Vol. 277, Issue 4, R1179-R1187, October 1999
Analysis of vasoconstrictor responses to histamine in the
hindlimb vascular bed of the rabbit
Hunter C.
Champion,
Trinity J.
Bivalacqua,
David G.
Lambert,
Rasheed A.
Abassi, and
Philip J.
Kadowitz
Department of Pharmacology, Tulane University School of
Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
Hemodynamic responses to histamine were
investigated in the anesthetized rabbit. Intravenous injections of
histamine induced dose-dependent decreases in systemic arterial
pressure that were blocked by the
H1-receptor antagonist pyrilamine
but not the H2 antagonist
cimetidine. Injections of histamine and the
H1 agonist 6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptanecardoxamide dimaleate (HTMT) into the hindlimb perfusion circuit increased hindlimb
perfusion pressure, whereas the H2
agonist dimaprit decreased perfusion pressure and the
H3-receptor agonist
R-(
)-
-methylhistamine did not alter perfusion pressure.
Pyrilamine reduced hindlimb vasoconstrictor responses to histamine and
HTMT but did not alter vasodilator responses to dimaprit. Cimetidine
reduced the response to dimaprit but did not alter vasoconstrictor
responses to histamine or HTMT. The
H3-receptor antagonist
thioperamide was without effect on responses to the histamine agonists.
These data suggest the presence of
H1 and
H2 receptors and that histamine
for the most part acts by stimulating
H1 receptors to produce
vasoconstriction in the hindlimb vascular bed of the rabbit. Responses
to histamine, HTMT, and norepinephrine were significantly enhanced by a
nitric oxide synthase inhibitor at a time when vasodilator responses to
dimaprit were unaltered and responses to acetylcholine were significantly reduced. Responses to histamine and the
H1 and
H2 agonists were not affected by
the cyclooxygenase inhibitor meclofenamate or by ATP-sensitive
K+ channel, -adrenergic, or
angiotensin AT1 receptor
antagonists. The present data suggest that
H1 receptors mediate both systemic vasodepressor and hindlimb vasoconstrictor responses to histamine.
differential responses to histamine; regional vascular bed; H3 receptors; ATP-sensitive
K+ channels; cyclooxygenase
products; nitric oxide; alpha receptors
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INTRODUCTION |
HISTAMINE IS WIDELY distributed in mammalian tissue and
has been implicated in a variety of physiological and
pathophysiological processes. Histamine is involved in
immediate hypersensitivity and allergic reactions and acts on vascular
smooth muscle by binding to three different types of receptors (5, 8,
19, 30). H1 receptors are coupled
to phospholipase C and mediate either smooth muscle contraction or
relaxation, depending on the vascular bed and species studied (19).
H2 receptors are believed to be coupled to adenylate cyclase and mediate smooth muscle relaxation, as
well as inhibition of mediator release (17, 19).
H3 receptors have been reported to
modulate cholinergic and adrenergic neurotransmission, as well as to
mediate vascular smooth muscle relaxation, directly or by releasing
nitric oxide (5, 6, 12, 13, 21). In the feline pulmonary vascular bed,
histamine produces tone-dependent responses with vasoconstriction
observed at low tone and vasodilation occurring at elevated tone,
whereas only a vasodilator response was observed in the hindquarters
circulation in the cat (12, 25).
There have been numerous studies on the mechanisms mediating
hemodynamic responses to histamine (1, 2, 6, 7, 10-18, 20-29,
31-36). The vascular actions of histamine not only vary among species but also vary among different blood vessels from the same species (22, 23, 34). These differences may be due to differential actions on the three histamine receptor subtypes or differences in the
population of receptors in different blood vessels. In a recent study,
histamine was shown to produce a vasodilator response in the feline
hindlimb vascular bed by activating
H1 and
H2 receptors and that
H1 receptor activation results in
both the opening of ATP-sensitive
K+
(K+ATP) channels and in the release of
nitric oxide (12).
In the rabbit, histamine has been shown to produce a biphasic change in
systemic arterial pressure and in hindlimb vascular resistance (3, 10,
11), whereas in another study histamine increased hindlimb vascular
resistance in the rabbit (24). Moreover, it has been shown that
histamine decreases blood flow to the femoral, mesenteric, and renal
vascular beds of the rabbit (28). In isolated rabbit arteries,
histamine acts on both H1 and
H2 receptors, with the
H1-receptor contractile response
masking the H2-receptor-mediated relaxant response (1, 25, 28). It was also shown that responses to
histamine in the rabbit depend on the specific artery studied (1, 26).
However, little if anything is known about the mechanism mediating
responses to histamine in the regional vascular bed in the rabbit under
constant-flow conditions. The present study was therefore undertaken to
investigate the receptors and mechanisms involved in mediating
responses to histamine in the hindlimb vascular bed of the rabbit.
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METHODS |
Surgical procedures.
Ninety-four male New Zealand White rabbits weighing 2.6-4.2 kg
were sedated with ketamine hydrochloride (20 mg/kg im) and anesthetized
with pentobarbital sodium (30 mg/kg ip). Supplemental doses of
pentobarbital were given as needed to maintain a uniform level of
anesthesia. The trachea was cannulated, and the rabbits breathed room
air or were ventilated with a Harvard model 607 respirator at a volume
of 40-60 ml at 15-22 breaths/min. The animals were maintained
at 37°C with a warming blanket. An external jugular vein was
catheterized for the intravenous administration of drugs, and a carotid
artery was catheterized for the measurement of systemic arterial
pressure. For constant-flow perfusion of the hindlimb vascular bed, a
3- to 4-cm segment of distal abdominal aorta was exposed through a
ventral midline incision and was cleared of surrounding connective
tissue by blunt dissection. After administration of heparin sodium
(1,000 U/kg iv), the aorta was ligated ~4 cm above the bifurcation
and catheters were inserted into the aorta proximal and distal to the
ligature. Blood was withdrawn from the proximal catheter and pumped at
a constant flow rate with a Sigmamotor model T-8 pump into the distal
aortic catheter. Perfusion pressure was monitored from a lateral tap in
the perfusion circuit located between the pump and the distal catheter.
Hindlimb perfusion pressure and systemic arterial (aortic) pressure
were measured with Statham P23 transducers and were recorded on a Grass
model 7 polygraph. Mean pressures were derived by electronic averaging, and the flow rate was set so that hindlimb perfusion pressure approximated systemic arterial pressure and was not changed during an
experiment. The flow rate was determined by timed collection and was
18-24 ml/min. The agonists were injected directly into the
hindlimb perfusion circuit distal to the pump in small volumes (30 and
100 µl) or intravenously in a random sequence, and the hindquarters
vascular bed was denervated by ligating and cutting the lumbar
sympathetic chain ganglia. In experiments in which the effects of
histamine on systemic arterial pressure were investigated, the amine
and the antagonists used in these experiments were injected intravenously.
Experimental protocol.
In the first series of experiments, responses to intravenous injections
of histamine were investigated, and the role of
H1, H2, and
H3 receptors was evaluated by
comparing responses to histamine before and after the
H2-receptor antagonist cimetidine
(1 mg/kg iv) and the H2-receptor
antagonist pyrilamine (1 mg/kg iv).
In the second series of experiments responses to histamine-receptor
agonists were investigated in the hindlimb vascular bed of the rabbit
under constant-flow conditions. The time course of the increase in
hindlimb perfusion pressure in response to injections of histamine was
assessed. In other experiments, vasoconstrictor responses to histamine
were measured over a period of 5 h to determine if responses were
reproducible with respect to time.
In the third series of experiments, the role of
H1,
H2, and
H3 receptors in mediating
responses to histamine was assessed. In experiments in which the
influence of the H1 receptor in
mediating responses to histamine was evaluated in the hindlimb vascular bed, responses to histamine, the
H1-receptor agonist
6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptanecardoxamide dimaleate (HTMT), the H2-receptor
agonist dimaprit, and the
H3-receptor agonist
R-()--methylhistamine were compared before and after administration of the H1-receptor
antagonist pyrilamine (1 mg/kg iv). In separate experiments the
influence of the H2-receptor antagonist cimetidine on responses to histamine, HTMT, dimaprit, and
R-()--methylhistamine was determined. These doses of
pyrilamine and cimetidine have been shown to inhibit responses to
histamine in the cat (12). In another series of experiments, the effect of the H3-receptor antagonist
thioperamide on responses to histamine, HTMT, dimaprit, and
R-()--methylhistamine was determined. Responses were compared
before and after administration of thioperamide in a dose of 30 mg/kg iv.
In the fourth series of experiments the mechanism of response to
histamine and the H1- and
H2-receptor agonists was
investigated. N
-nitro-L-arginine
methyl ester (L-NAME, 100 mg/kg
iv), an inhibitor of nitric oxide synthase, was used as previously
described to evaluate the role of nitric oxide and was injected over a
period of 10 min (12). Responses to the vasoactive agents were
evaluated 20 min after completion of the infusion, and injections of
the endothelium-dependent vasodilator acetylcholine were compared before and after administration of
L-NAME to assess the degree of
nitric oxide synthase inhibition. In other experiments U-37883A, a
vascular selective nonsulfonylurea
K+ATP-channel-blocking agent, was used as
previously described to evaluate the role of K+ATP channels in mediating responses to
histamine and the H1- and
H2-receptor agonists (12).
U-37883A (5 mg/kg iv) was injected over a 10-min period, and responses
to vasoactive agonists were evaluated beginning 20 min after completion
of the injection. Vasodilator responses to the
K+ATP-channel opener levcromakalim were
compared before and after administration of U-37883A to assess the
degree of K+ATP channel blockade. In
another series of experiments responses to histamine were compared
before and after administration of the sulfonylurea K+ATP-channel blocker glibenclamide. In
other experiments sodium meclofenamate, a cyclooxygenase inhibitor, was
used to evaluate the role of prostaglandins in mediating or modulating
responses to histamine, H1- and
H2-receptor agonists, and was
administered in a dose of 5 mg/kg iv. Injections of the prostaglandin
precursor arachidonic acid were compared before and after
administration of sodium meclofenamate to assess the degree of
cyclooxygenase blockade.
In experiments in which the role of -adrenergic receptors was
investigated, responses were compared before and after administration of phentolamine in a dose of 200 µg/kg iv. Injections of
norepinephrine were compared before and after administration of
phentolamine to assess the degree of -adrenergic blockade.
In experiments in which the role of angiotensin
AT1 receptors in mediating
responses to histamine and the H1-
and H2-receptor agonists was
investigated, responses were compared before and after administration
of the AT1-receptor antagonist in
a dose of 1 mg/kg iv. Injections of angiotensin II were compared before and after administration of candesartan to assess the degree of angiotensin AT1 receptor blockade.
Preparation of drugs.
Histamine dihydrochloride, acetylcholine chloride, norepinephrine
bitartrate, angiotensin II, sodium arachidonate,
L-NAME, sodium meclofenamate
(Sigma Chemical, St. Louis, MO), R-()--methylhistamine, thioperamide maleate, dimaprit dihydrochloride (Research Biochemical International, Natick, MA), phentolamine mesylate (Ciba-Geigy, Summit,
NJ), and albuterol sulfate (Schering, Kennelworth, NJ) were dissolved
in 0.9% NaCl with sonication. HTMT (Tocris-Cookson, St. Louis, MO) was
dissolved in 5% ethanol-saline solution at a concentration of 1 mg/kg
and diluted with 0.9% saline. The diethylamine-nitric oxide complex
sodium (Research Biochemical International) was dissolved in 0.9% NaCl
at ~20°C just before use. Levcromakalim (SmithKline Beecham,
Sussex, UK) was dissolved in 20% ethanol-saline solution at a
concentration of 1 mg/ml and was diluted with 0.9% NaCl. The solvents
for the drugs used in this study had no significant effect on vascular
pressures measured or on responses to the vasoactive agonists. All
solutions were stored in a freezer in amber bottles, and working
solutions were prepared on a frequent basis and kept on crushed ice.
Statistical analysis.
Responses were compared in terms of peak change in mean systemic
arterial or hindlimb perfusion pressure from baseline pressure. The
hemodynamic data are expressed as means ± SE and were analyzed using a one-way analysis of variance and Scheffé's
F test or a paired
t-test.
P < 0.05 was used as the criterion
for statistical significance.
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RESULTS |
Responses to intravenous injections of histamine.
Hemodynamic responses to intravenous injections of histamine and the
histamine-receptor subtype mediating those responses were investigated
in the systemic vascular bed of the rabbit, and these data are
summarized in Fig. 1. Injections of
histamine in doses of 3, 10, and 30 µg/kg iv caused dose-related
decreases in systemic arterial pressure. The decreases in systemic
arterial pressure in response to injections of histamine in a dose of
10 µg/kg iv were compared before and after administration of the H2-receptor antagonist cimetidine
(1 mg/kg iv) and the H1-receptor antagonist pyrilamine (1 mg/kg iv). After administration of cimetidine in a dose of 1 mg/kg iv, decreases in systemic arterial pressure in
response to intravenous injections of histamine were not altered (Fig.
1). In contrast, depressor responses to histamine were reduced significantly following administration of pyrilamine in a dose of
1 mg/kg iv (Fig. 1). Vasodepressor responses to histamine
were not altered after administration of the
H3-receptor antagonist thioperamide in a dose of 30 mg/kg iv (data not shown). The injection of histamine in doses of 10 and 30 µg/kg iv caused a significant increase in hindlimb perfusion pressure. The time course of the changes
in systemic arterial pressure and hindlimb perfusion pressure in
response to injection of histamine in a dose of 10 µg/kg iv is shown
in Fig. 2. After intravenous injection of
histamine, there was a rapid decrease in systemic arterial pressure,
followed by a delayed increase in hindlimb perfusion pressure when the amine reached the denervated hindlimb vascular bed of the rabbit (Fig.
2). Both pressures returned to baseline value ~3-5 min after the
intravenous injection of histamine (Fig. 2).
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Fig. 1.
A: decreases in systemic arterial
pressure in response to injections of histamine in doses of 3, 10, and
30 µg/kg iv in the rabbit. B: effect
of histamine H2-receptor
antagonist cimetidine and the
H1-receptor antagonist pyrilamine
on decreases in systemic arterial pressure in response to injection of
histamine in a dose of 10 µg/kg iv. Responses to histamine were
compared before and after administration of cimetidine or pyrilamine in
a dose of 1 mg/kg iv. n, no. of
animals. * Response is significantly different from control.
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Fig. 2.
Time course of changes in mean systemic arterial pressure and hindlimb
perfusion pressure in response to injection of histamine in a dose of
10 µg/kg iv. Histamine was injected at time
0. n, no. of
experiments.
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Responses to histamine in hindlimb vascular bed.
Responses to injections of histamine, the
H1-receptor agonist HTMT, the
H2-receptor agonist dimaprit, and
the H3-receptor agonist
R-()--methylhistamine into the hindlimb perfusion circuit were compared, and these data are summarized in Fig.
3 and Table 1. In contrast to the decreases in
systemic arterial pressure in response to histamine, injections of
histamine into the hindlimb perfusion circuit in doses of 0.1-10
µg caused dose-related increases in hindlimb perfusion pressure (Fig.
3). When injected at intervals over a 3-h period, vasoconstrictor
responses to histamine were not significantly different from control
(data not shown). Injections of the
H1-receptor agonist HTMT in doses
of 30-300 µg caused dose-related increases in hindlimb perfusion
pressure (Fig. 3). Injections of the
H2-receptor agonist dimaprit in
doses of 30-300 µg caused dose-related decreases in hindlimb
perfusion pressure (Fig. 3). Injections of the
H3-receptor agonist
R-()--methylhistamine in doses of 100-300 µg did not
alter hindlimb perfusion pressure (Table 1).
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Fig. 3.
A: peak increases in hindlimb perfusion pressure in
response to injections of histamine in doses of 0.1-10 µg into
hindlimb perfusion circuit. B: peak increases in hindlimb
perfusion pressure in response to injections of the
H1-receptor agonist
6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptanecardoxamide
dimaleate (HTMT) in doses of 30-300 µg into hindlimb perfusion
circuit. C: peak decreases in hindlimb perfusion pressure in
response to injections of H2-receptor agonist
dimaprit in doses of 30-300 µg into hindlimb perfusion circuit.
n, no. of experiments.
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Table 1.
Change in hindlimb perfusion pressure in response to histamine,
HTMT, dimaprit, and R-()--methylhistamine
during control period and after administration of thioperamide
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The time course of the increases in hindlimb perfusion pressure in
response to injection of histamine into the perfusion circuit in doses
of 3, 10, and 30 µg is shown in Fig. 4.
After injection into the perfusion circuit, hindlimb perfusion pressure
increased rapidly, responses were dose-dependent, and pressure returned to baseline value within ~4 min after administration of histamine (Fig. 4).
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Fig. 4.
A: time course of vasoconstrictor
response to injections of histamine in doses of 1, 3, and 10 µg into
hindlimb perfusion circuit. B:
dose-response curves for increases in perfusion pressure in response to
histamine, angiotensin (ANG) II, and norepinephrine (NE) in hindlimb
vascular bed of rabbit. n, no. of
experiments.
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In terms of relative vasoconstrictor activity, histamine was ~100- to
300-fold less potent than angiotensin II and ~10-fold less potent
than norepinephrine when doses were compared on a nanomole basis to
take molecular weight into account (Fig. 4).
Role of histamine H1,
H2, and H3
receptors in hindlimb vascular bed.
The effects of the H1-receptor
antagonist pyrilamine on hindlimb vascular responses to histamine and
HTMT were investigated, and these data are summarized in Fig.
5. Administration of pyrilamine in a dose
of 1 mg/kg iv did not alter baseline systemic arterial or hindlimb
perfusion pressure (Table 2). After
administration of pyrilamine in a dose of 1 mg/kg iv,
hindlimb vasoconstrictor responses to histamine were abolished or
reversed at the 3- and 10-µg doses, and vasoconstrictor responses to
HTMT were reversed at the 100-µg dose (Fig. 5). Vasodilator responses
to the H2-agonist dimaprit,
acetylcholine, and albuterol and vasoconstrictor responses to
norepinephrine and angiotensin II were not altered following administration of pyrilamine in a dose of 1 mg/kg iv (data not shown).
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Fig. 5.
A: effect of histamine
H1-receptor antagonist pyrilamine
on increases in hindlimb perfusion pressure in response to injections
of histamine and H1 agonist HTMT
into perfusion circuit. Decreases in perfusion pressure in response to
3- and 10-µg doses of histamine and 100-µg dose of HTMT after
pyrilamine were significant (P
<0.05). B: effect of histamine
H2-receptor antagonist cimetidine
on changes in perfusion pressure in response to injections of histamine
and H2 agonist dimaprit into
perfusion circuit. Responses to agonists were compared before and
beginning 20 min after administration of pyrilamine and cimetidine in a
dose of 1 mg/kg iv. n, no. of animals.
* Response is significantly different from control.
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Table 2.
Influence of pyrilamine, cimetidine, thioperamide, L-NAME,
U-37883A, meclofenamate, phentolamine, and candesartan on mean baseline
vascular pressures in the rabbit
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The effects of the H2-receptor
antagonist cimetidine on vasoactive responses to histamine and dimaprit
were investigated, and these data are also summarized in Fig. 5.
Administration of cimetidine in a dose of 1 mg/kg iv did not alter
baseline systemic arterial or hindlimb perfusion pressure (Table 2).
After administration of cimetidine in a dose of 1 mg/kg iv, the
hindlimb vasoconstrictor response to histamine was not significantly
altered at a time when vasodilator responses to the
H2-receptor agonist dimaprit were
significantly reduced (Fig. 5). Vasoconstrictor responses to the
H1 agonist HTMT, norepinephrine,
and angiotensin II and vasodilator responses to acetylcholine and
albuterol were not altered following administration of cimetidine in a
dose of 1 mg/kg iv (data not shown).
The potential role of the H3
receptor in mediating the response to histamine was investigated using
the H3-selective receptor antagonist thioperamide, and these data are summarized in Table 2.
Thioperamide in a dose of 30 mg/kg iv did not alter baseline systemic
arterial or hindlimb perfusion pressure (Table 2) and had no
significant effect on hindlimb vasoconstrictor responses to histamine
or HTMT or on vasodilator responses to the
H2-receptor agonist dimaprit
(Table 1). The H3-receptor agonist
R-()--methylhistamine when injected in doses of 100 and 300 µg did not significantly alter hindlimb perfusion pressure (Table 1).
In other experiments in three rabbits the influence of an 8-min
infusion of histamine into the hindlimb in doses of 1 and 10 µg · kg
1 · min1
was investigated. In these experiments infusions of histamine in doses
of 1 and 10 µg · kg1 · min1
into the hindlimb perfusion circuit induced dose-related, slowly developing increases in hindlimb perfusion pressure that were well
maintained once a plateau was reached. The increases in hindlimb perfusion pressure in response to infusion of histamine were not significantly altered by treatment with the
H2-receptor antagonist cimetidine
(1 mg/kg iv) but were significantly reduced following administration of
the H1-receptor antagonist
pyrilamine (1 mg/kg iv, P <0.05,
data not shown).
Influence of L-NAME.
The effect of the nitric oxide synthase inhibitor
L-NAME on responses to
histamine, HTMT, and dimaprit was investigated, and these data are
shown in Table 3.
L-NAME in a dose of 100 mg/kg iv
significantly increased baseline systemic arterial and hindlimb perfusion pressures (Table 2). After treatment with
L-NAME, vasoconstrictor responses to histamine, the
H1-receptor agonist HTMT and
norepinephrine were significantly enhanced (Table 3). Vasodilator
responses to acetylcholine were reduced following administration of the nitric oxide synthesis inhibitor (Table 3). Vasodilator responses to
albuterol and levcromakalim were not significantly changed after
administration of L-NAME (data
not shown).
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Table 3.
Influence of L-NAME on responses to histamine, HTMT,
dimaprit, acetylcholine, and norepinephrine in hindlimb vascular bed of
the rabbit
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Influence of meclofenamate and U-37883A.
The role of K+ATP-channel activation in
modulating vasoconstrictor responses to histamine was investigated, and
these data are summarized in Fig. 6.
U-37883A in a dose of 5 mg/kg iv did not alter baseline
systemic arterial or hindlimb perfusion pressure (Table 2). After
administration of the K+ATP-channel antagonist in a dose of 5 mg/kg iv, the vasoconstrictor response to
histamine was not changed, whereas the vasodilator response to the
K+ATP-channel opener levcromakalim was significantly reduced (Fig. 6). Responses to the
H1-receptor agonist HTMT and the
H2-receptor agonist dimaprit were
not altered following administration of U-37883A (data not shown). In a
separate series of experiments, responses to histamine, HTMT, and
dimaprit were compared before and after administration of glibenclamide
in a dose of 5 mg/kg iv, and results were similar to those obtained with U-37883A (data not shown).
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Fig. 6.
A: effect of ATP-sensitive
K+
(K+ATP)-channel antagonist U-37883A on
increases in hindlimb perfusion pressure in response to histamine and
decreases in perfusion pressure in response to
K+ATP-channel opener levcromakalim.
B: effect of cyclooxygenase inhibitor
sodium meclofenamate on increases in hindlimb perfusion pressure in
response to histamine and decreases in perfusion pressure in response
to prostaglandin precursor arachidonic acid. Responses to agonists were
compared before and beginning 20 min after administration of U-37883A
in dose of 5 mg/kg iv or sodium meclofenamate in a dose of 5 mg/kg iv.
n, no. of animals. * Response is
significantly different from control.
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The role of cyclooxygenase products in mediating or modulating
responses to histamine was investigated in the hindlimb vascular bed,
and these data are shown in Fig. 6. Sodium meclofenamate in a dose of 5 mg/kg iv significantly increased systemic arterial and hindlimb
perfusion pressures (Table 2). After administration of the
cyclooxygenase inhibitor sodium meclofenamate, the increase in hindlimb
perfusion pressure in response to histamine was not altered, whereas
the vasodilator response to the prostaglandin precursor arachidonic
acid was attenuated (Fig. 6).
Influence of phentolamine and candesartan.
The role of -adrenergic receptors in mediating hindlimb
vasoconstrictor responses to histamine was investigated, and these data
are summarized in Fig. 7. Administration of
phentolamine in a dose of 200 µg/kg iv significantly reduced systemic
arterial and hindlimb perfusion pressures (Table 2). After
administration of the -adrenergic-receptor blocking agent, increases
in perfusion pressure in response to histamine were not altered,
whereas the vasoconstrictor response to norepinephrine was
significantly reduced in the hindlimb vascular bed (Fig. 7).
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Fig. 7.
A: effect of -adrenergic receptor
antagonist phentolamine on increases in hindlimb perfusion pressure in
response to histamine and to norepinephrine.
B: effect of angiotensin
AT1-receptor antagonist
candesartan on increases in perfusion pressure in response to histamine
and angiotensin II. Responses to the agonists were compared before and
beginning 20 min after administration of phentolamine in a dose of 200 µg/kg iv and candesartan in a dose of 1 mg/kg iv.
n, no. of animals. * Response is
significantly different from control.
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The role of angiotensin AT1
receptors in mediating the response to histamine was investigated.
Administration of candesartan in a dose of 1 mg/kg iv did not alter
systemic arterial or hindlimb perfusion pressure (Table 2). After
administration of the AT1-receptor antagonist, vasoconstrictor responses to histamine were not changed, whereas hindlimb vasoconstrictor responses to angiotensin II were significantly reduced (Fig. 7).
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DISCUSSION |
Results of the present study show that intravenous injections of
histamine produced dose-dependent decreases in systemic arterial pressure that were attenuated by the
H1-receptor antagonist pyrilamine but were not altered by the
H2-receptor antagonist cimetidine. The systemic vasodepressor response to histamine was followed by a
delayed vasoconstrictor response in the hindlimb vascular bed. The
reason for the delay between the systemic response and the response in
the hindlimb vascular bed may be accounted for by the time necessary
for histamine to reach the hindlimb circulation through the perfusion
circuit. Injections of histamine into the hindlimb vascular bed
produced rapid dose-dependent vasoconstrictor responses that were
blocked by the H1-receptor
antagonist but not by the
H2-receptor antagonist. Slow
infusions of histamine into the hindlimb perfusion circuit produced
slowly developing increases in perfusion pressure that were blocked by
pyrilamine. These data indicate that an
H1-receptor mediated-increase in
perfusion pressure is the predominant response to histamine in the
hindlimb circulation and that a slowly developing
H2-receptor-mediated vasodilator
response was not observed. These data suggest that histamine produces
both a decrease in systemic arterial pressure and an increase in
hindlimb perfusion pressure, and these responses are mediated by the
activation of H1 receptors.
After H1-receptor blockade, a
small but significant vasodilator response was observed in response to
the 3- and 10-µg doses of histamine in the hindlimb vascular bed.
This small vasodilator response may be due to activation of the
H2 receptor, which is reported to
mediate a vasodilator response in the rabbit (2, 11, 24, 28). These
data are consistent with results showing that dimaprit produced
dose-dependent vasodilator responses that were blocked by cimetidine in
the hindlimb vascular bed. These results suggest that
H2 receptors are present in the
hindlimb circulation of the rabbit and may be interpreted to suggest
that histamine has greater affinity for the
H1 receptor in this vascular bed.
These findings are in agreement with earlier studies in isolated arterial strips from the rabbit and in the rabbit hindlimb vascular bed
(3, 17, 24). However, the results of the present study are in contrast
to earlier studies in the rabbit in which intravenous injections of
histamine produced a biphasic change in systemic arterial pressure with
the H1 receptor mediating the
pressor component and the H2
receptor mediating the depressor component of the response (2, 10, 11).
The reason for the differences in response to histamine is uncertain
but may be explained by differences in anesthetic used and experimental
procedure employed. Biphasic changes in systemic arterial pressures in
the rabbit were observed in animals anesthetized with urethan (1-3
µg/kg iv), and biphasic changes in hindlimb vascular resistance were
observed in conscious rabbits using a Doppler flow probe placed around
the distal abdominal aorta (2, 11). The relative contribution of
changes in cardiac output and total peripheral resistance to the
decrease in systemic arterial pressure in response to intravenous
injections of histamine in the present study is unknown because cardiac
output was not measured.
The mechanisms mediating hemodynamic responses to histamine appear to
vary with species and vascular bed studied (6, 7, 16, 20). It has been
reported that relaxation of vascular smooth muscle in response to
histamine is brought about by activation of the
H1 receptor, which results in the
release of endothelium-derived relaxing factor or
PGI2, although this is
controversial (29, 33, 36).
H2-receptor activation is reported
to increase cAMP levels, but it has recently been shown that
H2-receptor activation results in
the release of nitric oxide in the hindlimb vascular bed of the cat
(12, 17). The results of the present study show that
H2-receptor activation produces
vasodilation in the hindlimb vascular bed of the rabbit under
constant-flow conditions. Inasmuch as vasodilator responses to dimaprit
were not altered after administration of the nitric oxide synthase
inhibitor L-NAME, these data
suggest that the release of nitric oxide from the vascular endothelium
does not mediate a significant portion of the response. Moreover, the
observation that responses to dimaprit were not altered by the
K+ATP- channel antagonists U-37883A or
glibenclamide or the cyclooxygenase inhibitor sodium meclofenamate suggests that responses to the
H2-receptor agonist are not
mediated by the opening of K+ATP channels
or the release of vasodilator prostaglandins in the hindlimb vascular
bed of the rabbit. Based on the data in the present study, however, the role of cAMP via a direct activation of adenylate cyclase or the hyperpolarization of vascular smooth muscle by the opening of other
K+ channels cannot be ruled out.
H3-receptor activation has been
reported to inhibit adrenergic neurotransmission, histamine synthesis,
and release from histaminergic neurons, and it also has been shown to
produce a vasodilation in the pulmonary and hindlimb vascular bed of
the cat and to decrease systemic arterial pressure in the guinea pig
(4, 12, 26, 30). The existence of
H3 receptors in the hindlimb
vascular bed of the rabbit are uncertain. Results of the present study demonstrate that at doses of up to 300 µg the
H3-selective-receptor agonist
R-()--methylhistamine produces no measurable change in
hindlimb perfusion pressure. Moreover, the
H3-selective-receptor antagonist
thioperamide in doses up to 30 mg/kg iv did not alter responses to
histamine. It has been previously reported that the effective dose of
thioperamide in other species is 3 mg/kg iv, and future studies with
other H3-selective-receptor
agonists and antagonists are required to test the hypothesis that
H3 receptors are not involved in
mediating vascular responses to histamine in the rabbit (12).
The hypothesis that histamine elicits vasoconstriction in the hindlimb
vascular bed of the rabbit by releasing vasoconstrictor products in the
cyclooxygenase pathway was investigated, and administration of sodium
meclofenamate in a dose that antagonized responses to the prostaglandin
precursor arachidonic acid did not alter vasoconstrictor responses to
histamine. These data suggest that release of cyclooxygenase products
is not involved in mediating or modulating responses to histamine in
the hindlimb circulation of the rabbit. Experiments with the
angiotensin AT1-receptor
antagonist candesartan and the -receptor antagonist phentolamine in
doses that attenuated responses to angiotensin II and norepinephrine
show that vasoconstrictor responses to histamine were not altered and
suggest that responses to histamine in the hindlimb vascular bed of the
rabbit are not mediated through activation of angiotensin
AT1 or -adrenergic receptors.
In a recent study in isolated smooth muscle cells from rabbit
mesenteric artery, activation of the
H1 receptor by histamine was found
to inhibit K+ATP channels, leading to depolarization and vasoconstriction (9). However, in the
present study, the K+ATP-channel
antagonists U-37883A or glibenclamide in a dose that attenuated the
response to the K+ATP-channel opener
levcromakalim did not change the hindlimb vasoconstrictor response to
histamine. These data suggest that responses to histamine are not
mediated or modulated by changes in
K+ATP-channel activity in resistance vessel elements in the hindlimb vascular bed of the rabbit. The role of
nitric oxide in modulating hindlimb vasoconstrictor responses to
histamine was investigated in experiments with
L-NAME. The administration of
the nitric oxide synthase inhibitor in a dose that attenuated
vasodilator responses to acetylcholine enhanced hindlimb
vasoconstrictor responses to histamine and HTMT. However, because
hindlimb vasoconstrictor responses to norepinephrine were also
increased, the enhanced response to histamine and HTMT is not specific
for H1-receptor-mediated responses
in the rabbit hindlimb.
In summary, results of the present investigation show that histamine
produces both a decrease in systemic arterial pressure and an increase
in hindlimb perfusion pressure in the rabbit. Both systemic
vasodepressor and hindlimb vasoconstrictor responses were blocked by
the H1-receptor antagonist
pyrilamine, whereas the
H2-receptor antagonist cimetidine
had little if any effect. These results suggest that
H1 receptors mediate systemic
vasodepressor and hindlimb vasoconstrictor responses in the rabbit,
with the H2 receptor playing
little if any role. Vasoconstrictor responses to histamine in the
hindlimb vascular bed were not attenuated by meclofenamate,
phentolamine, candesartan, or U-37883A, suggesting that the release of
prostaglandins, activation of -adrenergic or angiotensin
AT1 receptors, or alterations in
K+ATP-channel activity do not mediate or
modulate the hindlimb vasoconstrictor response to histamine in the
rabbit. The present data suggest that histamine
H1 receptors mediate different
responses in the systemic and hindlimb vascular beds in the rabbit.
Perspectives
The results of the present study show that histamine decreases systemic
arterial pressure and increases hindlimb vascular resistance in the
rabbit. The finding that both systemic vasodepressor and hindlimb
vasoconstrictor responses to histamine are attenuated by pyrilamine
indicates that they are mediated by the activation of
H1 receptors. These data
demonstrate that histamine
H1-receptor activation can produce
opposite responses in different regions of the circulation. In addition
to producing an unusual
H1-receptor-mediated hindlimb
vasoconstrictor response, this response is not dependent on the
activation of angiotensin AT1 or
-adrenergic receptors, or changes in
K+ATP-channel activity, or the release of
cyclooxygenase products. The data suggest that the
H1 receptor can be linked to
different signaling mechanisms in different vascular beds.
| |
ACKNOWLEDGEMENTS |
We thank Janice Ignarro for editorial assistance.
| |
FOOTNOTES |
This study was supported in part by a grant from the American Heart
Association-Louisiana. H. C. Champion was supported by the National
Heart, Lung, and Blood Institute Grant HL-09474.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. J. Kadowitz,
Dept. of Pharmacology SL83, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112.
Received 2 March 1999; accepted in final form 12 May 1999.
| |
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