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Histamine H1- and H2-receptors in the gastric vasculature of the rabbit
E u ~ p ~ n J o u ~ d of Pharmaco~g~ 71 (1981) 515--519 © ~ f i ~ / N o r ~ - H o l l a n d Biomedi~l Pre~
515
S h o ~ communication HISTAMINE H1- AND H r R E C E P T O R S IN THE GASTRIC VASCULATURE OF THE RABBIT BRIAN P. CURWAIN and NICHOLAS C. TURNER Department of Physio~gy, St Ma~ ~ Hospi~l Medical Schoo~ Norfo~ Place P a d d ~ o ~
London W2 1PG, ~
Rec~ved 26 March 1981, accepted 27 March 1981
B.P. CURWAIN and N.C. TURNER, His~mine H~- and H 2 - r ~ e p ~ in the gastr~ vasculature of the mbbi~ European • Ph~mac~. 71 (1981) 515--519. The h ~ m ~ e ~ c e ~ o ~ ~ ~ e mbb~ ~ood p ~ d g~tfic v ~ c ~ u r e w~e an~y~d p h ~ m a c o l o ~ l ~ . H~m~e ~ed a monopha~c ~ e ~ e ~ p ~ o n ~essure wh~h w~ an~go~zed by mepyramine and enhanced by mefiam~e. The ma~mum obs~ved ~aponse was enhanced by m ~ m ~ e tot that produced by a speOfic Hl~eceptor agon~t. ~ ~ concluded that ~ e ~stfic v ~ c ~ u ~ ~sponds to ~ s ~ m ~ e w~h an Hireceptor m e d ~ d v a ~ e o n s ~ t ~ n and an H2~eceptor m e d ~ d dilatation. In th~ ~epamt~n the H ~ f f e ~ predomina~s ~ ~sponse ~ inj~t~n of ~s~mine. Ga~c va~u~ V~o~fion
Hi~am~e
R~e~ors
1. Introduction In the rabbit u n f k e other spe~es changes in blood pressure ~ i t e d by injection of histamine are t y p i c ~ l y biphasic and thought to reflect the b ~ a n c e between an H~-recepto~ mediated v a s o c o n s ~ t i o n and an H2~ecepto~ mediated vasodflatation (Parsons and Owen, 1973; Owen, 1977). A~hough Angus and Korner (1977) were u n a b ~ to show any ~gns of c o n s ~ f i o n in the r e n ~ and mesentefic beds of unanaesthet~ed r a b b i s during H~receptor s t i m u h t i o n , H~-medhted pressor and H:-mediated depressor responses have been reported in the Krebs-perfused ~olated rabb~ kidney (BSkesoy and Tfirker, 1974) and in perfused rabb~ ears (Parsons and Owen, 1973). We have recently d e m o n s ~ a t e d an H~-receptor-rnediated inhib~ory effect of histamine on gastric acid secretion which measuremen~ of aniline clearance suggest may operate fia vasocons~iction in the ~ o m a c h (Curw~n and Turner, 1981). We have, therefore, investigated the l o c ~ effects of histamine on the gas~ic vasculature, and
Rabbits
V~o~ o ~ f i o n
the receptors involved in the response, in a fituation where perfusion rate ~ kept constant and changes in perfu~on pre~ure reflect vasoc o n s ~ t i o n or vasodflatation.
2. Materi~s and methods E x p e f i m e n ~ were performed on m ~ e , pentobarbitone (30-40 mg/kg i.v.) a n a e ~ h ~ fised New Z e ~ a n d White r a b b i s 2.0-2.7 kg, w h ~ h had been starved overnight but ~ l o w e d ~ e e access to water. The m e t h o d has been developed from that described by Harvey et ~. (1980) in the cat. The abdomen was opened ~ a a ~ ~ansverse i n d ~ o n , p a r ~ l ~ to and a p p r o x i m a t ~ y 1 cm below the base of the fib cage. The d u o d e n ~ blood v e ~ d s derived ~ o m the mesentefic c~culation were fled just d~tal to the pylorus. The blood ve~ se~ ~upplying the spleen were fled as do~e as po~ible to the organ to preserve the artefi~ supply to the greater curvature; the hepatic artery was ~gated. The gastric vasculature was perfused fia a catheter in the co~iac artery,
516
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F~. 1. The effee~ of three h ~ m ~ e receptor a g o n ~ on the perfu~on ~ e ~ e reeotded from t~e blood per~sed ~abb~ g ~ c v ~ u ] a t u r e . The v e ~ b ~ a~e ~e~u~e e ~ s t ~ ( ~ ~ ) w~h an uFw~d d e l e t i o n of the trace d e n o ~ an ~ e ~ e in ~ u r ~ ~he ho~zon~] ba~ ~ d ~ e time (2 rain). ~ u ~ do~s ~ e ~ o w n ~ m~¢.
VASCULAR
HI o A N D
H2-RECEPTORS IN T H E RABBIT
517
with blood taken ~ o m a carotid artery. The blood was p u m p e d at constant flow rate through a roller pump. Pressure in the perfu~ o n c~cu~ was measured by a Ball and H o w e ~ pressure ~ansducer finked to a De~ces pen recorde~ The p u m p was set to ~ve a
3~-
pressure approximately e q u ~ to a r t e ~ blood pressure at the completion of surgery. At this pressure flow rate was between 10 and 14 mUmin. It was then kept constant for the duration of the expe~ment. Heparin (1000 IU/kg i.v.) was ~ven and drugs in s~ine (5-50 pl) were injected into the perfusion c~cuit immediately before the pump. Resu~s are e x p r e ~ e d as the mean percentage change in perfusion pressure (±S.E.) compared to that prior to injection of the drug. The maximum observed response to 2-TEA and h~tamine
200-
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3. Results The results are shown in figs. 1 and 2. H~tamine ~ . 3 4 × 10-%2.67 × 1 0 -7 mol/kg) caused a m o n o p h a s ~ increase in p e r f u ~ o n pressure lasting 1-3 rain. The response was d o s ~ d e p e n d e n t w ~ h a maximum observed increase of 144 ± 22.2% (n = 5). The spec~ic Hz~eceptor agonist 2-(2-aminoethyl)thiazo~ dihydrochloride (2-TEA) (2.24 × 1 0 - ~ 1 . 1 2 × 10 -~ mol/kg) a~o caused a d o s ~ d e p e n d e n t increase in perfu~on pressure. In 5 e x p e l ments the maximum increase o b t ~ n e d in response to injection of 2-TEA (240 ± 32%) was significantly greater than that observed to histamine (P < 0.05). Mepyramine (1.25 × 10 -s mo~kg) d~placed the histamine dos~response curve to the ~ght. Treatment w ~ h mefiamide (2 × 10 -~ mol/kg/min i.v.) d ~ p h c e d the cur~e to the left and p o t e n t a t e d the maximum increase in perfu~on pre~ure to an average of 222% (n = 4, range 185-274%) w~ich ~ ~m~ar to the maximum response o b t ~ n e d w ~ h 2-TEA. In 6 expe~ments the spe~fic H ~ e c e p t o r agoni~ impromidine (1.0 or 2 . 0 × 1 0 - S t o o l /
in perfu~on p r e ~ u ~ (% basal,
o ~ a ~ ) of the rabb~ gast~c v~culatu~ showing an~gon~m of the control responses to h ~ m i n e (~) by mepy~m~e 1.25 × 10 -s m~]kg (~) and enhanc~ ment by me~am~e 2 × 10 -6 mol]k~min (©~ (m) ~ the r~ponse to the H~gon~t 2 - ( 2 ~ m i n o e ~ ) t~az~e d~ydroc~o~de. V ~ c M b~s ~e S.E.M. (n = 4~). kg) caused a longAasfing (5-20 min) reduction in p e r f u ~ o n pressure of 19-35%. We have not ~ u d i e d t h ~ response in detail, howeve~ our resu~s confEm those of Aksulu et ~. (1979) who have reported that impromidineproduces a lon~la~ing f ~ l in perfusion pre~ure of the ~ o h t e d perfused rabbit kidney. Changes in systemic blood pressure following injec~on of h~tamine ~r 2-TEA into the perfu~on cEcu~ were minimM. In some an~ m a ~ histamine eli~ted small presso~ depre~ sot or bipha~c changes depending on the dose, whereas, impromidine ~ w a y s caused a lon~lasting depressor response which was characte~sed b y a r e d u c ~ o n in sy~olic and pulse pressure. Intr~arte~ infu~on of histamine ( 2 ~ 10.6 × 10 -s mol/kg per rain) over a 10 min p e ~ o d e~cited a monophasic increase in
518
perfu~on p ~ u r e w ~ c h w ~ d o ~ e d and sustained for the duration cf the h f u ~ o ~ after ~ r m ~ a t ~ n of the ~ f u ~ o n the pegu~cn p ~ u r e ~ t u r n e d to c o n ~ ~ e ~ .
4. D~cu~ion In the v~cular beds of most m a m m a s histam~e ~ a p o i n t vasodflato~ and ~ear e~dence h ~ been prodded ~ o m ~ u ~ ~ the g~tric v ~ c u l ~ u r e of the c ~ and r ~ (Harvey et ~., 1980; Guth and Smith, 1978) and the dog m e ~ n ~ r ~ c ~ c ~ a t ~ n (Pawfk et ~., 1977) that t ~ s response ~volves both H~and H:~ecepto~. In the rabbit, howeveL histamine has been reported to produce both vasocon~c~on and v~odfl~afion, the f o r m ~ respon~ b e r g media~d by H~-rece~ tots and the la~er by H:-~ceptom (Parsons and Owen, 1973; BSkesoy and Tfirker, 1974; S u z u ~ and C ~ s , 1979). Furthermore, ~ the coronary vasculature B r o a d l y (1975)has r e p o s e d t h ~ the o n ~ d~ect effect exerted by histamine ~ H~-receptor-medh~d vasoconst~n. In c o n ~ t Angus and K o r n ~ (1977) weze neith~ ab~ to d e m o n s ~ a ~ any clear H ~ ¢ e c e p t o p m e ~ a ~ d v ~ o c o n s t r i ~ o r ac~on of h ~ t a m ~ e ~ the m e ~ n ~ c and ren~ v ~ c ~ a r beds ncr were they aMe to show any changes ~ ~ a n c e during histam~e ~ f u ~ons ~ the h ~ d ~g and carotid beds of consciousrabMts, The present e x p e ~ m e n ~ show that dose arterial ~ j e c ~ o n of histam~e produced dos~ ~ h ~ d inc~ases in p ~ f u ~ o n pressure w h ~ h c o u ~ be antagonised w~h mepyram~e. If ~ the rabb~ H~¢ecepto~ subserve v~odflat~ fion then one might expect t h ~ ~ the presence of H,¢eceptor b ~ c k a d e M~amine would eHdt a fa~ ~ pe~usion pr~sure, Indeed Parsons and Owen (1973) ~ p o ~ e d that ~ the c ~ e of rabb~ sys~mic Mood pre~ure, antagon~m of histamine p ~ o r responses by mepyramine uncovers a depre~ sot response w h ~ h can be antagonised by burimamide. HoweveL u n ~ the v ~ c ~ a r tone of the preparation w ~ e ~ v a ~ the
~ P . CURWAIN, N.C. TURNER
~ m e w o r k , s were unab~ to d e m o n s ~ a ~ a fall ~ peffusion pr~sure ~ the rabb~ ear to histamine foHow~g H~¢eceptor ~ o c k a d ¢ suggest~g t h ~ th~ v~cular bed w ~ already ma~m~ ~ h t e d . In our expe~men~, howeveL the respon~ ~o i m p r o m ~ e demom s ~ a ~ d t h ~ the gastric vascuhture w ~ capa~e of d f l ~ n and ~ ~ fik~y that the m s ~ u ~ vasoconstri~or responses to h~tm m ~ e foHow~g ~eatment w~h mepyramine w e ~ s~ll suffi~ent to m ~ k the H:~eceptow medi~ed d i l a t i o n . In the p ~ f u ~ d r a b ~ t ear (Parsons and Owen, 1973) addition of m e p y r a m ~ e ~ o n e to the peffusion f l ~ d caused a marked redu~ fion ~ the maximum ~ s p o n ~ to histamine. This w o ~ d be expected if the H~-receptow me~a~d vasoconst~n w ~ o p p o ~ d by an H:-receptowmedia~d v~odilatation. In our expe~men~ even in the presence of mep y r a m ~ e large doses of h ~ t a m ~ e were ~equenfly ~ t h ~ and consequently a max~ mum response was unobtainable. Howeve~ the f i n d ~ of P~sons and Owen (1973}, coupled with our ob~rvation that, following H ~ e c e p t o r ~ o c k a d e by me~amide, v~oconstri~n to histamine was enhance~ ~ d i c a ~ that the observed response to h~tw m ~ e mfle~s the b~ance between a pr~ d o m ~ a n t v ~ o c o n s t r i ~ o r ac~on m e ~ e d by H ~ e c e p t o ~ and v ~ o d f l ~ a t ~ n m e ~ a ~ d by H:~ecepto~. Th~ dilatation, though m ~ k e d by the c o n s ~ t o r response, does p a r t ~ c o u n ~ r a ~ the c o n s ~ f i o n . I~ecfion of the spedfic H ~ e c e p t o r agonist 2-TEA ~ t o the perfu~on c~cu~ caused a m o n o p h ~ increase in perfu~on p ~ u ~ with a ggnificantly g e a ~ r ob~rved maximum than that to Mstam~e ~one. The ~ s p o n ~ to 2-TEA was ~mflar to that to Mstam~e in the p r e sence of methmide confirming that the H~pr~sor response ~ norm~ly opposed by an H:-receptor-media~d dilatation. D~e~ e~dence for an H:-receptor-mediated vasodilator mechan~m ~ shown by the monoph~ic reduc~on ~ pe~usion pre~ure e ~ d ~ d by impromid~e, wMch h ~ been zepo~ed to be a spe~fic H:~eceptor agon~t ~ the c~dio-
VASCULAR H1- AND H2-RECEPTORS IN THE RABBIT vascular system (Owen et al., 1979). In the cat gastric vasculature Harvey et al. (1980) have shown that the vasodilator
response to an infu~on of histamine has two components. The in~ial peak dilatation ~ mediated by H,~eceptors and ~ followed by a
maintained H2-recepto~mediated dilatation. This contrasts with the maintained vasoconst~cfion we have observed in the rabbit following histamine infu~on. In conclu~on the rabbR gast~c vasculature responds to histamine w~h an H ~ e c e p t o ~ mediated vasoconstriction and an H:~ecepto,mediated vasodilatation. The H ~ e c e p t o ~
mediated vasoconstriction predominates both after close arterial injection and close arte~al infu~on of histamine and ~ ~ t h ~ vasoconstfic~on which seems to constrain the acid secretory and mucosal blood flow responses in rabbits stimulated by i.v. infu~on of hista-
mine. Acknowledgement We world Hke to thank the Joint Standing Research CommRtee of St Mary~ Hospit~ M e d ~ School for thor support. References Aksulu, H.E., Z.S. Ercan and R.K. Tfirker, 1979, A comparat~e ~udy w~h impromidine (SKF
519 92676), a potent a g o ~ for hi,amine HTrecepto~, Agen~ Act~ns 9 (516~ 461. Angu~ J.A. and P.I. Korner, 1977, Re,ohM vasc~ar re~stance~Hl.and ~. ^ rate : h -responses ~e_ a r med~ted t unanae~h~e~ d h r o u g h an~abbR.. ,2-histamiE ~=uropea~eCeptoj. ~Pharmacol, . n the 45, 45. Bbkesoy, T.A. and R.K. Tfirker, 1974, The presence of H2~ecepto~ in rabbR kMney, Arch. Intern. Pharmacodyn. 209,114. Br°a~eYt ' o r s~ the v "S''acoronary s1975, c ~ The K rOleresponseO ar f H~- and to ~am~H e~ecepof ~ a t e d perfused hea~s of gu~em~gs and rabbRs, Br. J. Pharmacol. 54, 511. Curw~n, B~. and N.C. Turne~ 1981, The inv~v~ acmid ent secr~° f hN~mina n end mucosar ecept°r1 blooS dubtype;o~n i~a~rtiChe a n a ~ h ~ e d rabbR, J. P h y ~ . 311,431. Guth, P.H. and E. SmRh, 1978, H~tam~e receptors in the g a ~ c m~rockc~at~n, Gut 19, 1059. Harvey, C.A., D.A.A. Owen and K.D. Shaw, 1980, i~denct e h ega~rf°ric b°tv hasc~aturh eiStam~oef thHe ~"cata, nd BrH .~ecept°j. rSphar" mac~. 69, 21. Owen, D.A.A., 1977, H~tamine receptors in the card~vasc~ar sy~ern, Gen. PharmacY. 8, 141. Parsons, M.E. and D.A.A. Owen, 1973, Recepto~ mine~ ,v~Ve~n:inproct .he IntC .ard~va~s a r y mon p , H~tam~e Hesp°nses ~ r e c e r to ~st~ ptor A g o n ~ , London 1973, ed. C~. Wood and M.A. ~mkins (SK & F Labs Ltd., W~wyn Garden CRy) p. 127. PawlS, W., L.L. Tague, B.L. Tepp~man, T.A. M~ler and E.D. Jacobson, 1977, H~tamine Hr and H~ Aecept°r t~n, m r . vaso~htat~j nPhy~ol. . 233~f(3c)aninEe219i, nte~inM ~ Suzuki, H. and R. C a ~ e ~ 1979, Effect of h ~ m h e on the sma2 arteries in the Gracil~ muscle of the rabbR, J. PharmacY. Exp. Ther. 211,430.
515
S h o ~ communication HISTAMINE H1- AND H r R E C E P T O R S IN THE GASTRIC VASCULATURE OF THE RABBIT BRIAN P. CURWAIN and NICHOLAS C. TURNER Department of Physio~gy, St Ma~ ~ Hospi~l Medical Schoo~ Norfo~ Place P a d d ~ o ~
London W2 1PG, ~
Rec~ved 26 March 1981, accepted 27 March 1981
B.P. CURWAIN and N.C. TURNER, His~mine H~- and H 2 - r ~ e p ~ in the gastr~ vasculature of the mbbi~ European • Ph~mac~. 71 (1981) 515--519. The h ~ m ~ e ~ c e ~ o ~ ~ ~ e mbb~ ~ood p ~ d g~tfic v ~ c ~ u r e w~e an~y~d p h ~ m a c o l o ~ l ~ . H~m~e ~ed a monopha~c ~ e ~ e ~ p ~ o n ~essure wh~h w~ an~go~zed by mepyramine and enhanced by mefiam~e. The ma~mum obs~ved ~aponse was enhanced by m ~ m ~ e tot that produced by a speOfic Hl~eceptor agon~t. ~ ~ concluded that ~ e ~stfic v ~ c ~ u ~ ~sponds to ~ s ~ m ~ e w~h an Hireceptor m e d ~ d v a ~ e o n s ~ t ~ n and an H2~eceptor m e d ~ d dilatation. In th~ ~epamt~n the H ~ f f e ~ predomina~s ~ ~sponse ~ inj~t~n of ~s~mine. Ga~c va~u~ V~o~fion
Hi~am~e
R~e~ors
1. Introduction In the rabbit u n f k e other spe~es changes in blood pressure ~ i t e d by injection of histamine are t y p i c ~ l y biphasic and thought to reflect the b ~ a n c e between an H~-recepto~ mediated v a s o c o n s ~ t i o n and an H2~ecepto~ mediated vasodflatation (Parsons and Owen, 1973; Owen, 1977). A~hough Angus and Korner (1977) were u n a b ~ to show any ~gns of c o n s ~ f i o n in the r e n ~ and mesentefic beds of unanaesthet~ed r a b b i s during H~receptor s t i m u h t i o n , H~-medhted pressor and H:-mediated depressor responses have been reported in the Krebs-perfused ~olated rabb~ kidney (BSkesoy and Tfirker, 1974) and in perfused rabb~ ears (Parsons and Owen, 1973). We have recently d e m o n s ~ a t e d an H~-receptor-rnediated inhib~ory effect of histamine on gastric acid secretion which measuremen~ of aniline clearance suggest may operate fia vasocons~iction in the ~ o m a c h (Curw~n and Turner, 1981). We have, therefore, investigated the l o c ~ effects of histamine on the gas~ic vasculature, and
Rabbits
V~o~ o ~ f i o n
the receptors involved in the response, in a fituation where perfusion rate ~ kept constant and changes in perfu~on pre~ure reflect vasoc o n s ~ t i o n or vasodflatation.
2. Materi~s and methods E x p e f i m e n ~ were performed on m ~ e , pentobarbitone (30-40 mg/kg i.v.) a n a e ~ h ~ fised New Z e ~ a n d White r a b b i s 2.0-2.7 kg, w h ~ h had been starved overnight but ~ l o w e d ~ e e access to water. The m e t h o d has been developed from that described by Harvey et ~. (1980) in the cat. The abdomen was opened ~ a a ~ ~ansverse i n d ~ o n , p a r ~ l ~ to and a p p r o x i m a t ~ y 1 cm below the base of the fib cage. The d u o d e n ~ blood v e ~ d s derived ~ o m the mesentefic c~culation were fled just d~tal to the pylorus. The blood ve~ se~ ~upplying the spleen were fled as do~e as po~ible to the organ to preserve the artefi~ supply to the greater curvature; the hepatic artery was ~gated. The gastric vasculature was perfused fia a catheter in the co~iac artery,
516
B.~ C U R W A I ~
N.C. T U R N E R
HI STAMI NE
~
-
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F~. 1. The effee~ of three h ~ m ~ e receptor a g o n ~ on the perfu~on ~ e ~ e reeotded from t~e blood per~sed ~abb~ g ~ c v ~ u ] a t u r e . The v e ~ b ~ a~e ~e~u~e e ~ s t ~ ( ~ ~ ) w~h an uFw~d d e l e t i o n of the trace d e n o ~ an ~ e ~ e in ~ u r ~ ~he ho~zon~] ba~ ~ d ~ e time (2 rain). ~ u ~ do~s ~ e ~ o w n ~ m~¢.
VASCULAR
HI o A N D
H2-RECEPTORS IN T H E RABBIT
517
with blood taken ~ o m a carotid artery. The blood was p u m p e d at constant flow rate through a roller pump. Pressure in the perfu~ o n c~cu~ was measured by a Ball and H o w e ~ pressure ~ansducer finked to a De~ces pen recorde~ The p u m p was set to ~ve a
3~-
pressure approximately e q u ~ to a r t e ~ blood pressure at the completion of surgery. At this pressure flow rate was between 10 and 14 mUmin. It was then kept constant for the duration of the expe~ment. Heparin (1000 IU/kg i.v.) was ~ven and drugs in s~ine (5-50 pl) were injected into the perfusion c~cuit immediately before the pump. Resu~s are e x p r e ~ e d as the mean percentage change in perfusion pressure (±S.E.) compared to that prior to injection of the drug. The maximum observed response to 2-TEA and h~tamine
200-
Werp ea~e~Ompareo dbserva~onsU.sing a Student~ t ~ e ~ for un-
~00-
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I~ ~.
~
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3. Results The results are shown in figs. 1 and 2. H~tamine ~ . 3 4 × 10-%2.67 × 1 0 -7 mol/kg) caused a m o n o p h a s ~ increase in p e r f u ~ o n pressure lasting 1-3 rain. The response was d o s ~ d e p e n d e n t w ~ h a maximum observed increase of 144 ± 22.2% (n = 5). The spec~ic Hz~eceptor agonist 2-(2-aminoethyl)thiazo~ dihydrochloride (2-TEA) (2.24 × 1 0 - ~ 1 . 1 2 × 10 -~ mol/kg) a~o caused a d o s ~ d e p e n d e n t increase in perfu~on pressure. In 5 e x p e l ments the maximum increase o b t ~ n e d in response to injection of 2-TEA (240 ± 32%) was significantly greater than that observed to histamine (P < 0.05). Mepyramine (1.25 × 10 -s mo~kg) d~placed the histamine dos~response curve to the ~ght. Treatment w ~ h mefiamide (2 × 10 -~ mol/kg/min i.v.) d ~ p h c e d the cur~e to the left and p o t e n t a t e d the maximum increase in perfu~on pre~ure to an average of 222% (n = 4, range 185-274%) w~ich ~ ~m~ar to the maximum response o b t ~ n e d w ~ h 2-TEA. In 6 expe~ments the spe~fic H ~ e c e p t o r agoni~ impromidine (1.0 or 2 . 0 × 1 0 - S t o o l /
in perfu~on p r e ~ u ~ (% basal,
o ~ a ~ ) of the rabb~ gast~c v~culatu~ showing an~gon~m of the control responses to h ~ m i n e (~) by mepy~m~e 1.25 × 10 -s m~]kg (~) and enhanc~ ment by me~am~e 2 × 10 -6 mol]k~min (©~ (m) ~ the r~ponse to the H~gon~t 2 - ( 2 ~ m i n o e ~ ) t~az~e d~ydroc~o~de. V ~ c M b~s ~e S.E.M. (n = 4~). kg) caused a longAasfing (5-20 min) reduction in p e r f u ~ o n pressure of 19-35%. We have not ~ u d i e d t h ~ response in detail, howeve~ our resu~s confEm those of Aksulu et ~. (1979) who have reported that impromidineproduces a lon~la~ing f ~ l in perfusion pre~ure of the ~ o h t e d perfused rabbit kidney. Changes in systemic blood pressure following injec~on of h~tamine ~r 2-TEA into the perfu~on cEcu~ were minimM. In some an~ m a ~ histamine eli~ted small presso~ depre~ sot or bipha~c changes depending on the dose, whereas, impromidine ~ w a y s caused a lon~lasting depressor response which was characte~sed b y a r e d u c ~ o n in sy~olic and pulse pressure. Intr~arte~ infu~on of histamine ( 2 ~ 10.6 × 10 -s mol/kg per rain) over a 10 min p e ~ o d e~cited a monophasic increase in
518
perfu~on p ~ u r e w ~ c h w ~ d o ~ e d and sustained for the duration cf the h f u ~ o ~ after ~ r m ~ a t ~ n of the ~ f u ~ o n the pegu~cn p ~ u r e ~ t u r n e d to c o n ~ ~ e ~ .
4. D~cu~ion In the v~cular beds of most m a m m a s histam~e ~ a p o i n t vasodflato~ and ~ear e~dence h ~ been prodded ~ o m ~ u ~ ~ the g~tric v ~ c u l ~ u r e of the c ~ and r ~ (Harvey et ~., 1980; Guth and Smith, 1978) and the dog m e ~ n ~ r ~ c ~ c ~ a t ~ n (Pawfk et ~., 1977) that t ~ s response ~volves both H~and H:~ecepto~. In the rabbit, howeveL histamine has been reported to produce both vasocon~c~on and v~odfl~afion, the f o r m ~ respon~ b e r g media~d by H~-rece~ tots and the la~er by H:-~ceptom (Parsons and Owen, 1973; BSkesoy and Tfirker, 1974; S u z u ~ and C ~ s , 1979). Furthermore, ~ the coronary vasculature B r o a d l y (1975)has r e p o s e d t h ~ the o n ~ d~ect effect exerted by histamine ~ H~-receptor-medh~d vasoconst~n. In c o n ~ t Angus and K o r n ~ (1977) weze neith~ ab~ to d e m o n s ~ a ~ any clear H ~ ¢ e c e p t o p m e ~ a ~ d v ~ o c o n s t r i ~ o r ac~on of h ~ t a m ~ e ~ the m e ~ n ~ c and ren~ v ~ c ~ a r beds ncr were they aMe to show any changes ~ ~ a n c e during histam~e ~ f u ~ons ~ the h ~ d ~g and carotid beds of consciousrabMts, The present e x p e ~ m e n ~ show that dose arterial ~ j e c ~ o n of histam~e produced dos~ ~ h ~ d inc~ases in p ~ f u ~ o n pressure w h ~ h c o u ~ be antagonised w~h mepyram~e. If ~ the rabb~ H~¢ecepto~ subserve v~odflat~ fion then one might expect t h ~ ~ the presence of H,¢eceptor b ~ c k a d e M~amine would eHdt a fa~ ~ pe~usion pr~sure, Indeed Parsons and Owen (1973) ~ p o ~ e d that ~ the c ~ e of rabb~ sys~mic Mood pre~ure, antagon~m of histamine p ~ o r responses by mepyramine uncovers a depre~ sot response w h ~ h can be antagonised by burimamide. HoweveL u n ~ the v ~ c ~ a r tone of the preparation w ~ e ~ v a ~ the
~ P . CURWAIN, N.C. TURNER
~ m e w o r k , s were unab~ to d e m o n s ~ a ~ a fall ~ peffusion pr~sure ~ the rabb~ ear to histamine foHow~g H~¢eceptor ~ o c k a d ¢ suggest~g t h ~ th~ v~cular bed w ~ already ma~m~ ~ h t e d . In our expe~men~, howeveL the respon~ ~o i m p r o m ~ e demom s ~ a ~ d t h ~ the gastric vascuhture w ~ capa~e of d f l ~ n and ~ ~ fik~y that the m s ~ u ~ vasoconstri~or responses to h~tm m ~ e foHow~g ~eatment w~h mepyramine w e ~ s~ll suffi~ent to m ~ k the H:~eceptow medi~ed d i l a t i o n . In the p ~ f u ~ d r a b ~ t ear (Parsons and Owen, 1973) addition of m e p y r a m ~ e ~ o n e to the peffusion f l ~ d caused a marked redu~ fion ~ the maximum ~ s p o n ~ to histamine. This w o ~ d be expected if the H~-receptow me~a~d vasoconst~n w ~ o p p o ~ d by an H:-receptowmedia~d v~odilatation. In our expe~men~ even in the presence of mep y r a m ~ e large doses of h ~ t a m ~ e were ~equenfly ~ t h ~ and consequently a max~ mum response was unobtainable. Howeve~ the f i n d ~ of P~sons and Owen (1973}, coupled with our ob~rvation that, following H ~ e c e p t o r ~ o c k a d e by me~amide, v~oconstri~n to histamine was enhance~ ~ d i c a ~ that the observed response to h~tw m ~ e mfle~s the b~ance between a pr~ d o m ~ a n t v ~ o c o n s t r i ~ o r ac~on m e ~ e d by H ~ e c e p t o ~ and v ~ o d f l ~ a t ~ n m e ~ a ~ d by H:~ecepto~. Th~ dilatation, though m ~ k e d by the c o n s ~ t o r response, does p a r t ~ c o u n ~ r a ~ the c o n s ~ f i o n . I~ecfion of the spedfic H ~ e c e p t o r agonist 2-TEA ~ t o the perfu~on c~cu~ caused a m o n o p h ~ increase in perfu~on p ~ u ~ with a ggnificantly g e a ~ r ob~rved maximum than that to Mstam~e ~one. The ~ s p o n ~ to 2-TEA was ~mflar to that to Mstam~e in the p r e sence of methmide confirming that the H~pr~sor response ~ norm~ly opposed by an H:-receptor-media~d dilatation. D~e~ e~dence for an H:-receptor-mediated vasodilator mechan~m ~ shown by the monoph~ic reduc~on ~ pe~usion pre~ure e ~ d ~ d by impromid~e, wMch h ~ been zepo~ed to be a spe~fic H:~eceptor agon~t ~ the c~dio-
VASCULAR H1- AND H2-RECEPTORS IN THE RABBIT vascular system (Owen et al., 1979). In the cat gastric vasculature Harvey et al. (1980) have shown that the vasodilator
response to an infu~on of histamine has two components. The in~ial peak dilatation ~ mediated by H,~eceptors and ~ followed by a
maintained H2-recepto~mediated dilatation. This contrasts with the maintained vasoconst~cfion we have observed in the rabbit following histamine infu~on. In conclu~on the rabbR gast~c vasculature responds to histamine w~h an H ~ e c e p t o ~ mediated vasoconstriction and an H:~ecepto,mediated vasodilatation. The H ~ e c e p t o ~
mediated vasoconstriction predominates both after close arterial injection and close arte~al infu~on of histamine and ~ ~ t h ~ vasoconstfic~on which seems to constrain the acid secretory and mucosal blood flow responses in rabbits stimulated by i.v. infu~on of hista-
mine. Acknowledgement We world Hke to thank the Joint Standing Research CommRtee of St Mary~ Hospit~ M e d ~ School for thor support. References Aksulu, H.E., Z.S. Ercan and R.K. Tfirker, 1979, A comparat~e ~udy w~h impromidine (SKF
519 92676), a potent a g o ~ for hi,amine HTrecepto~, Agen~ Act~ns 9 (516~ 461. Angu~ J.A. and P.I. Korner, 1977, Re,ohM vasc~ar re~stance~Hl.and ~. ^ rate : h -responses ~e_ a r med~ted t unanae~h~e~ d h r o u g h an~abbR.. ,2-histamiE ~=uropea~eCeptoj. ~Pharmacol, . n the 45, 45. Bbkesoy, T.A. and R.K. Tfirker, 1974, The presence of H2~ecepto~ in rabbR kMney, Arch. Intern. Pharmacodyn. 209,114. Br°a~eYt ' o r s~ the v "S''acoronary s1975, c ~ The K rOleresponseO ar f H~- and to ~am~H e~ecepof ~ a t e d perfused hea~s of gu~em~gs and rabbRs, Br. J. Pharmacol. 54, 511. Curw~n, B~. and N.C. Turne~ 1981, The inv~v~ acmid ent secr~° f hN~mina n end mucosar ecept°r1 blooS dubtype;o~n i~a~rtiChe a n a ~ h ~ e d rabbR, J. P h y ~ . 311,431. Guth, P.H. and E. SmRh, 1978, H~tam~e receptors in the g a ~ c m~rockc~at~n, Gut 19, 1059. Harvey, C.A., D.A.A. Owen and K.D. Shaw, 1980, i~denct e h ega~rf°ric b°tv hasc~aturh eiStam~oef thHe ~"cata, nd BrH .~ecept°j. rSphar" mac~. 69, 21. Owen, D.A.A., 1977, H~tamine receptors in the card~vasc~ar sy~ern, Gen. PharmacY. 8, 141. Parsons, M.E. and D.A.A. Owen, 1973, Recepto~ mine~ ,v~Ve~n:inproct .he IntC .ard~va~s a r y mon p , H~tam~e Hesp°nses ~ r e c e r to ~st~ ptor A g o n ~ , London 1973, ed. C~. Wood and M.A. ~mkins (SK & F Labs Ltd., W~wyn Garden CRy) p. 127. PawlS, W., L.L. Tague, B.L. Tepp~man, T.A. M~ler and E.D. Jacobson, 1977, H~tamine Hr and H~ Aecept°r t~n, m r . vaso~htat~j nPhy~ol. . 233~f(3c)aninEe219i, nte~inM ~ Suzuki, H. and R. C a ~ e ~ 1979, Effect of h ~ m h e on the sma2 arteries in the Gracil~ muscle of the rabbR, J. PharmacY. Exp. Ther. 211,430.