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Current Review
Pharmacology 23: 1-13 (1981)
Evidence for and against Heterogeneity in the Histamine
Hî-Receptor Population
Giulio Berlaccini. Gabriella Coruzzi
Institute of Pharmacology, University of Parma. Parma, Italy
Key Words. Histamine • H2-receptors • H2-receptor subtypes ■H2-agonists and
antagonists
Abstract. Evidence for and against heterogeneity in the histamine H2-receptor population is
reported: it was based on different degrees of potency and also of efficacy among the H2receptor-selective agonists; less striking but still evident differences in the potency of H2antagonists; atypical interactions between H2-agonists and antagonists in particular experi­
mental conditions and finally inability of Hr and H2-reccptor antagonists to block some of the
effects of histamine. Binding studies gave equivocal results. All the data reported in this
review suggest that, although it is premature to speak about H2-rcceptor subtypes, further
investigations are needed to check whether or not H2- and perhaps also H,-receptors represent
homogeneous populations of histamine receptors.
Black et al. [19] opened a new era in the
history of histamine with the discovery of the
H2-receplors whose possible occurrence had
been hypothesized by Ash and Schild [5].
Black ci al. [19] defined as H2-receptors those
which were not blocked by the common anti­
histamines such as mepyramine and related
drugs. The use of a selective H2-receptor ago­
nist (4-methylhistamine1) and an antagonist
(burimamide) allowed these investigators to
establish the localization of the H2-receptors
which were found to be present in gastric
1 This compound can alternatively be called 5methylhistaminc: both possibilities are correct: the
difference is connected to the numbering of the side
chain of histamine which can be considered either as a
2-(4-imidazoiyl)ethylamine or as a 2-(5-imidazolyl)ethylamine.
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Introduction
Bertaccini/Coruzzi
mucosa of different animals, in guinea pig
atria and in rat uterus. Subsequent studies,
however, showed that H2-receptors were
much more widely distributed than pre­
viously suspected as they were identified in
the central nervous system, respiratory sys­
tem. skin, gastrointestinal muscle, vascular
muscle, adipose tissue and some lymphocyte
subpopulations [for references, see 79].
Moreover, the synthesis of a number of new
potent and selective stimulants (5-methyl-Nmethylhistamine, dimaprit and impromidine) and inhibitors (metiamide, cimetidine,
ranitidine, tiotidine and oxmetidine) of the
H2-receptors [11, 33, 79] provided important
information about these receptors and re­
vealed some interesting phenomena which in
some cases could be related to nonspecific
actions of these compounds but in other cases
were difficult to explain.
Black ct al. [ 19] and Black [ 18] stated that
homogeneity for histamine H2-receptors for
heart muscle, uterus and gastric mucosa was
defined by a calculated common dissociation
constant for the burimamide/histamine re­
ceptor interaction. The new data obtained
with recent agonists and antagonists of the
H2-receptors were sometimes contradictor)'
and raised doubts on the homogeneity of this
receptor population.
The most important findings concerning
the affinity and efficacy of different stimu­
lants and inhibitors of Hj-receptors together
with some interesting binding studies are re­
ported in this review.
H2-Receptor-Selective Agonists
Tables 1 and II compare the relative po­
tencies of H2-receptor agonists on different in
vitro and in vivo preparations with hista­
mine. The degree of potency of these drugs
varied considerably in the different prepara­
tions but this could be related to the charac­
teristics of the specific molecules and the con­
sequent affinity for the H2-receptors. Impromidine was the most potent compound
being from 5 to 100 times as potent as hista­
mine. As for other compounds the ratio of
activity between dimaprit and histamine was
extremely variable being less than 1% on the
rabbit heart, 70-90% on the guinea pig
atrium but actually 400-500% on cat gastric
secretion. As for 5(4)-methylhistamine, dif­
ferences were not so striking but again this
compound had 25-30% of the activity of his­
tamine on the rat uterus but 100% on iso­
lated guinea pig fundus and 180% on cat gas­
tric secretion. Most discrepancies occurred in
vivo and it is recognized that the whole ani­
mal is not a good tool for the study of recep­
tors. The interference of different factors (ki­
netics of the compounds, metabolism, blood
transport and systemic effects of the drugs) is
likely to influence the net effect on H2-receptors. Therefore, the evaluation of the relative
potencies in vivo seems not to be a depend­
able criterion to assess the heterogeneity of
H2-receptors.
More important findings are probably re­
presented by the differences in the 'efficacy'
(that is maximum effect) of the H2-agonists
(table III) which are evident not only in vivo
but also in vitro. Considering only isolated
preparations 5-mcthyl-N-methylhistamine
and dimaprit always had the same efficacy as
histamine with the exception of adenylate
cyclase of the guinea pig ventricle in which
the efficacy of dimaprit was 55-60% that of
histamine. Impromidine behaved quite dif­
ferently as it acted in several preparations as
a partial agonist of the H2-receptors with an
efficacy varying from 50 to 81 % in compari-
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2
3
Heterogeneity of Hr Receptors
Table I. Relative activity of some H ragonists in different isolated preparations, in comparison with histamine taken as 100
Dimaprit
Impromidine
43 [19]
30 [9b]
90 [29]
70 [66]
4,810 [34]
30 [10]
10(10]
3,500 [8]
Preparation
Histamine
5-Methylhistamine
Guinea pig atrium
100
Guinea pig papillary muscle
100
Guinea pig isolated working
heart (inotropic effect)
100
1,620 [64]
Guinea pig isolated working
heart (chronotropic effect)
100
2,650 [64]
Rabbit heart rate
100
Guinea pig isolated fundus
(secretion)
100
100 [52]
25 [52]
Rat uterus
100
25 [19]
30 [14]
100[ 14]
17.5 [66]
Rat gastric secretion
100
Cat tracheal muscle (relaxation)
100
< 1 [28]
516'
930 [34]
10.000 167]
67.3 [1]
1.947 [1]
References are in brackets.
1 C'oruizi. unpublished.
Table II. Relative activity of some Hj-reccptor agonists in different in vivo tests, in comparison with hista­
mine taken as 100
Histamine
Rat
100
Cat
100
180 [51]
Dog
100
100 [13]
References are in brackets.
1 Bertaccini, unpublished.
2 Anesthetized animals.
5-Methylhistamine
38.9 [19]
40 [13]
Dimaprit
19.5 [66]
180'
400-500-' [66]
58 [66]
Impromidine
1.680 [34]
2.700 [34]
2.200 [34]
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Gastric secretion
4
Bertaccini/Coruzzi
Table III. Efficacy of different H;-rcceptor agonists on different in vivo and in vitro preparations
Preparation
Histamine
5-Methylhistamine
Dimaprit
5-MethylN-methylhistamine
Rat uterus
I
1 [14]
1 [14]
1 [14]
Rat gastric secretion
(in vitro)
1
Guinea pig atrium
(chronotropic effect)
1
1 [9b]
1 [29]
1 [34]
Guinea pig papillary muscle
1
1 [10]
1 HO]
0.81' [8]
Guinea pig isolated working
heart (chronotropic effect)
1
1 [64]
Guinea pig isolated working
heart (inotropic effect)
1
1 [64]
Guinea pig fundus secretion
1
Guinea pig gastric adenylate
cyclase
1
Guinea pig ventricle
adenylate cyclase
1
0.55-0.60' [53]
Cat tracheal muscle
(relaxation)
1
1m
Rat tracheal muscle
(relaxation)
1
0.2' [35]
Cat gastric secretion
I
1 [51]
1.21' [66]
1.42' [49]
1.14 [34]
Dog gastric secretion
1
1 [121
1 [47]
1.18' [66]
1.19 [46]
1 [46]
1.18 [34]
Impromidine
0.80' [34]
0.50' [67]
1 [52]
1 [52]
0.50' [57]
1 HI
son with that of histamine. Though quantita­
tive data were not reported, the maximum
response to impromidine was found to be
much lower than that of histamine also on
the rabbit atria (inotropic effect) [69]. Of
course these data could represent a peculiar­
ity of the impromidine molecule: Lewin et al.
[57] suggested that the H2-receptor is a dimer
and the two heterocyclic groups of improm­
idine bind with the two receptor subunits
thereby activating both agonistic and antago­
nistic moieties and thus producing only a
moderate activation of the receptor itself.
However, there are other data which do not
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References are in brackets.
1 Statistically significant difference versus histamine.
fit in this model: in the isolated working heart
of the guinea pig, impromidine had the same
efficacy as histamine considering both sinus
rate and contractility [64]. The same was ob­
served with the chronotropic effect of guinea
pig atrium [34], Furthermore, impromidine
and histamine had the same efficacy in the
relaxant effect on cat tracheal muscle con­
tracted by acetylcholine or 5-hydroxytryptamine [1].
All of these observations are apparently in
favor of a heterogeneity rather than a homo­
geneity in the population of H2-receptors.
However, according to Ariens et al. [4], differ­
ences in activity for particular agonists in dif­
ferent tissues do not necessarily mean that
the receptors arc different and the antagonists
are much more suitable for detecting a possi­
ble differentiation in receptor subtypes than
are the agonists. Evidence against the hetero­
geneity in the population of Hj-receptors may
be represented also by the fact that changes in
the relative potencies of the H2-agonists were
not uniform in the different tissues. This pre­
cludes so far any exact subclassification and
may reflect artifacts of the experimental con­
ditions or peculiarities of the molecules
rather than of the receptors involved in the
respective interactions.
H2-Receptor Antagonists
The relative potency of the most impor­
tant H2-blockers against the effects of hista­
mine on different preparations is reported in
table IV. In comparison with data on the ago­
nists, those on the antagonists are much more
homogeneous and apparently are not in favor
of the hypothesis of subtypes of the H2-receptors. However, analysis of table IV shows
that some values are remarkably at variance
5
from those which could be expected consid­
ering an absolute identity of receptors. This is
the case for metiamide as an inhibitor of his­
tamine on guinea pig and mouse gastric se­
cretion (pA2 values were 4.82 and 5.08, re­
spectively) [3, 75] and of cimetidine on
mouse gastric secretion (pA2 5.14) with pA2
values noticeably different from those ob­
served in other tissues. Also, in the case of the
rabbit atria, the pA2 values of metiamide and
cimetidine were found to be significantly
lower considering the inotropic versus the
chronotropic effect. Conversely, in the same
experimental conditions the pA2 values for
tiotidine were virtually identical [69]. More­
over, Fjalland [37] reported a striking disso­
ciation between the action of cimetidine and
that of burimamide as inhibitors of the clonidine (considered as an H2-agonist)-induced
suppression of electrically stimulated guinea
pig ileum and histamine-induced chronotropy in guinea pig atria. In the first case buri­
mamide was about 25 times as potent as
cimetidine whereas in the second cimetidine
was about 50 times as potent as burimamide:
apparently these differences may be ex­
plained by the existence of different hista­
mine receptors in the atria and in the ileum.
From studies with cimetidine and ranitidine
on gastric mucosa adenylate cyclase. Sewing
[pers. commun.] concluded that the absolute
potency of either drug as well as their relative
potencies depend very much on the assay sys­
tem employed. Moreover, a parameter which
is often neglected and could represent a no­
ticeable source of errors is that of the equili­
bration time on the antagonism of histamine
response by the various H2-blockers. It was
recently pointed out [55] that insufficient
equilibration times resulted in nonlinear
Schild regressions with slopes greater than
unity. In this condition a mean slope of unity
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Heterogeneity of H>-Receptors
Bertaccini/Coruzzi
6
Table IV. pA, values of different H2-receptor antagonists against histamine on various isolated preparations
Cimetidine
Ranitidine
Oxmetidine
Tiotidine
6.04 [19]
6.11 [9b]
6.304
6.10 [3]
6.55 [21]
7.20 [21]
-■ [20]
7.113
7.802 [79]
Rabbit atrium
(chronotropic effect)
5.89 [69]
7.27 [69]
8.31 [69]
Rabbit atrium
(inotropic effect)
5.24 [69]
6.68 [69]
8.43 [69]
6.18 [9b]
6.40 [8]
4.82 [75]
5.82 [75]
Preparation
Burimamidc Metiamide
Guinea pig atrium
(chronotropic effect)
5.11 [19]
5.17 [71]
Guinea pig papillary
muscle
5.39 [71]
Guinea pig isolated
stomach (secretion)
Guinea pig ventricle
adenylate cyclase
5.0 [53]
6.0 [53]
6.2 [53]
Rat uterus
5.17 [19]
6.11 [14]
6.394
6.05 [14]
6.184
Mouse gastric secretion
4.59 [3]
5.08 [3]
5.14 [3]
5.05 [17b]
4.97 [17b]
5.00 [591
Mouse vas deferens
7.09 [27]
8.24 [27]
7.19 [21]
6.94 [32]
References are in brackets.
Exact pAj values could not be established.
Calculated against dimaprit.
Coruzzi. unpublished.
Bradshaw, unpublished.
can be found for an antagonist which nor­
mally would have yielded a slope of less than
unity.
In our personal experience [27] we had
some interesting findings with ranitidine.
This drug was found to be approximately 8
times as potent as cimetidine in the guineapig-isolated gastric fundus and in a number
of other in vivo experiments (Heidenhain
pouch dogs, anesthetized or conscious cats
with gastric fistula, anesthesizcd rats, etc.)
but only 1.2 times as active as cimetidine on
the isolated papillary muscle of the guinea pig
(pA2 6.60). Moreover, in recent studies on
alkyl analogs of histamine and metiamide we
observed that the compound etiamide.
N-methyl-N'[2-(5-ethy!imidazol-4yl)methylthiojethylthiourea. a rather selective Hr
blocker, behaved as a competitive antagonist
of histamine on the guinea pig atrium and
papillary muscle (pA3 values of 5.78 and
5.55. respectively) but showed a typical non­
competitive antagonism on cat gastric secre­
tion [9b. 50],
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1
2
3
4
6.60 [8]
7
Heterogeneity of H:-Receptors
Table Va. Effects of histamine or of selective H2-agonists which are not inhibited by selective H.-antago­
nists
Tissue
Agonist
Effect
Noncflcclivc
antagonist
Ref.
Guinea pig duodenum
impromidine
dimaprit
tolazoline
clonidine
relaxation of the contraction
induced by histamine and
acetylcholine
metiamide
cimetidine
ranitidine
oxmetidine
16
Guinea pig ileum
dimaprit
relaxation of the contraction
induced by histamine
cimetidine
15
Cat bronchi and
trachea
histamine
4-methyl histamine
relaxation
burimamide
metiamide
24
Rat trachea
histamine
dimaprit
relaxation
cimetidine
35
Ferret trachea
and bronchi
histamine
4-methyl histamine
relaxation
burimamide
metiamide
cimetidine
25
Rat hypothalamus
histamine
4-methyl histamine
reduction in noradrenaline
content
metiamide
cimetidine
63
Table Vb. Effects of histamine which are inhibited by H2-antagonists but not mimicked by Hr■receptorselective agonists
Tissue
Effect
Antagonist
Nonefifectivc
agonist
Guinea pig ileum
inhibition of tetanic spasm
by field stimulation
burimamide
4-methylhistamine
2
Cat skeletal muscle
extravasation of albumin
and edema
metiamide
dimaprit
39
Aplysia ganglion
slow K+-dependenl
depolarization
cimetidine
dimaprit
42
clonidine
N.N-dimethyl-histamine
Bullfrog gastric mucosa
acid secretory response
cimetidine
dimaprit
45
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Ref.
Bertaccini/Coruzzi
8
Atypical Interactions between H2Agonists and Antagonists on the
Receptors
Tables Va and b show some atypical inter­
actions between H2-agonists and ^-antago­
nists in particular experimental conditions
which again seem to favor the existence of
subtypes of the classical histamine receptors.
Table Va shows effects of histamine and of a
number of the most selective H2-agonists
available so far which were not blocked by
the common H2-blockers administered in
doses capable of provoking complete H2reccptor blockade in other test systems.
All the effects described in table Va were
observed in vitro, thus the interference of
systemic changes could be excluded. How­
ever, the interference of nonspecific effects of
the H2-stimulants could not be completely
excluded since sometimes the doses of ago­
nists exceeded those usually employed to
stimulate H2-receptors.
Table Vb illustrates the opposite situation,
that is, effects of histamine which were pre­
sumably elicited through excitation of H2receptors since they were completely blocked
by the H2-antagonists but were not mimicked
by H2-agonists. In the bullfrog gastric mucosa
[45] the effect of histamine was competitively
inhibited by cimetidine (pA2 6.8) and mim­
icked by 2-pyridylethylamine, an Hr agonist.
better than by dimaprit which was actually
found to act in this preparation as an antago­
nist of histamine.
Many of these findings may be criticized
because sometimes only one agonist and one
antagonist were used.
Inability of Ht- and H2-Receptor
Antagonists to Block the Effect of
Histamine
Examples similar but not identical to
those described in the preceding section are
shown in table VI which lists a series of hista­
mine effects not modified by Hr and H2-
Effect
Ref.
Hypothermia in mice
Excitation of hypothalamic cells (rat and cat)
Behavioral changes in the rat (depression)
Excitation o f Achatina fúlica neurons
Fast chloride-dependent hyperpolarizing response (Aplysia ganglion)
Negative inotropic and chronotropic effect (isolated rat heart)
Inotropic response (guinea pig atria)
Relaxation of rabbit trachea
Relaxation of cat bronchi
Contraction of the rat pylorus
Chemoattractant activity of histamine on eosinophils
Inhibitory effect on platelet aggregation
Metabolic changes in chicks (glycogen levels and phosphorylase a activity)
30
43
23
76
42
31
77
38
24
9a
26
60
62
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Table VI. Effects of histamine completely or partially unaffected by administration of Hr and Hj-receptor
blockers
Heterogeneity of H ,-Receptors
9
mine did not parallel their biological activi­
ties (impromidine for instance was 10-20
times less potent than histamine on the bind­
ing sites although this drug is known to be
10-100 times more active on H2-receptors).
In addition, H,- and H2-antihistamines had a
very low inhibitory potency and also their
relative activity at the binding sites was quite
different from that at the classical ^-recep­
tor levels.
Sewing [pers. commun.] who has done
binding studies with histamine in isolated
and enriched gastric mucosal parietal cell
populations observed that inappropriate
treatment of the cell membranes may change
to a certain extent the receptor sensitivity and
specificity. Moreover, recent binding studies
Binding Studies
carried out in guinea pig cerebral cortex and
gastric mucosa membrane preparations [72],
Binding studies concern mainly the cen­ emphasized the need for careful evaluation of
tral nervous system and they have been per­ the data obtained with this technique. In fact
formed with both agonists and antagonists of the displacement experiments indicated that
H2-receptors. Whereas ’H-mcpyramine was only cimetidine and metiamide were able to
used successfully to label H,-receptors [74] displace 3H-cimetidine binding with high af­
the situation in the case of Hj-receptors ap­ finity. Dimaprit did not displace 'H-cimetidpeared more difficult: a saturable binding of ine and the affinities of 2- and 4-methylhis3H-cimetidine to brain homogenates [22] tamine did not correspond at all to their
gave unsatisfactory results inasmuch as the reported H,- and H2-specificities. The au­
Kd of cimetidine was about 100 times lower thors concluded that the affinity binding site
than its Ki regarding histamine antagonism is probably related to an imidazole recogni­
in a well-defined H2-receptor system and in tion site rather than the histamine Hr recepaddition the inhibitory potency of different tor.
histaminergic agents did not reflect their
Even taking into account the still poor
pharmacological potency. Apparently more reliability of binding studies for the definition
reliable results were obtained using 3H-hista- of the Hj-receptor, other data concerning the
mine as a ligand [6, 65]: however, many central nervous system arc deemed of inter­
doubts arise with this system also and the est: histamine- or dimaprit-stimulatcd ade­
authors claimed that the pharmacological nylate cyclase activity in homogenates of
specificity o f ’H-histamine binding sites does guinea pig hippocampus was inhibited to a
not correspond to that of histamine receptors greater extent by amitriptyline (pA2 7.23), an
of either the H, or the H2 type: the potency of antidepressant, than by cimetidine (pA2
histamine agonists in displacing 3H-hista- 6.22), a typical H2-antagonist [41]. Later on.
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antagonists administered separately or as a
mixture. In many instances not only antihis­
tamine compounds but also other inhibitors
like atropine, a-and p-adrenoceptor antago­
nists. tetrodotoxin. etc. were employed [9a].
Of course in this case not only a subtype but
actually a third type of histamine receptors
may be hypothesized. It is obvious that only
the availability of a specific, competitive an­
tagonist of such effects could allow us to
define whether or not such a situation exists
or simple artifacts due to particular experi­
mental conditions must be considered as re­
sponsible.
Bertaccini/Coruzzi
10
in the same experimental conditions [40],
LSD, a hallucinogen and a 5-hydroxytryptamine antagonist, was found to have the same
effect as metiamide or cimetidine whereas
the bromoderivative (2-bromo-LSD. BOL)
was actually 10 times more potent.
Whether or not all of these data can be
taken as evidence for a heterogeneity of the
Hj-receptor in the brain, remains to be estab­
lished.
Acknowledgements
Original work of the authors was supported by a
grant from the Consiglio Nazionale dclle Ricerche.
Roma. The authors are indebted to and wish to thank
Prof. Alan Bennett (London). Dr. Morton Grossman
(Los Angeles) and Prof. Karl Sewing (Hannover) for
reading the manuscript and giving useful suggestions.
Thanks are also due to the SKF Laboratories (Welwyn
Garden. England) for the generous supply of all kinds
of agonists and antagonists of the H,-reccptors which
enabled the authors to perform original work de­
scribed in this review.
Conclusions
References
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parative study with impromidine (SKF 92676) a
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On the whole, evidence for a definite het­
erogeneity in the H2-receptor population is
far from conclusive and it is probably prema­
ture to speak about subtypes of the classical
histamine receptors even if they were already
hypothesized [36]. However, several data of
the recent literature suggest that this possibil­
ity should be more carefully investigated and
new kinds of experimental models should be
studied in order to check whether or not H:and (why not) also Hr receptors represent ho­
mogeneous populations of receptors. It seems
worth mentioning here that subsets of'classi­
cal' receptors have been described and are
now commonly accepted: (3,-and (^-adrener­
gic receptors [56, 61]; a r and a2-adrencrgic
receptors [17a. 48] and D,- and D>-dopamine
receptors [54, 73]. Other subclassifications
were, so far, only hypothesized like those of
the muscarinic receptors [7, 44] and the
opioid receptors [58. 68. 70]. Controversies
exist about these distinctions, but it must be
emphasized that they were based on the same
criteria (different ratio of activity of various
agonists and antagonists, binding studies,
etc.) described in this review for the hista­
mine receptors.
9a Bertaccini. G.; Coruzzi. G.; Molina. E.; Chiavarini.
M.: Action of histamine and related compounds
on the pyloric sphincter of the rat. Rend. Gastroent. 9: 163-168 (1977).
9b Bertaccini, G.; Coruzzi. G.; Scarpignato, C.: Effects
of alkyl analogues of histamine and metiamidc on
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