European Journal of Pharmacology, 34 (1975) 237--240
237
© North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands
Short communication SELECTIVE IMPAIRMENT OF ATRIOVENTRICULAR CONDUCTION BY 2-(2-PYRIDYL)-ETHYLAMINE AND 2-(2-THIAZOLYL)-ETHYLAMINE, TWO HISTAMINE H, -RECEPTOR AGONISTS* ROBERTO LEVI, C. ROBIN GANELLIN**, GEOFFREY ALLAN and HOWARD J. WILLENS
Department of Pharmacology, Cornell University Medical College, New York, N.Y. 10021, U.S.A., and **The Research Institute, Smith Kline and French Laboratories Ltd., Welwyn Garden City, Hertfordshire, England Received 28 July 1975, accepted 9 September 1975
R. LEVI, C.R. GANELLIN, G. ALLEN and H.J. WILLENS, Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H 1-receptor agonists, European J. Pharmacol. 34 (1975) 237--240. To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H l-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine. Cardiac histamine receptors Atrioventricular conduction
2-(2-Pyridyl)-ethylamine
1. Introduction Histamine receptors have been characterized pharmacologically into two types, H, and H2, by the use of selective competitive antagonists (Ash and Schild, 1966; Black et al., 1972). Receptor differentiation may also be indicated with compounds which act as selective agonists (Black et al., 1972). A distinctive cardiac effect of histamine is its ability to impair atrioventricular conduction (negative dromotropic effect; Levi, 1972). This effect appears to be mediated by histamine H~ -receptors since it is sensitive to antagonism
* Supported by USPHS Grant 1 RO1 GM 20091, by a grant-in-aid of the New York Heart Association and by the John Polachek Foundation for medical research.
2-( 2-Thiaz olyl)-e thylamine
by classical antihistamine drugs (Levi and Kuye, 1974), and since it is reproduced by 2-methylhistamine (Levi et al., 19751, a selective Hj-receptor agonist (Black et al., 1972). However, 2-methylhistamine possesses sufficient H2-agonist activity and displays a noticeable positive chronotropic effect which indirectly contributes to the impairment of atrioventricular conduction {Levi et hi., 1975). The net result is that receptor differentiation is incomplete. Further study would be assisted by using agonists of greater selectivity. 2-(2-Pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, which have previously been shown to possess histamine-like activity (Hunt and Fosbinder, 1942; Lee and Jones, 1949), have recently been identified as being H,-receptor agonists which are more selective than 2-methylhistamine (Durant et al., 1975). Using these compounds we have attempted to further
238
R. LEVI ET AL.
characterize the receptor mediating the negative dromotropic effect of histamine.
~J F-
n
I00(
=E
2. Materials and methods Male Hartley guinea pigs (250--300 g) were used. Their hearts were isolated and perfused in a Langendorff apparatus as previously described {Levi et al., 1975). All drugs were injected intra-aortically in increasing doses after a stabilization period of 30--45 min. Histamine dihydrochloride was purchased from Sigma Chemical Co. (St. Louis, Missouri, U.S.A.). 2-Methylhistamine dihydrochloride, 4-methylhistamine dihydrochloride, 2-(2-pyridyl)ethylamine dihydrochloride and 2-(2-thiazolyl)-ethylamine dihydrochloride (fig. 1) were synthesized at Smith Kline and French Laboratories (Welwyn Garden City, Hertfordshire, England). All doses refer to the free base.
oz
80 I
~
60
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.~, "~.
4-MeH ,2-MeH
I--(~
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2o
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o
120
B
100 .L
.c_ 80
.. " Y
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o
~
6o
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20
3. Results 00.1
2-(2-Pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, as a function of dose, increased the sinus rate and the force of ventricular contraction of the isolated guinea pig heart. The dose--response curves for the positive inotropic and chronotropic effects of 2-(2pyridyl)- and 2-(2-thiazolyl)-ethylamine were parallel and fell to the right of those of histamine, 4-methylhistamine and 2-methylhistamine in the order shown (fig. 2A and B). 2-(2-Pyridyl)- and 2-(2-thiazolyl)-ethylamine markedly impaired atrioventricular conduction, as expressed by the prolongation of the P--R interval in the surface electrogram (fig. 3). A drug may prolong the P--R interval directly by acting on the atrioventricular node, in-
~
H2CH2NH2
2 -(2-Pyridyl ) ethylamine
/S___~CH2CH2NH2
2-(2-Tlniozolyl ) ethy[omine
Fig. 1. Structural formulas of 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine.
I
IO
I00
I000
MICROGRAMS Fig. 2. Effects of histamine (H), 4-methylhistamine (4-MeH), 2-methylhistamine (2-MeH), 2-(2-pyridyl)ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA) on ventricular contraction (A) and sinus rate (B) of isolated guinea pig hearts. Points (means, -+ S.E., n = 6--10) are maximum increases from the values immediately preceding each drug injection.
directly by way of its positive chronotropic effect, or by a combination of both mechanisms (Levi, 1972). Since 2-(2-pyridyl)- and 2-(2-thiazolyl)-ethylamine concomitantly displayed negative dromotropic and positive chronotropic effects, the prolongation of the P--R interval was plotted against the increase in sinus rate, so as to exclude the indirect component of the negative dromotropic effect (fig. 4). For any given rate, the P--R interval was larger with 2-(2-thiazolyl)- and 2-(2-pyridyl)-ethylamine than with 2-methylhistamine and histamine. With 4-methylhistamine the prolongation of the P--R ~nterval was very modest.
HISTAMINE H1-AGONISTS ON A--V CONDUCTION
239
II0
100
o0 =
li
../.
I"
~-7"hEA
I:
p
90
/"
t
l,'"
zc
-
80
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/ 70
d
/"
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/"
2(2-Thiozolyl)ethylomine
o
/
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...." '~'-.2-MeH = "--
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Fig. 3. Effects of PEA and ThEA on the atrioventricular conduction of the isolated guinea pig heart• Points (means, ± S.E., n = 6:--7) are maximum increases in P--R interval duration from the values immediately preceding each drug injection.
, 3°1
4. Discussion In our previous investigations we had pharmacologically defined cardiac histamine receptors into H1 -type, mediating the negative dromotropic effect, and H2-type, mediating the positive inotropic and chronotropic effects of histamine (Levi and Kuye, 1974; Levi et al., 1975). We considered our classification of car-
i
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./ /
/
/~
/
:: .'/o
./
.': • 7"
...~~
...' / ....4/
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Histamine
/~I~
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oo
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With both 2-(2-pyridyl)- and 2-(2-thiazolyl)-ethylamine conduction arrhythmias occurred as a function of dose (10--1000 pg) with increasing incidence and severity. However, with 2-(2-thiazolyl)-ethylamine arrhythmias occurred more often and lasted longer than with equal doses of 2-(2-pyridyl}-ethylamine. Arrhythmias of automaticity developed at the higher doses with these compounds but only after the onset of conduction arrhythmias.
./
/
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i/
,,
/ 2 (2-Pytidyl) I sthylomine ~
ao
i el
2- Methylhistomine ~
~ . I 20
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SINUS RATE (increase in beats/mln) Fig. 4. Comparison of the negative dromotropic effects of PEA and ThEA. Maximum increases in P--R interval (ordinate) are plotted against corresponding maximum increases in sinus rate (abscissa). Same data as in figs. 1 and 2.
diac H~ -receptors to be only provisional, pending the availability of a more selective H1 -agonist. Indeed the results obtained with 2-(2-pyridyl)-ethylamine and 2- (2-thiazolyl)-ethylamine have further substantiated our hypothesis that the negative dromotropic effect of histamine in the guinea pig heart is mediated b y H1 -receptors. 2-(2-Pyridyl)- and 2-(2-thiazolyl)-ethylamine produced a weak dose-related positive inotropic and chronotropic effect (fig. 2); however, they produced a marked negative dramatropic effect (fig. 3). The efficacy of these compounds in impairing atrioventricular con-
240
duction was exemplified when their negative dromotropic effect was measured at equal rate increments, so as to exclude the indirect chronotropic c o m p o n e n t from their negative dromotropic effect (fig. 4). Two orders of relative potencies clearly emerged from these studies. For the positive chronotropic and inotropic effects the order of potency was histamine > 4-methylhistamine > 2-methylhistamine > 2-(2-thiazolyl)-ethylamine and 2-(2-pyridyl)-ethylamine; this is also the order for the relative H2 -receptor activities of these c o m p o u n d s when assayed as stimulants of gastric acid secretion in the anesthetized rat (viz: 1, 0.4, 0.02, 0.003 and 0.002 respectively; Durant et al., 1975). For the negative dromotropic effect relative to sinus rate, the order was 2-(2-thiazolyl)-ethylamine > 2-(2-pyridyl)-ethylamine > 2-methylhistamine > histamine > 4-methylhistamine; this is also the sequence for selectivity for stimulating H1 (guinea-pig ileum) relative to H2 (rat gastric acid secretion) receptors (Durant et al., 1975; the published results provide approximate ratios H1 : H2 of, respectively, 90, 30, 8, 1 and 0.006). Thus, the two orders of relative potencies strongly support our hypothesis (Levi and Capurro, 1973; Levi and Kuye, 1974; Levi et al., 1975) that the increases in sinus rate and in force of ventricular contraction are mediated by histamine H2-receptors, whereas the slowing of atrioventricular conduction is mediated by H1 -receptors. 2-(2-Thiazolyl)-ethylamine caused conduction arrhythmias of greater incidence and severity than any other compound. 2-{2-Thiazolyl)ethylamine was not more potent than histamine in prolonging the P--R interval, but was simply more selective. Indeed the dose--response curve for the prolongation of the P--R interval by 2-(2-thiazolyl)-ethylamine (fig. 3) was superimposable with that of histamine in the range of 3--30 pg and was an extension of it b e y o n d 30 pg. Cardiac contracture occurred at doses of histamine higher than 30 pg, whereas cardiac contracture did not occur with 2-(2thiazolyl)-ethylamine. Thus, the effects of 2-(2-thiazolyl)-ethylamine on atrioventricular
R. LEVI ET AL.
conduction could be examined at doses up to 1,000 pg. Arrhythmias of automaticity rarely occurred with 2-(2-thiazolyl)- and 2-(2-pyridyl)ethylamine, and then probably as a consequence of the severe conduction arrhythmias. Increase in ventricular automaticity by histamine appears to be an H2-response (Levi and Zavecz, unpublished observations). In conclusion, our results add further evidence in support of the hypothesis that both types of histamine receptors mediate the cardiac effects of histamine. Furthermore, our data indicate that, by plotting P--R interval prolongation vs. sinus rate increase, the relative selectivity of agonists for H1 - or H2-receptors can be clearly delineated. References Ash, A.S.F. and H.O. Schild, 1966, Receptors mediating some actions of histamine, Brit. J. Pharmacol. 27,427. Black, J.W., W.A.M. Duncan, C.J. Durant, C.R. Ganellin and E.M. Parsons, 1972, Definition and antagonism of histamine H 2-receptors, Nature (London) 236, 385. Durant, G.J., C.R. Ganellin and M.E. Parsons, 1975, Chemical differentiation of histamine H1- and H 2receptor agonists, J. Med. Chem. (in press). Hunt, W.H. and R.J. Fosbinder, 1942, A study of some beta-2, and 4, pyridylalkylamines, J. Pharmacol. Exptl. Therap. 75, 299. Lee, H.M. and R.G. Jones, 1949, The histamine activity of some ~-aminoethyl heterocyclic nitrogen compounds, J. Pharmacol. Exptl. Therap. 95, 71. Levi, R., 1972, Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison, J. Pharmacol. Exptl. Therap. 182, 227. Levi, R. and N. Capurro, 1973, Histamine H2-rece ptor antagonism and cardiac anaphylaxis, International Symposium on Histamine H 2-Receptor Antagonists, eds. C.J. Wood and M.A. Simkins (Smith Kline & French, Lt~i., London) p. 175. Levi, R., N. Capurro and C.-H. Lee, 1975, Pharmacological characterization of cardiac histamine receptors: sensitivity to H 1- and H2-receptor agonists and antagonists, European J. Pharmacol. 30, 328. Levi, R. and J.O. Kuye, 1974, Pharmacological characterization of cardiac histamine receptors: sensitivity to H~-receptor antagonists, European J. Pharmacol. 27,330.
237
© North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands
Short communication SELECTIVE IMPAIRMENT OF ATRIOVENTRICULAR CONDUCTION BY 2-(2-PYRIDYL)-ETHYLAMINE AND 2-(2-THIAZOLYL)-ETHYLAMINE, TWO HISTAMINE H, -RECEPTOR AGONISTS* ROBERTO LEVI, C. ROBIN GANELLIN**, GEOFFREY ALLAN and HOWARD J. WILLENS
Department of Pharmacology, Cornell University Medical College, New York, N.Y. 10021, U.S.A., and **The Research Institute, Smith Kline and French Laboratories Ltd., Welwyn Garden City, Hertfordshire, England Received 28 July 1975, accepted 9 September 1975
R. LEVI, C.R. GANELLIN, G. ALLEN and H.J. WILLENS, Selective impairment of atrioventricular conduction by 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, two histamine H 1-receptor agonists, European J. Pharmacol. 34 (1975) 237--240. To further characterize the receptor mediating histamine-induced impairment of atrioventricular conduction, the effects of two selective histamine H l-receptor agonists, 2-(2-pyridyl)-ethylamine (PEA) and 2-(2-thiazolyl)ethylamine (ThEA), were investigated using the isolated guinea pig heart. These effects were compared with those of histamine and other selective agonists. PEA and ThEA produced a weak stimulation of cardiac rate and contractility; however, they produced a marked prolongation of atrioventricular conduction. The orders of relative potencies observed substantiate the hypothesis that H2-receptors mediate the positive inotropic and chronotropic effects and H1-receptors mediate the negative dromotropic effect of histamine. Cardiac histamine receptors Atrioventricular conduction
2-(2-Pyridyl)-ethylamine
1. Introduction Histamine receptors have been characterized pharmacologically into two types, H, and H2, by the use of selective competitive antagonists (Ash and Schild, 1966; Black et al., 1972). Receptor differentiation may also be indicated with compounds which act as selective agonists (Black et al., 1972). A distinctive cardiac effect of histamine is its ability to impair atrioventricular conduction (negative dromotropic effect; Levi, 1972). This effect appears to be mediated by histamine H~ -receptors since it is sensitive to antagonism
* Supported by USPHS Grant 1 RO1 GM 20091, by a grant-in-aid of the New York Heart Association and by the John Polachek Foundation for medical research.
2-( 2-Thiaz olyl)-e thylamine
by classical antihistamine drugs (Levi and Kuye, 1974), and since it is reproduced by 2-methylhistamine (Levi et al., 19751, a selective Hj-receptor agonist (Black et al., 1972). However, 2-methylhistamine possesses sufficient H2-agonist activity and displays a noticeable positive chronotropic effect which indirectly contributes to the impairment of atrioventricular conduction {Levi et hi., 1975). The net result is that receptor differentiation is incomplete. Further study would be assisted by using agonists of greater selectivity. 2-(2-Pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, which have previously been shown to possess histamine-like activity (Hunt and Fosbinder, 1942; Lee and Jones, 1949), have recently been identified as being H,-receptor agonists which are more selective than 2-methylhistamine (Durant et al., 1975). Using these compounds we have attempted to further
238
R. LEVI ET AL.
characterize the receptor mediating the negative dromotropic effect of histamine.
~J F-
n
I00(
=E
2. Materials and methods Male Hartley guinea pigs (250--300 g) were used. Their hearts were isolated and perfused in a Langendorff apparatus as previously described {Levi et al., 1975). All drugs were injected intra-aortically in increasing doses after a stabilization period of 30--45 min. Histamine dihydrochloride was purchased from Sigma Chemical Co. (St. Louis, Missouri, U.S.A.). 2-Methylhistamine dihydrochloride, 4-methylhistamine dihydrochloride, 2-(2-pyridyl)ethylamine dihydrochloride and 2-(2-thiazolyl)-ethylamine dihydrochloride (fig. 1) were synthesized at Smith Kline and French Laboratories (Welwyn Garden City, Hertfordshire, England). All doses refer to the free base.
oz
80 I
~
60
A T i
#-MeH
.~, "~.
4-MeH ,2-MeH
I--(~
Z,E 8 g 4o N
2o
U
Z UJ
A C
o
120
B
100 .L
.c_ 80
.. " Y
T
,1. ......... =
o
~
6o
U.J
~
20
3. Results 00.1
2-(2-Pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine, as a function of dose, increased the sinus rate and the force of ventricular contraction of the isolated guinea pig heart. The dose--response curves for the positive inotropic and chronotropic effects of 2-(2pyridyl)- and 2-(2-thiazolyl)-ethylamine were parallel and fell to the right of those of histamine, 4-methylhistamine and 2-methylhistamine in the order shown (fig. 2A and B). 2-(2-Pyridyl)- and 2-(2-thiazolyl)-ethylamine markedly impaired atrioventricular conduction, as expressed by the prolongation of the P--R interval in the surface electrogram (fig. 3). A drug may prolong the P--R interval directly by acting on the atrioventricular node, in-
~
H2CH2NH2
2 -(2-Pyridyl ) ethylamine
/S___~CH2CH2NH2
2-(2-Tlniozolyl ) ethy[omine
Fig. 1. Structural formulas of 2-(2-pyridyl)-ethylamine and 2-(2-thiazolyl)-ethylamine.
I
IO
I00
I000
MICROGRAMS Fig. 2. Effects of histamine (H), 4-methylhistamine (4-MeH), 2-methylhistamine (2-MeH), 2-(2-pyridyl)ethylamine (PEA) and 2-(2-thiazolyl)-ethylamine (ThEA) on ventricular contraction (A) and sinus rate (B) of isolated guinea pig hearts. Points (means, -+ S.E., n = 6--10) are maximum increases from the values immediately preceding each drug injection.
directly by way of its positive chronotropic effect, or by a combination of both mechanisms (Levi, 1972). Since 2-(2-pyridyl)- and 2-(2-thiazolyl)-ethylamine concomitantly displayed negative dromotropic and positive chronotropic effects, the prolongation of the P--R interval was plotted against the increase in sinus rate, so as to exclude the indirect component of the negative dromotropic effect (fig. 4). For any given rate, the P--R interval was larger with 2-(2-thiazolyl)- and 2-(2-pyridyl)-ethylamine than with 2-methylhistamine and histamine. With 4-methylhistamine the prolongation of the P--R ~nterval was very modest.
HISTAMINE H1-AGONISTS ON A--V CONDUCTION
239
II0
100
o0 =
li
../.
I"
~-7"hEA
I:
p
90
/"
t
l,'"
zc
-
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/ ."
/ 70
d
/"
60
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/"
2(2-Thiozolyl)ethylomine
o
/
•
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z"
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,
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...." '~'-.2-MeH = "--
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,.,
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~.
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MICROGRAMS
Fig. 3. Effects of PEA and ThEA on the atrioventricular conduction of the isolated guinea pig heart• Points (means, ± S.E., n = 6:--7) are maximum increases in P--R interval duration from the values immediately preceding each drug injection.
, 3°1
4. Discussion In our previous investigations we had pharmacologically defined cardiac histamine receptors into H1 -type, mediating the negative dromotropic effect, and H2-type, mediating the positive inotropic and chronotropic effects of histamine (Levi and Kuye, 1974; Levi et al., 1975). We considered our classification of car-
i
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LA
/
/
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./ /
/
/~
/
:: .'/o
./
.': • 7"
...~~
...' / ....4/
•
/
/
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Histamine
/~I~
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......
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oo
. . . . . . . . . . .
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With both 2-(2-pyridyl)- and 2-(2-thiazolyl)-ethylamine conduction arrhythmias occurred as a function of dose (10--1000 pg) with increasing incidence and severity. However, with 2-(2-thiazolyl)-ethylamine arrhythmias occurred more often and lasted longer than with equal doses of 2-(2-pyridyl}-ethylamine. Arrhythmias of automaticity developed at the higher doses with these compounds but only after the onset of conduction arrhythmias.
./
/
/"
i/
,,
/ 2 (2-Pytidyl) I sthylomine ~
ao
i el
2- Methylhistomine ~
~ . I 20
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l 40
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I 60
,
I 80
n
I 100
n
I
120
SINUS RATE (increase in beats/mln) Fig. 4. Comparison of the negative dromotropic effects of PEA and ThEA. Maximum increases in P--R interval (ordinate) are plotted against corresponding maximum increases in sinus rate (abscissa). Same data as in figs. 1 and 2.
diac H~ -receptors to be only provisional, pending the availability of a more selective H1 -agonist. Indeed the results obtained with 2-(2-pyridyl)-ethylamine and 2- (2-thiazolyl)-ethylamine have further substantiated our hypothesis that the negative dromotropic effect of histamine in the guinea pig heart is mediated b y H1 -receptors. 2-(2-Pyridyl)- and 2-(2-thiazolyl)-ethylamine produced a weak dose-related positive inotropic and chronotropic effect (fig. 2); however, they produced a marked negative dramatropic effect (fig. 3). The efficacy of these compounds in impairing atrioventricular con-
240
duction was exemplified when their negative dromotropic effect was measured at equal rate increments, so as to exclude the indirect chronotropic c o m p o n e n t from their negative dromotropic effect (fig. 4). Two orders of relative potencies clearly emerged from these studies. For the positive chronotropic and inotropic effects the order of potency was histamine > 4-methylhistamine > 2-methylhistamine > 2-(2-thiazolyl)-ethylamine and 2-(2-pyridyl)-ethylamine; this is also the order for the relative H2 -receptor activities of these c o m p o u n d s when assayed as stimulants of gastric acid secretion in the anesthetized rat (viz: 1, 0.4, 0.02, 0.003 and 0.002 respectively; Durant et al., 1975). For the negative dromotropic effect relative to sinus rate, the order was 2-(2-thiazolyl)-ethylamine > 2-(2-pyridyl)-ethylamine > 2-methylhistamine > histamine > 4-methylhistamine; this is also the sequence for selectivity for stimulating H1 (guinea-pig ileum) relative to H2 (rat gastric acid secretion) receptors (Durant et al., 1975; the published results provide approximate ratios H1 : H2 of, respectively, 90, 30, 8, 1 and 0.006). Thus, the two orders of relative potencies strongly support our hypothesis (Levi and Capurro, 1973; Levi and Kuye, 1974; Levi et al., 1975) that the increases in sinus rate and in force of ventricular contraction are mediated by histamine H2-receptors, whereas the slowing of atrioventricular conduction is mediated by H1 -receptors. 2-(2-Thiazolyl)-ethylamine caused conduction arrhythmias of greater incidence and severity than any other compound. 2-{2-Thiazolyl)ethylamine was not more potent than histamine in prolonging the P--R interval, but was simply more selective. Indeed the dose--response curve for the prolongation of the P--R interval by 2-(2-thiazolyl)-ethylamine (fig. 3) was superimposable with that of histamine in the range of 3--30 pg and was an extension of it b e y o n d 30 pg. Cardiac contracture occurred at doses of histamine higher than 30 pg, whereas cardiac contracture did not occur with 2-(2thiazolyl)-ethylamine. Thus, the effects of 2-(2-thiazolyl)-ethylamine on atrioventricular
R. LEVI ET AL.
conduction could be examined at doses up to 1,000 pg. Arrhythmias of automaticity rarely occurred with 2-(2-thiazolyl)- and 2-(2-pyridyl)ethylamine, and then probably as a consequence of the severe conduction arrhythmias. Increase in ventricular automaticity by histamine appears to be an H2-response (Levi and Zavecz, unpublished observations). In conclusion, our results add further evidence in support of the hypothesis that both types of histamine receptors mediate the cardiac effects of histamine. Furthermore, our data indicate that, by plotting P--R interval prolongation vs. sinus rate increase, the relative selectivity of agonists for H1 - or H2-receptors can be clearly delineated. References Ash, A.S.F. and H.O. Schild, 1966, Receptors mediating some actions of histamine, Brit. J. Pharmacol. 27,427. Black, J.W., W.A.M. Duncan, C.J. Durant, C.R. Ganellin and E.M. Parsons, 1972, Definition and antagonism of histamine H 2-receptors, Nature (London) 236, 385. Durant, G.J., C.R. Ganellin and M.E. Parsons, 1975, Chemical differentiation of histamine H1- and H 2receptor agonists, J. Med. Chem. (in press). Hunt, W.H. and R.J. Fosbinder, 1942, A study of some beta-2, and 4, pyridylalkylamines, J. Pharmacol. Exptl. Therap. 75, 299. Lee, H.M. and R.G. Jones, 1949, The histamine activity of some ~-aminoethyl heterocyclic nitrogen compounds, J. Pharmacol. Exptl. Therap. 95, 71. Levi, R., 1972, Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison, J. Pharmacol. Exptl. Therap. 182, 227. Levi, R. and N. Capurro, 1973, Histamine H2-rece ptor antagonism and cardiac anaphylaxis, International Symposium on Histamine H 2-Receptor Antagonists, eds. C.J. Wood and M.A. Simkins (Smith Kline & French, Lt~i., London) p. 175. Levi, R., N. Capurro and C.-H. Lee, 1975, Pharmacological characterization of cardiac histamine receptors: sensitivity to H 1- and H2-receptor agonists and antagonists, European J. Pharmacol. 30, 328. Levi, R. and J.O. Kuye, 1974, Pharmacological characterization of cardiac histamine receptors: sensitivity to H~-receptor antagonists, European J. Pharmacol. 27,330.
