Investigative Ophthalmology & Visual Science, Vol. 32, No.

1, January 1991
Copyright © Association for Research in Vision and Ophthalmology

Histamine Induces Endothelium-Dependenf Relaxation

of Bovine Retinal Arteries
Sara Benedifo,* Dolores Prieto,* Per J. Nielsen,f and Niels C. Berg NyborgJ

The effect of histamine on bovine isolated retinal small arteries (internal diameter, approximately 240
urn) was studied. Histamine induced a concentration-dependent relaxation in 43 of 53 vessels. The
histamine-induced relaxation involves primarily activation of Hj-receptors, with H2-receptors also
affected as evidenced by the effect of selective histamine-receptor agonists and antagonists. The
histamine-induced relaxation was dependent on the endothelium and seem to involve release of both
endothelium-derived relaxing factor (EDRF) and a product which was inhibited by indomethacin,
probably prostaglandin I2 (prostacyclin). The development of tachyphylaxis to the action of histamine
seemed to rely on desensitization of the vascular smooth muscle cells to the relaxing effect of EDRF.
Invest Ophthalmol Vis Sci 32:32-38,1991

Retinal blood flow shows a remarkable ability to Materials and Methods

autoregulate.' However the mechanisms responsible
for regulation of retinal blood flow and vascular resis-
tance are not clear. Previous in vivo studies on retinal
circulation in the cat and rat indicate that histamine
does not cause any change in perfusion.2'3 Arbones et
al.,4 using an isotopic-enzymatic assay detected the
presence of this vasoactive amine and its related en-
zymes in rat and bovine retina at concentrations
comparable to those measured in whole brain and
brain cortex. This suggests that histamine may play a
role as an endogenous chemical modulator of the
retinal microcirculation controlling ocular blood
flow5 as it does in the brain.6
We wanted to know whether or not isolated bovine
retinal resistance arteries show a specific direct re-
sponse to histamine and, if so, to determine the type
of histamine receptors and their cellular location, ie,
either on the endothelium and/or vascular smooth
muscle.
From the ^Department of Pharmacology, Aarhus University,
Aarhus C, and the fEye Department, Hjorring Hospital, Hjorring,
Denmark.
•Present address: Faculty of Veterinary, Department of Physiol-
ogy, Complutense University of Madrid, 28040-Madrid, Spain.
Supported by the Danish Medical Research Council, Grant No.
12-8717 and Dansk Blindesamfund. Drs. Benedito and Prieto re-
ceived a scholarship from the Spanish Ministry of Education and
Science.
Submitted for publication: May 8, 1990; accepted July 9, 1990.
Reprint requests: Dr. Niels C. Berg Nyborg, Department of Phar-
macology, Aarhus University, DK-8000 Aarhus C, Denmark.
Bovine eyes obtained at a local slaughterhouse
were immediately placed in ice-cold oxygenated (5%
CO2 in O2) physiologic saline solution (PSS) with the
following composition: NaCl 119 mM, NaH2CO3 25
mM, KC1 4.7 mM, CaCl2 1.5 mM, KH2PO4 1.18
mM, MgSO4 1.17 mM, disodium ethylenediamine-
tetraacetate 0.026 mM, and glucose 11 mM.
Segments of retinal arteries (one to two per cow)
(internal diameter, approximately 240 /xm) were dis-
sected free as previously described7 and mounted as
rings on an isometric myograph which allowed direct
measurement of wall force while the internal circum-
ference was controlled.8"10
The vessels were equilibrated at 37°C, pH 7.4, for
30 min and then stretched to their optimal lumen
diameter, l0, for active tension development, corre-
sponding to 90% of the diameter the vessels would
have when relaxed. They were subjected to a trans-
mural pressure of 13.3 kPa (100 mmHg).11
The arteries were activated repeatedly with a high
potassium (125 mM)-containing solution (K-PSS),
by using an equimolar substitution of NaCl for KC1,
until the vessel responses were reproducible.
Cumulative concentration response experiments
using either histamine dihydrochloride (Merck,
Darmstadt, Germany), dimaprit (SK&F, Welwyn
Garden City, UK), 2-pyridylethylamine (SK&F),
(R)a-methyl-histamine (a gift from Dr. J. M. Arrang,
Paris, France), sodium nitroprusside (Sigma, St.
Louis, MO), and acetylcholine chloride (Sigma) were
then done by adding the drug in volumes exceeding

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 No. 1 HISTAMINE EFFECT ON RETINAL ARTERIES / Denediro er ol
not more than 0.3% of the tissue bath to reach the
final required concentration. The dilator effect of
histamine was studied after the arteries had been pre-
contracted with 1CT5 M prostaglandin F2a (PGF2a)
(Dinoprost; Upjohn, Berese, Belgium); this concen-
tration yielded a stable level of contraction of suffi-
cient duration to allow for analysis of relaxant re-
sponses. Histamine-receptor antagonists: cimetidine
(SK&F), mepyramine maleate (Sigma); a cyclooxy-
genase enzyme inhibitor: indomethacin (Merck); and
an endothelium-derived relaxing factor (EDRF) in-
hibitor: methylene blue (DAK, Copenhagen, Den-
mark) were all added to the bathing solution 30 min
before the vessel response to histamine was tested.
Histamine tachyphylaxis was studied not only cumu-
latively, but also by making experiments with retinal
resistance arteries which were precontracted with
10"5 M PGF2a and then exposed to one concentra-
tion (10~5 M) repeatedly at 30-min intervals to obtain
four consecutive responses. After the maximal re-
sponse to each stimulation with histamine was
reached, the vessels were washed with drug-free PSS
before the sequence was repeated.
For each concentration-response experiment, the
concentration required to give a half-maximal re-
sponse (IC50[M]) was calculated by linear interpola-
tion of plots of responses with concentration on a
logarithmic scale. Vessel sensitivity is given in terms
of pD2 = -log(IC50[M]). Maximal contractile capac-
ity, Emax, of the vessels were determined by stimulat-
ing the vessels with a cocktail consisting of K-PSS,
10"5 M PGF2a, and 10~5 M serotonin (Sigma).
The retinal artery endothelium was removed along
its entire internal length by inserting a human scalp
hair through the lumen of the vessel, gently pushing
2 mN
5 mN
5 min
Fig. 1. Tracings showing the relaxant (upper) and the weak con-
tractile effect (lower) of the histamine (HA), 10~9 M-10" 3 M, on
bovine retinal arteries precontracted with 10~5 M prostaglandin
F2a. Concentrations of histamine is given as log[M]-values. w indi-
cated washout with drug-free PSS. Vertical scale shows active force
in milliNewtons (mN). Horizontal scale shows time.
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33
the hair back and forth about four times, and rotating
the vessel on the mounting wires. The absence of
endothelium was tested by the lack of acetylcholine-
induced relaxation of vessels precontracted with 10"5
M PGF2a without loss of response to papaverine hy-
drochloride (Sigma).
The vessel responses are either expressed as active
wall tension (N/m), calculated as an increase in vessel
wall force (N) above the resting level divided by twice
the vessel segment length (m) or as the relative re-
sponse, ie, fraction of the vessel contraction induced
by 10~5 M PGF2a just before addition of histamine or
related agonists. The results are given as the mean
± the standard error of the mean (number of vessels).
Differences between means were analyzed using the
student t-test for paired and unpaired data where ap-
propriate. A probability less than 0.05 was considered
significant.
Results
Effect of Histamine on Precontracted Retinal
Resistance Arteries
Histamine, 10~9-10"3 M, had a concentration-de-
pendent relaxing effect in 43 of the 53 vessel segments
preconstricted with 10~5 M PGF2a. The pD2 value for
the histamine-relaxing effect was 5.86 ± 0.09 (n = 43)
corresponding to an IC50[M] concentration of about
3 X 10~6 M. The maximal relaxation induced by his-
tamine corresponded to 59 ± 4 % (n = 43) of the
PGF2a-induced precontraction (1.15 ± 0.07 N/m).
Effective lumen diameter of the arteries was 263 ± 5
/urn (n = 53). A weak contractile response to hista-
mine on top of the PGF2a-induced contraction was
observed in ten vessels but only at concentrations of
or above 10~5 M. Figure 1 shows tracings of vessels
exhibiting both kinds of responses to histamine.
The relaxant effect of histamine was variable, in-
ducing almost a 100% relaxation in some of the ves-
sels and only a modest relaxation in others. More-
over, tachyphylaxis to histamine developed in the ret-
inal arteries as indicated by the rightward shift of the
concentration-response curve and reduced maximal
relaxing effect of histamine in the second of two con-
secutive concentration-response experiments; the
pD2 values were 5.47 ± 0.24 and 4.70 ± 0.29 (n = 9)
in the first and second curves, respectively (P < 0.01).
Maximal histamine-induced relaxation was 46 ± 6%
and 32 ± 7% (n = 9) in the first and second curves,
respectively (P < 0.01) (Fig. 2). Additions of a single
high concentration of histamine (10~5 M) to PGF2a
precontracted vessels also showed a loss of relaxing
effect to histamine between the first and second ex-
posure (Fig. 3A). We could not prevent tachyphylaxis
by administering indomethacin (10~5 M) (Fig. 3B).
 04 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991 Vol. 32

The contractile effect of histamine could be re-

peated, but we were unsuccessful in determining the
receptor type mediating the contraction. The con-
1.0 tractile response was resistant to mepyramine (10~7
o
CL
m M), cimetidine (10~5 M), atropine (10~6 M), pro-
a)
pranolol (10~6 M), prazosin (10~6 M), and indometh-
acin (10~5 M). The response of the retinal arteries to
10"5 M PGF2a or 125 mM K+ was reproducible.
a>
cc
0.5 J; Characterization of the Histamine-Receptor Subtype
I Mediating Relaxation
-9 -8 -7 -6 -5 -4 -3
log (Histamine, [M]) A selective H,-receptor agonist, 2-pyridylethyla-
mine (PEA), 10"9-10"3 M, relaxed 10"5 M PGF2«
Fig. 2. First (unfilled circle) and second (filled circle) cumulative
concentration-response curves for histamine in isolated bovine ret- precontracted retinal arterial segments in a concen-
inal arteries precontracted with 10~5 M prostaglandin F 2a . Each tration-dependent manner. The potency of histamine
point shows mean value of nine vessels and vertical bars show ±SE was tenfold higher than that of PEA (pD2 value
mean. = 4.50 ± 0.05 with n = 6) and the maximal dilatory
response to PEA was 34 ± 10% (n = 6). Dimaprit,
10~9-10~3 M, a H2-receptor agonist, induced only a 7
Furthermore, tachyphylaxis (desensitization of the ± 2% (n = 6) relaxation of the retinal arteries (Fig. 4).
retinal vessels) was also observed for the relaxing ef- We also used the selective H r and H2-receptor an-
fect of sodium nitroprusside. The pD2 value de- tagonists, mepyramine and cimetidine, respectively,
creased from 4.75 ± 0.07 to 4.32 ± 0.10 (n = 9) (P to determine the histamine-receptor subtype respon-
< 0.01) for the first and second sodium nitroprusside sible for the histamine-induced relaxation. The incu-
curves, respectively. The maximal relaxation induced bation of the retinal-artery preparations with cimeti-
was not affected by repeated exposures; it was 36 dine (10~5 M) had a clear inhibitory effect on the
± 2% in the first and 38 ± 2 % (n = 9) in the second histamine-induced relaxation (Fig. 5). The hista-
curve. Because the occurrence of tachyphylaxis was mine-induced concentration-response curve was also
unpredictable, we could not make control histamine partly inhibited by mepyramine (10~7 M, Fig. 5).
curves or ones in the presence of antagonist using the Only combined treatment with both antagonists
same vessel preparation. (same concentrations) suppressed the relaxing effect

100i

CL)
CO
c
1.0
60-
T o
Q.
cn
QJ
40-
T
20-
QJ
az 0.5

Fig. 3. (A) Four consecutive responses to a single dose of hista- -9 -8 -7 -6 -5 -4 -3

mine (10~5 M) obtained at 30-min intervals. Each column and
vertical bar represents mean value and SE mean, respectively, of
four experiments. **P < 0.01 compared with the first response. (B)
Effect of indomethacin (10~5 M) on the development of tachyphy-
laxis. Each column represents a mean value and each vertical bar
the SE mean of four experiments. *P < 0.05 compared with the first
response.
log (Agonist, [M])
Fig. 4. Effect of the selective H, -receptor agonist, 2-pyridylethy-
lamine (filled circle) (n = 6), and the selective H2-receptor agonist,
dimaprit (filled triangle) (n = 6) in isolated bovine retinal arteries
precontracted with 10"5 M prostaglandin F2a. Mean values are
shown with vertical lines indicating ±SE mean.

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 No. 1 HISTAMINE EFFECT ON RETINAL ARTERIES / Denediro er ol 35

O)
en
o
1.0 c
o
1.0
Q.
a. in
a> CD
c_
c_
I
x>
a: CO
0.5 0.5
I_
-9 -8 -7 -6 -5 -4 -3 -9 - 8 -7 -6 -5 -4 -3
log (Histamine, [M]) log (Histamine, [M])
Fig. 5. Cumulative concentration-response curves for histamine Fig. 6. Cumulative concentration-response curves for histamine
(unfilled circle) (n = 53) in isolated bovine retinal arteries precon- in isolated bovine retinal arteries precontracted with 10~5 M prosta-
tracted with 1CT5 M prostaglandin F2a and in the presence of 10"7 glandin F2a with endothelium (unfilled circle) (n = 53), with endo-
M mepyramine (filled triangle) (n = 18), 10"5 M cimetidine (filled thelium in the presence of methylene blue (filled circle) (n = 8) and
circle) (n = 16) and both mepyramine and cimetidine (filled dia- indomethacin (filled triangle) (n = 15), and without endothelium
mond) (n = 18). Mean values are shown with vertical lines indicat- (filled square) (n = 20). Mean values are shown with vertical lines
ing SE mean. indicating SE mean.

of histamine totally (Fig. 5). The selective H3-receptor mine.1314 This conclusion was based exclusively on
agonist, (R)a-methyl-histamine, did not relax eight in vivo perfusion experiments.
retinal arteries tested. We showed that precontracted bovine retinal small
arteries are sensitive to histamine. Most of the arteries
responded to histamine with relaxation; in only a few
Cellular Location of the Histamine Receptors and arteries histamine caused an unspecified and weak
Characterization of Mediators of the Histamine- contractile effect. We were unable to determine the
Induced Relaxation mechanisms behind the diverging reaction to hista-
The role of the endothelium was studied in a series
of experiments. The relaxing effect of acetylcholine
(10~5 M) was used to test the efficiency of endothe-
lium removal; loss of acetylcholine-induced relax- 100
ation without loss of response to papaverine was con-
sidered evidence for removal of the endothelium
cells. 80
Removal of the endothelium abolished completely
the relaxation induced by histamine as shown in Fig-
ure 6. The maximal relaxations induced by acetyl- S 60
choline and histamine were linearly correlated in
vessels with intact endothelium (Fig. 7). Methylene
40
blue, 3X10~6 M, a presumed antagonist of the effect
of EDRF,12 also abolished the response of the retinal
arteries to histamine (Fig. 6). The histamine-induced
20
relaxation was partly blocked in the presence of in-
domethacin (10~5 M), a cyclooxygenase pathway in-
hibitor (Fig. 6).
0 20 40 60 80 100
Discussion ACH-induced relaxation. %
Fig. 7. Plot showing the relation between maximal relaxation
It is well known that histamine is a potent vasoac- induced by acetylcholine and histamine in isolated bovine retinal
tive substance; however, the retinal blood vessels arteries precontracted with 10"5 M prostaglandin F2a (n = 13)
have been regarded as totally insensitive to hista- (Slope = 0.968387 ± 0.27; r2 = 0.5356; P = 0.0045).

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 36 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
mine in these vessels. The action of histamine on
vascular smooth muscle may vary depending on the
tissue and/or species, but the discrepancy between
our in vitro experiments and the previously published
in vivo results may be due to methodologic differ-
ences. The presence of a blood-retinal barrier proba-
bly does not account for the lack of response of the
retinal vasculature to histamine in perfusion experi-
ments2 as the histamine receptors are present on the
endothelium.
The histamine receptors can be divided into hista-
mine Hi, H2, l516 and H3 receptors.17 Both H r and
H2-receptor types are present in the circulation, but
the H2 type seems generally to be the dominant re-
ceptor type participating in the vasodilator responses
to histamine. 18 This response seemed, however,
mainly to be mediated via H[ receptors in the bovine
retinal arteries although H2 receptors also participate
in the relaxation induced by histamine. Thus, both
Hi -receptor blockade with mepyramine and H2-re-
ceptor blockade by cimetidine caused a partial block-
ade of the relaxing effect of histamine in the retinal
arteries. The two selective agonists, PEA, a selective
Hi-receptor agonist, and dimaprit, a selective H2-re-
ceptor agonist, had, however, different activities in
the retinal arteries. The PEA was more potent than
dimaprit in relaxing the retinal arteries. This indi-
cates that only a small component of the vasodilatory
response to histamine is mediated through H2 recep-
tors. Any conclusion about receptor type based on
the action of selective agonists is controversial, how-
ever, because selective agonists often behave as par-
tial agonists in tissues where the receptor density
Combined treatment with both H,- and H2-recep-
tor antagonists resulted in a complete suppression of
the relaxing effect of histamine. This supports the
view that both Hi and H2 receptors are needed to
produce a full dilatory response to histamine in the
retinal arteries. This result is similar to that obtained
in the rat stomach microcirculation,20 human cere-
bral arteries,21 and renal artery.22 Because of the de-
velopment of tachyphylaxis to the relaxing effect of
histamine, we could not make a Schild-plot analysis
to describe the histamine receptor subtypes in detail.
The H3-receptor agonist did not induce any relax-
ation of the retinal arteries in a concentration range
where its action could be considered to be specific
mediated for H3 receptors,17 thus excluding hista-
mine receptors of this kind as involved in regulation
of tone in the bovine retinal circulation.
Histamine can evoke endothelium-dependent re-
laxation in several vascular beds.23 Our experiments
demonstrate that the presence of the vascular endo-
thelium is essential for the relaxing effect of hista-
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Vol. 32
mine in bovine retinal arteries. The relaxing effect of
histamine and the acetylcholine-induced relaxation
was variable. This suggests that the endothelium was
damaged to some degree. The histamine-induced re-
laxation was correlated linearly to the relaxation in-
duced by acetylcholine, again correlated linearly to
the relaxation induced by sodium nitroprusside
(slope equal to unity, results not shown). This latter
finding does not support the idea that the endothe-
lium was partly damaged in the retinal arteries but
rather that the variable endothelium-dependent re-
laxation was due to intracellular variations in the sol-
uble guanylate-cyclase enzyme activity.
Histamine seems to mediate its relaxation by re-
lease of EDRF because methylene blue abolished the
histamine-induced relaxation completely.12 These re-
sults agree with those obtained in a number of other
arteries; cerebral arteries,24'25 aorta,18'26 pulmonary
arteries,27 coronary arteries,28 renal artery,22 and re-
sistance vessels of the perfused kidney and mesen-
tery.29 Histamine has also been shown to induce re-
lease of arachidonic acid derivatives with vasodila-
tory properties,18 possibly PGI2,30 from the arterial
wall. The partial inhibition of the histamine-induced
relaxation by indomethacin indicates that histamine
causes release of vasodilatory prostaglandins and
EDRF (NO) in bovine retinal arteries. The inhibitory
effect of indomethacin could also be due to a block-
ade of an endogenous production of a vasodilator
substance like PGI2. The contraction induced by
PGF2a in the presence of indomethacin would then
be stronger and therefore harder to overcome by his-
tamine.
The histamine-induced relaxation of the retinal ar-
teries was characterized by tachyphylaxis, ie, repeti-
tive exposures of the arteries to histamine resulted in
acute desensitization and loss of the relaxing effect.
Development of tachyphylaxis to histamine has been
observed in various tissues31"35 including vascular
smooth muscle.36 However, there is no simple theory
which can explain the mechanism behind the devel-
opment of tachyphylaxis. Tozzi33 showed that tachy-
phylaxis to the relaxant effect of histamine in the rat
uterus is due to the decreased release of catechol-
amines from sympathetic nerve terminals. This ex-
planation seems unlikely since there is only a minor37
or no sympathetic innervation38 in the retinal vessels.
Prostaglandin production has also been implicated in
the mechanisms of tachyphylaxis to histamine in iso-
lated guinea-pig mesenteric artery,36 but this seems
implausible in our experiments because pretreatment
of the retinal arteries with indomethacin did not
avoid development of tachyphylaxis to histamine.
The relaxation of the PGF2a-contracted retinal
 No. 1 HISTAMINE EFFECT ON RETINAL ARTERIES / Denediro er ol
vessels by sodium nitroprusside, which directly re-
laxes the vascular smooth muscle through activation
of the same pathway as EDRF does,39 could not be
reproduced. This indicates that the mechanism be-
hind the development of tachyphylaxis to histamine
and other EDRF-dependent responses is partly re-
lated to the vascular smooth muscle.
In conclusion, our studies provide evidence for a
functional population of histamine receptors in the
bovine retinal circulation. The histamine receptors
mediating relaxation of the retinal arteries are located
in the endothelium and stimulation of these recep-
tors, primarily of the H! type, causes release of both
EDRF and a cyclooxygenase product, probably pros-
tacyclin. The histamine receptors may thus play a
role in the regulation of retinal arterial tone, perhaps
most importantly in cases where inflammatory pro-
cesses have destroyed the blood-retina barrier; this
may lead to introduction of extravascular histamine
into the retinal circulation.
Key words: histamine, cimetidine, mepyramine, dimaprit,
2-pyridylethylamine, endothelium, retinal arteries, bovine
Acknowledgments
Cimetidine, PEA, and dimaprit was provided by Smith,
Kline & French Laboratories, Welwyn Garden City, En-
gland. (R)a-methyl-histamine was a gift from Dr. Arrang,
Unite 109 de Neurobiologie et Pharmacologie, Centre Paul
Broca de 1'INSERM, Paris, France. The authors thank
Aarhus Offentlige Slagtehus for the donated eyes.
References
1. Aim A and Bill A: Ocular circulation. In Adler's Physiology of
the Eye, Moses RA, editor. St. Louis, CV Mosby, 1987, pp.
183-203.
2. Ashton N and Cunha-Vaz JG: Effect of histamine on the per-
meability of the ocular vessels. Arch Ophthalmol 73:211, 1965.
3. Aim A: Effects of norepinephrine, angiotensin, dihydroergota-
mine, papaverine, isoproterenol, histamine, nicotinic acid, and
xanthinol nicotinate on retinal oxygen tension in cats. Acta
Ophthalmol (Copenh) 50:707, 1972.
4. Arbones L, Garcia-Verdugo J, Picatoste F, and Garcia A: Pres-
ence and distribution of histaminergic components in rat and
bovine retina. Neurochem Int 13:97, 1988.
5. Nowak JZ and Socko R: Histamine levels and activities of
histamine metabolizing enzymes in mammalian ocular tissues:
Comparison between day and night. Pol J Pharmacol Pharm
40:25, 1988.
6. Gross PM: Cerebral histamine: Indications for neuronal and
vascular regulation. J Cereb Blood Flow Metab 2:3, 1982.
7. Nielsen PJ and Nyborg NCB: Adrenergic responses in isolated
bovine retinal resistance arteries. Int Ophthalmol 13:103,
1989.
8. Mulvany MJ and Halpern W: Mechanical properties of vascu-
lar muscle cells in situ. Nature 260:617, 1976.
9. Mulvany MJ and Nyborg N: An increased calcium sensitivity
of mesenteric resistance vessels in spontaneously hypertensive
rats. BrJ Pharmacol 71:585, 1980.
Downloaded From: http://iovs.arvojournals.org/ on 02/04/2018
37
10. Mulvany MJ and Halpern W: Contractile properties of small
arterial resistance vessels in spontaneously hypertensive and
normotensive rats. Circ Res 41:19, 1977.
11. Nyborg NCB, Korsgaard N, and Nielsen PJ: Active wall ten-
sion-length curve and morphology of isolated bovine retinal
small arteries: Important feature for pharmacodynamic stud-
ies. Exp Eye Res 51:217,1990.
12. Martin W, Villani GM, Jothianandan D, and Furchgott RF:
Selective blockade of endothelium-dependent and glyceryl
trinitrate-induced relaxation by hemoglobin and methylene
blue in the rabbit aorta. J Pharmacol Exp Ther 232:708, 1985.
13. Stjernschrantz J: Autacoids and neuropeptides. In Pharmacol-
ogy of the Eye, Marvin LS, editor. Handbook of Pharmacol-
ogy, Volume 69, Springer Verlag, Berlin: 1984, pp. 311-365.
14. Braunagel SC, Xiao JG, and Chiou GCY: The potential role of
adenosine in regulating blood flow in the eye. J Ocul Pharma-
col 4:61, 1988.
15. Asch ASF and Schild HO: Receptors mediating some actions
of histamine. BrJ Pharmacol 27:427, 1966.
16. Black JW, Duncan WAM, Durant CJ, Ganellin CR, and Par-
sons ME: Definition and antagonism of histamine ^-recep-
tors. Nature 236:385, 1972.
17. Arrang JM, Garbarg M, and Schwartz J-C: Autoinhibition of
brain histamine release mediated by a novel class (H3) of his-
tamine receptor. Nature 302:832, 1983.
18. Van de Voorde J and Leusen I: Role of the endothelium in the
vasodilator response of rat thoracic aorta to histamine. Eur J
Pharmacol 87:113, 1983.
19. Kenakin TP: Agonist affinity. In Pharmacologie Analysis of
Drug-Receptor Interaction, Kenakin TP, editor. New York,
Raven Press, 1988, pp. 163-204.
20. Koo A: In vivo characterization of histamine H r and ^ - r e -
ceptors in the rat stomach microcirculation. Br J Pharmacol
78:181, 1983.
21. Ottosson A, Jansen I, and Edvinsson L: Pharmacological char-
acterization of histamine receptors in the human human tem-
poral artery. Br J Clin Pharmacol 27:139, 1989.
22. Krstic MK, Stepanovic RM, Krstic SK, and Katusic ZS: Endo-
thelium-dependent relaxation of the rat renal artery caused by
activation of histamine Hi-receptors. Pharmacology 38:113,
1989.
23. Furchgott RF and Vanhoutte PM: Endothelium-derived re-
laxing and contracting factors. FASEB J 3:2007, 1989.
24. Sercombe R, Verrecchia C, Philipson V, Oudart N, Dimitria-
dou V, Bouchad C, and Seylaz J: Histamine-induced constric-
tion and dilatation of rabbit middle cerebral arteries in vitro:
Role of the endothelium. Blood Vessels 23:137, 1986.
25. Chang JY, Hardebo JE, and Owman CH: Differential vaso-
motor action of noradrenaline, serotonin, and histamine in
isolated basilar artery from rat and guinea-pig. Acta Physiol
Scand 132:91, 1988.
26. Moritoki H, Tanioka A, Haeshiba Y, Iwamoto T, Ishida Y,
and Araki H: Age-associated decrease in histamine-induced
vasodilatation may be due to reduction of cyclic GMP forma-
tion. BrJ Pharmacol 95:1015, 1988.
27. Satoh H and Inui J: Endothelial cell-dependent relaxation and
contraction induced by histamine in the isolated guinea-pig
pulmonary artery. Eur J Pharmacol 97:321, 1984.
28. Toda N: Mechanisms of histamine-induced relaxation in iso-
lated monkey and dog coronary arteries. J Pharmacol Exp
Ther 239:529, 1986.
29. Bhardwaj R and Moore PK: Endothelium-derived relaxing
factor and the effects of acetylcholine and histamine on resis-
tance blood vessels. BrJ Pharmacol 95:835, 1988.
 38 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / January 1991
30. Toda N, Konishi M, and Miyazaki M: Involvement of endoge-
nous prostaglandin I2 in the vascular action of histamine in
dogs. J Pharmacol Exp ther 223:257, 1982.
31. Biilbring E and Burnstock G: Membrane potential changes
associated with tachyphylaxis and potentiation of the response
to stimulating drugs in smooth muscle. Br J Pharmacol 15:611,
1960.
32. Gosselin RE and Gosselin RS: Tachyphylaxis of guinea-pig
ileum to histamine and furtrethonium. J Pharmacol Exp Ther
184:494, 1973.
33. Tozzi S: The mechanism of action of histamine on the isolated
rat uterus. J Pharmacol Exp Ther 187:511, 1973.
34. Anderson WH, Krzanowski JJ, Poison JB, and Szentivanyi A:
Characteristics of histamine tachyphylaxis in canine tracheal
smooth muscle. Naunyn Schmiedebergs Arch Pharmacol
308:117, 1979.
Downloaded From: http://iovs.arvojournals.org/ on 02/04/2018
Vol. 32
35. Krzanowski JJ, Anderson WH, Poison JB, and Szentivanyi A:
Prostaglandin mediated histamine tachyphylaxis in subhuman
primate tracheal smooth muscle. Arch Int Pharmacodyn Ther
247:155, 1980.
36. Satoh H, Inui I, Kimura T, and Nakamura T: Development of
histamine tachyphylaxis in the guinea-pig mesenteric artery. J
Pharmacol Exp Ther 229:527, 1984.
37. Furukawa H: Autonomic innervation of preretinal blood ves-
sels of the rabbit. Invest Ophthalmol Vis Sci 28:1752, 1987.
38. Laties AM: Central retinal artery innervation: Absence of
adrenergic innervation to intraocular branches. Arch Ophthal-
mol 77:405, 1967.
39. Rapoport RM and Murad F: Agonist-induced endothelium-
dependent relaxation in rat thoracic aorta may be mediated
through cGMP. Circ Res 52:352, 1983.