. & Stephens, 1955). Anaphylaxis was then Short communications 365 induced with horse serum in each calf as the dose of burimamide was increased before. to 5 x 10- mol kg-' min-'. Group 3 consisted of two calves identi- In the four calves of group 6, agonists cally treated to group 2 except that the were tested before and after administra- dose of mepyramine was increased to tion of burimamide (3 x 10-7 mol kg-' 2-5 x 10-5 mol kg-'. min-') continuously as in group 4. How- In group 4, following the establishment ever, after 20 min of burimamide infusion, of agonist dose-response curves, four mepyramine (5 x 1o-6 mol kg-') was calves received burimamide (3 x 10-7 mol administered as a single injection. After kg-' min-') continuously to the end of a further 10-15 min, agonist dose-ratios the experiment. Agonists were re-tested were established and anaphylaxis induced. and dose-response curves re-established prior to challenge with antigen after 30 Results. - As previously reported, minutes. histamine and 5-hydroxytryptamine caused Group 5 consisted of two calves carotid depressor responses (Lewis & identically treated to group 4 except that Eyre, 1972; Eyre et al., 1973). Metha-

(4) (4) a) (4) Po 3 F_ t 8 . t 10 S

a. S fC

'50 3 0. S S _S to I S I, M g S .0 S Io0 S T S 6 S

z Control minBurlmam3x molde ~~~~~13'0-1 mol kg-' min-4 Mepyramine i Burimamide 5x 04 mol kg 3 Sx 104 mol kg-1 min-. Mepyramine XMepyramine Sx IO mol kg- 2 5xI0-' mol WI1 Burimamide 3 x I0-7 mol kg-1 min-i FIG. 1. Mean percentage decrease in femoral arterial blood pressure (± S.D.) in six groups of calves subjected to acute systemic anaphylactic shock under pentobarbitone anaesthesia. Group 1, the open column, represents control anaphylactic shock equivalent to -90 mmHg, (mean arterial pressure) converted to 100%. Prior to induction of anaphylaxis, mepyramine wa administered to groups 2 and 3, burimamide to groups 4 and 5, and mepyramine and burimamide combined to group 6. Numbers in parentheses on columns refer to numbers of observations. 366 Short communications choline (>0 05 jug kg-') consistently block all the participating 'depressant' Hl- reduced systemic blood pressure. receptors, which may thus have continued Anaphylaxis in the control group was to neutralize any postulated Ha-pressor characterized by systemic arterial depres- component. It was not possible ta sion representing a change in mean examine the effects of greater doses of arterial pressure of -90 mmHg (-64%: mepyramine owing to toxic manifestations n=4). After injection of mepyramine of the drug. (5 x 10-6 mol kg-'), the dose-response Responses of calves to histamine differ curve to histamine was displaced to the from those of cats. Black et al. (1972k right (mean dose-ratio=26:n=4), whereas described Hl- and H2-receptors, both the effects of 5-hydroxytryptamine and acting in the same direction to lower methacholine were unchanged. In the blood pressure in the cat. Hence in that same calves, systemic anaphylactic shock, species, mepyramine and burimamide measured in terms of mean carotid blood reinforce each other in the blockade of pressure, was suppressed 40% (n=4) histamine depressor responses. In the calf (Figure 1). The five-fold increase in it appears that the H.-receptors modulate mepyramine dosage to group 3 blocked the depressor effects of H,-receptor anaphylaxis 60% (n=2), and increased the stimulation. Preliminary studies of H2- histamine dose-ratio to 100 (n=2). receptor distribution in ruminants have In contrast, burimamide (3 X 1O- mol revealed that histamine-induced vaso- kg-' min-') clearly potentiated the constrictions of calf pulmonary vascula- depressor response to histamine (dose- ture were potentiated by burimamide, and ratio=0-55: n=4) without displacing the these could be blocked by mepyramine. dose-response curves to 5-hydroxytrypt- This suggests a wider distribution of both amine or methacholine. Anaphylactic types of histamine receptors. shock induced in the presence of burim- It is not unreasonable to presume that amide was identical to that in the control tissue histamine released endogenously by group. Increasing the concentration of antigen/antibody interaction would stimu- burimamide to 5 x 10-6 mol kg-' min-' late both classes of histamine receptors in further potentiated histamine depressor the same way as exogenously injected responses (dose-ratio 0-35: n=2) and histamine. Bearing in mind that anaphy- furthermore intensified anaphylactic shock laxis involves many chemical mediators by 20% (n=2). in addition to histamine, it is possible to suggest that part of the action of The potentiating action of burimamide histamine liberated in anaphylaxis in calves. was antagonized completely by serves to modulate the overall systemic mepyramine (Figure 1). depressor response. The failure of mepyramine to antagonize anaphylaotic hypotension in calves probably is not due Discussion.-Present findings are con- to the activation of H,-receptors. It does sistent with a dual histamine receptor not seem likely that burimamide will be mechanism in peripheral blood vessels of of value in controlling diseases of cattle calves. It seems possible that systemic which involve anaphylactic hyper- depressor responses to histamine in the sensitivity. calf may represent an algebraic sum of two components (1) a mepyramine-sensi- We are indebted to Professor H. G. tive depressor effect, presumably mediated Downie for his continued support and en- by H,-receptors; (2) a mepyramine-re- couragement and to Mr. T. R. Deline for sistant, burimamide-sensitive anti-depressor invaluable technical assistance. We grate- effect, evidently mediated by H2 receptors. fully acknowledge generous gifts of drugs: The full extent of the depressor compo- mepyramine maleate from Dr. F. Poulin of nent was revealed by burimamide, par- Poulenc Ltd., Montreal, Canada, and burim- ticularly in group 5 at the dose rate of amide from Dr. J. W. Black of Smith, Kline burimamide 5 x 10-6 mol kg-' min-'. How- & French Ltd., Welwyn Garden City, Eng- ever, large doses of mepyramine (2-5 X 10-5 land. The work was supported in part by- mol kg-') failed to 'unmask' any actual the Ontario Ministry of Agriculture and pressor effeot of histamine. Indeed, this Food and also by grant A5937 of the. concentration of mepyramine failed to National Research Council of Canada. Short communications 367

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