Glucose metabolism in relation to adaptation of guinea pigs to histamine

Lüe 8ciencea Vol. 12, Part II, pp . 357-387, 1973 Printed in Great Britain

Pergaanon Press

GLIICOSE METABOLISM IN RELATION TO ADAPTATION OF GIIINEA PIGS TO HISTAtdINE Czealaw Ma .§liiiski, Janina YVyozdlkowaka and Hanna Szyo with teohnioal assistanoe oß Zdzislawa Mrdz

Department oß Biogenio Amines oß Molecular and Maoromoleoular Research Center oß the Polish Academy oß Sciences, Ldd~, Narutowicza 60~ Poland (Received in final form 5 March 1973) Summar~r The changes in gluoose metabolism i .e . blood sugar

laotio acid, pyruvio aoid and the ratio oß laotio aoid to pyruvio aoid were examined in guinea pigs treated with histamine aerosols over a long period . The levels

oß hyperglycaemia, laotio and pyruvic acids and the ra-

tio oß laotio aoid to pyruvio aoid aßter exposure to the histamine aerosol depend on the sensitivity oß guinea pigs to histamine and the level oß dyspnoea . The animals succesaßully adapted to histamine do not show any bhange

in gluoose metabolism ; the level oß adaptation to histamine is very low . The changes in glucose metabolism may be treated as a measure oß the responsiveness oß a guinea pig to histamine .

Although there are a large number oß experimental procedures leading to histamine adaptation, there are no adequate methods to determine the state oß adaptation . Furthermore

the eßßeots

oß histamine vary in dißßerent animal species /15/ . In guineapigs~ the broaohooonstriotor eßßeot oß the amine /14,1516/ results in oxygen deficiency /4~15/~ which in turn aßßeots metabolic prooesses~ thereby altering the levels oß the oompoaents oß the glyoolytio process /6/ . Alterations in the level oß gluoose and gluoose metabolites are known to occur aßter doses oß histamine /15,1719/ .

357

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Effect od Histamine on Glucose Metabolism

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During the adaptation period s a new level oß balance oß metabolic processes is probably established /1~3~12/ . Apart from this

transßormations in the pathways oß histamine catabolism

may ocour /2,9,13/ . In the present study

we have attempted to

ßollow changes in glucose metabolism as adaptation to histamine occurs in guinea-pigs . Exper mental Procedure Experiments were perßormed on 44 coloured guinea-pigs oß either sex y wéighing 560 ± 82 g~ ßed on the standard granulated ßeed, oarrots and hay, Histamine /as the dihydrochloride/ was inhâled by the animals /14/ in concentrations increasing from 0 .5 to 1 ;6, as an aerosol from a generator D-30 under 1 atm . pressure . The size oß the sprayed particles of the solution did not exceed 0 .5 /u . P.nimals were submitted daily to exposure to histamine aerosol . The duration depended on the appearance oß the symptoms oß deep dyspnoea whioh usually preoeeded the histamine shock, Animals in whioh the time oß exposure in 1 ;ô histamine aerosol exoeeded 20 minutes /usually aßter 2-3 months/ and thus squired a certain degree oß tolerance to histamine have been termed ~~adapted° . Control animals were kept under the same conditions and ßor the same time as the histamine-treated ones . The levels oß blood glucose

laotic sold and pyruvio acid were estimated

beßore and aßter exposure to the histamine aerosol for 3 or 20 min as well as 15,30 and 60 minutes later . /tcoeleration oß respiratory rate s and the production oß cough and choking were deßined as moderate dyspnoea . The appearance oß robust movements of the respiratory muscles, abdominal press, and the slowing down and prolongation oî breathing /14/were recorded as deep dyspnoea .

Vol. 12, No. 8

ls~ect `~ Hietaai~e on Glucose Metabolism

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Effect ad Histamine on Glucose Metabolism

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1 .5 - 2 .0 ml oß blood were taken ßrom the aurioular vein of esoh animal into heparinized test-tubes and divided for gluoose /0 .1 ml/ and laotic and pyruvio aoid /1 .4 - 1 .8 ml/ determina tions . In 9 control and

3 "adapted" animals, blood was taken only

ßor gluoose estimations . Deproteinization ßor laotio and pyruvic acid determinations was parried out with cold

6â perchlorio aoid

/1 :1 v/v/, and for glucose with 0 .05 N NaOH and 10~ ZnS0 4 . Glucose

laotic acid and pyruvic aoid levels were estimated by

enzymatio methods /gluoose - Blutzucker-Test~ Bestell Nr 501/175 Fermognost ; laotic acid - TC-B-15972 TLAA Boehringer P.~lannheim GD~H ; pyruvic acid - Pyruvat-Test, Bestell Nr 507 Fermognost/. For each sample oß blood y the ratio of laotio aoid to pyruvio aoid /L/P/ was calculated as a criterion oß anoxaemia

/6/.

Results Blood sugar . About halß the control animals showed signs of deep dyspnoea when exposed to the histamine aerosol ßor

3 min i

and signißioant increases in the blood sugar levels were found both at 15 and

30 min after the exposure /Table 1/ . The remain-

der oß the guinea-pigs showed signs of moderate dyspnoea but the blood sugar values were not significantly different ßrom oontrol values . All the animals adapted to histamine showed no untoward signs when exposed to the histamine aerosol for

3 min and there

were no changes in the blood sugar level . Qut of 19 guinea-pigs exposed for 20 min i 12

/63°x/ showed signs oß deep dyspnoea and

had increases oß up to 100°b in the blood sugar levels 15 min after exposure and these returned to oontrol levels by

60 min .

The remainder oß the group had moderate dyspnoea and a slight rise in the blood sugar levels at 15 min . Blood lactic acid . As with the blood sugar results

halß of the

oontrol animals showing deep dyspnoea after 3 min exposure had

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significantly raised levels of blood lactic acid at 15 min. In the adapted animals, there was no increase in blood lactic acid after 3 min exposure and no dyapnoea but after 20 min exposure, the increase was related to the degree of dyapnoea, particularly at 15 min /Table 2/ . Blood pvruvic acid . The changes in the blood pyruvie acid levels closely followed those of lactic acid, again adapted animals showing no dyapnoea and no increase in pyruvate after 3 min exposure but significant increases when dyapnoea was marked after 20 min exposure /Table 3/ " The ratio of lactic acid to pyruvic acid in blood . In the control animals after 3 min exposure to the histamine aerosol, there was increase in the ratio L/P in blood and it was related to the degree of dyapnoea. When dyapnoea was marked, significant increases in the Z/P ratio were found at 15 and 30 min after the exposure /Table 4/ . In the adapted animals there was no dyapnoea and no increase in the ratio L/P in blood, but after 20 min exposure, Z/P was raised at 15 min after exposure as in control animals after 3 min exposure, and the increase was related to the degree of dyapnoea . Discussion In this paper, an arbitrary division of the animals into those reacting intensely and those reacting weakly to histamine has been made, based on the degree of dyapnoea . This division showed that the level of hyperglycaemia after the application of histamine aerosol is related to the degree of the animale~sensitivity to histamine . For the greater the intensification of dyapnoea, the higher is the degree of hyperglycaemia . The hyperglycaemic reaction of the control animals weakly sensitive to

384

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Eüect ad Histamine on Glucose Metabolism

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histamine and showing a moderate dyspnoea was similar that oß histamine-adapted animals submitted to a 3 minutes exposure . The intensity oß hyperglyoaemia is also dependent on the time oß duration oß the histamine inhalation . For example s the blood glucose oß the oontrol animals was lower despite the symptoms oß a deep dyspnoea during the exposure oß 3 minutes in histamine aerosol than that oß histamine-adapted animals submitted to 20 min exposure . In the latter oase s the symptoms oß dyspnoea were slightly less intense

but they lasted longer . Adrenaline

released in large quantities 'from the adrenals after histamine applioation, may be the mediator oß this hyperglyusemio reaotion /~~10~11 ~15~18/. The parallelism oß the intensity oß dyspnoea under the inßluenue of histamine and the extent oß the hyperglycaemic reaotions /as well as the inorease of L/P ratio/ indicates that these re sults may be used as a measure oß the responsiveness oß guinea pig to histamine . The quantity oß histamine absorbed by the blood of the aerosol-tested animals is about 8 .4 /ug for 3 min oß exposure /5~8/~ but the adaptation to greater quantities oß absorbed histamine is different . The prolonged exposures over 20 min by the animals result in a considerable intensißioation oß anaerobio glycolysis and an inorease oß the L/P ratio s indioating that the anoxaemia /6/ is proportional to the intensißioation oß the dyspnoea symptoms . This partioular toleranoe to histamine cannot be treated as adaptation s as the animals have not acquired the new level oß regulation oß metabolio processes whioh is the manifestation of adaptation .

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Effect od Histamine on Glucose Metabolism

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Acknowledgment The paper has been done with technical assistance of tdrs Zdzislawa T,Trßz . References 1 . E .F . ADO?1PH~ Am . J . Physiol . 1~~ 18 - 28 /1956/ . 2 . S .G .A . ALIVISATOS~ in Handbook of Experimental Pharmacology vol . 18/I~ p . 726 - 733, Springer-Verlag s Berlin /1966/ . 3 . E . B~!1JUSZ, physiology and Pathology of Adaptation T,°echanisms ~ Pergamon Press e Oxford /1969/ . 4 . G . CORDILR~

r . COßDIEIt, J . Physiol . /Paris/ ~~ 141 - 143

/1955/ . 5 . L . DAUTIZfBANDr~ tlicroaerosols , Academic Press e New York /1962/ . 6 . 7l .E . HUCKABEE~ J. Clin . Investig . ~,~,~ 244 - 254 /1958/ . 7 . D.J . INGLE~ J .E . N13ZANI5~ K.R . ßICL~ Endocrinology ~ ~~ 14 - 20 /1950/ . 8 . J . IHiAJET7SKA~ Dootor Thesis ~ Lbd~ /1968/ . 9 . T .H . LIPPERT, N. G. ~lATON~ Int . Arch . Allergy ~~ 292 - 298 /1968/ . 10 . J . PiAL1~IfhJAC~ A . GßOSS~ G. NEVI3RR1;~ C .ß . Soc .ßiol . /Paris/ 145, 704 - 707 /1951 /. 11 . Cz . PiIA~LII~SKI~ Bull . Aoad . ï'olon . Sci .~ C1 .VI~ 8~ 473 - 477 /1960/ . 12 . Cz . TJ.GSLINShI~ Przegl . Lek . 2~ 304 - 308 /1970/ . 13 . Cz . T~A~LII~SKI~ J .T~I . FHZAJE47SIOi, Eur . J . Pharmacol . ~~ 213 - 219 /1969/ . 14 . Cz . P.4A$LII~SKI~ J . 17ISNIh~IIS}{A~ Aroh, int . Pharmacodyn . Therap , 1~, 196 - 204 /1965/ . 15 . P, N .AßAPiJO, in Handbook of Experimental Pharmaoology ~ vol . 18/I, p . 179 - 201

Springer-Verlag s Berlin /1966/ .

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Effect ad Histamine on Glucose Metabolism

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16 . J .E . PdILLS~ J .G . 49IDDICOP?fBE~ Brit . J . Pharmacol . ~~ 724 731 /1970/ . 17 . C .A . P~IPACOSTAS~ P . MOZD.G N~ H .R . LOf;tiV~ Proc . Soc . Exp . Biol . P~led . ~7, 297 - 299 /1958/ . 18 . P .J . PIPN'R~ H.O .J . COLLIî.ß~ Nature 21~~ 838 - 840 /1967/ . 19 . J .C . YlHLLS~ Can . J . Biochem . PY~ysiol . ~7,, 347 - 351 /1969/ .