© 1996 American Heart Association, Inc.
Articles |
Activation of Histamine H3-Receptors Inhibits Carrier-Mediated Norepinephrine Release During Protracted Myocardial Ischemia
Comparison With Adenosine A1-Receptors and 
2-Adrenoceptors
Presented as preliminary data at the Experimental Biology '95 meeting in Atlanta, Ga, and published in abstract form (FASEB J. 1995;9:A9).
From the Department of Pharmacology, Cornell University Medical College, New York, NY.
Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi@med.cornell.edu.
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Abstract |
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Abstract We previously showed that prejunctional histamine H3-receptors downregulate norepinephrine exocytosis, which is markedly enhanced in early myocardial ischemia. In the present study, we investigated whether H3-receptors modulate nonexocytotic norepinephrine release during protracted myocardial ischemia. In this setting, decreased pHi in sympathetic nerve endings sequentially leads to a compensatory activation of the Na+-H+ antiporter (NHE), accumulation of intracellular Na+, reversal of the neuronal uptake of norepinephrine, and thus carrier-mediated release of norepinephrine. Accordingly, norepinephrine overflow from isolated guinea pig hearts undergoing 20-minute global ischemia and 45-minute reperfusion was attenuated
80% by desipramine (10 nmol/L) and 70%
by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA, 10
µmol/L), inhibitors of norepinephrine uptake
and NHE, respectively. The H3-receptor agonist imetit (0.1
µmol/L) decreased carrier-mediated norepinephrine
release by 50%. This effect was blocked by the
H3-receptor antagonist thioperamide (0.3
µmol/L), indicating that H3-receptor activation inhibits
carrier-mediated norepinephrine release. At lower
concentrations, imetit (10 nmol/L) or EIPA (3 µmol/L) did not inhibit
carrier-mediated norepinephrine release. However, a
25% inhibition occurred with imetit (10 nmol/L) and EIPA (3 µmol/L)
combined. This synergism suggests an association between
H3-receptors and NHE. Conceivably, activation of
H3-receptors may lead to inhibition of NHE. In fact,
2-adrenoceptor activation, which is known to stimulate
NHE, enhanced norepinephrine release, whereas
2-adrenoceptor blockade attenuated it. Furthermore,
activation of adenosine A1-receptors markedly
attenuated norepinephrine release, whereas their inhibition
potentiated it. Because norepinephrine release directly
correlated with the severity of reperfusion arrhythmia and
imetit reduced the incidence of ventricular fibrillation by
50%, our findings with H3-receptor agonists may further
the development of novel pharmacological means to reduce reperfusion
arrhythmias in the clinical setting.
Key Words: ischemia/reperfusion • norepinephrine release • histamine H3-receptors • adenosine A1-receptors • 2-adrenoceptors • arrhythmias
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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We have recently reported the presence of histamine H3-receptors on sympathetic nerve terminals in the heart.1 We found that their activation by an endogenous ligand, most likely histamine, leads to the attenuation of norepinephrine exocytosis in pathophysiological conditions associated with enhanced adrenergic activity, such as acute myocardial ischemia.2
Protracted myocardial ischemia causes an even greater release of norepinephrine from sympathetic nerves. In this case, excessive norepinephrine release is "carrier mediated" rather than exocytotic.3 4 It is caused by a reversal of the carrier responsible for the reuptake of norepinephrine by nerve endings.3 4 5 Exaggerated norepinephrine release increases oxygen demand by stimulating heart rate and contractility and decreases oxygen supply by constricting the coronary vessels.6 This accelerates the progression of cell damage in the ischemic area and border zones and potentiates the arrhythmogenicity of norepinephrine.6 7 Therefore, limiting norepinephrine release and its dysfunctional consequences is of vital importance.
The purpose of the present study was to assess the potential
of H3-receptor activation as a novel way to attenuate
norepinephrine release in protracted myocardial
ischemia. In this context, we compared the effectiveness of the
H3-receptor with that of other prejunctional modulatory
receptors, namely, the 2-adrenoceptor and the
adenosine A1-receptor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Ischemia/Reperfusion Experiments
Male Hartley guinea pigs (Hilltop, Pa) weighing 250 to 300 g were killed by cervical dislocation under light anesthesia with CO2 vapor. After midline thoracotomy, the heart was rapidly excised and perfused retrogradely at a constant pressure of 40 cm H2O in a Langendorff apparatus with Ringer's solution at 37°C saturated with 100% O2 (pH 7.5).8 The composition of the Ringer's solution was (mmol/L) NaCl 154.0, KCl 5.61, NaHCO3 5.55, CaCl2 2.16, and dextrose 5.95 (pH 7.5). As previously described,2 hearts were first perfused with oxygenated Ringer's solution for 30 to 45 minutes until heart rate, left ventricular contractile force, and coronary flow reached a steady state. Heart rate was determined from surface electrograms recorded from the right atrium and the left ventricle. Isometric left ventricular contractile force was measured with a force-displacement transducer (model FT03, Grass) and continuously recorded on a polygraph.
After a 30-minute preischemic stabilization period, normothermic global ischemia was induced by complete interruption of coronary perfusion for 20 minutes. This was followed by a 45-minute reperfusion period. The coronary effluent was collected into tubes. In the preischemic period, tubes were replaced every 5 minutes. In the first 10 minutes of reperfusion, tubes were replaced every 2 minutes and every 5 minutes during the last 35 minutes. The volume of effluent collected for each period was measured and subsequently analyzed for norepinephrine and histamine content. All drugs were added to the perfusion solution. Hearts were perfused with a given drug or drug combination for the entire duration of the experiment, beginning 30 minutes before global ischemia. Hearts were weighed at the end of the experiment.
In the absence of drugs (ie, in control conditions), preischemic left ventricular contractile force and coronary flow were 3.3±0.2 g and 4.9±0.3 mL/min (n=10), respectively. After global ischemia, when cardiac standstill occurred, contractile force slowly recovered during reperfusion and reached a maximum of 72±3% of preischemic control. Coronary flow increased by 44±7% over preischemic values during the first 2 minutes of reperfusion; it then slowly decreased to a level 17±4% below preischemic values, which was reached by 45 minutes of reperfusion.
Norepinephrine and Histamine Assays
Norepinephrine and
histamine were assayed in
the coronary perfusate by high-performance
liquid chromatography coupled to electrochemical
detection and by a commercial enzyme immunoassay kit (Immunotech
International), respectively, as previously described.2
Values are expressed in picomoles per gram of wet heart weight.
Briefly, perchloric acid and EDTA were added to samples to achieve
final concentrations of 0.01N and 0.025%, respectively. After a short
period of storage (<2 weeks) at -70°C, the samples were
thawed. The norepinephrine present in the effluent was
adsorbed on acid-washed alumina adjusted at pH 8.6 with Tris/2%
EDTA buffer and then extracted into 150 µL of 0.1N perchloric acid.
These final sample aliquots were kept frozen until injected onto a
3-µm ODS reverse-phase column (3.2x100 mm, Bioanalytical
Systems, Inc) with an applied potential of 0.65 V. The mobile phase
consisted of monochloroacetic acid (75 mmol/L), Na2EDTA
(0.5 mmol/L), sodium octylsulfate (0.5 mmol/L), and acetonitrile
(1.5%) at pH 3.0. The flow rate was 1.0 mL/min. Dihydroxybenzylamine
was added to each sample as an internal standard before alumina
extraction and used for recovery calculation. The recovery of
norepinephrine was 77%, and the detection limit was 0.2
pmol. The histamine present in the coronary effluent was
assayed with the use of a commercial enzyme immunoassay kit (Immunotech
International Co). The recovery of histamine was 100%, and the
detection limit was 0.02 pmol.
Statistics
Values are expressed as mean±SEM.
Comparison of more than
two groups was performed by ANOVA, with the Bonferroni t
test used for post hoc analysis. A value of P<.05
was considered statistically significant. The Yates' corrected
2 test was used to analyze the difference
in the incidence of arrhythmias.
Drugs
The selective H3-receptor agonist imetit and
the selective adenosine A1-receptor
antagonist N-0861 were gifts of Prof C.R. Ganellin,
Department of Chemistry, University College, London, UK, and of Whitby
Research, Inc, respectively.
5-(N-Ethyl-N-isopropyl)-amiloride (EIPA),
N6-cyclopentyladenosine (CPA), idazoxan
hydrochloride, (-)norepinephrine bitartrate,
rauwolscine hydrochloride, and UK 14,304 were purchased from Research
Biochemicals International. Yohimbine hydrochloride and desipramine
hydrochloride were purchased from Sigma Chemical Co. Thioperamide
maleate was purchased from Cookson Chemicals. EIPA, desipramine,
thioperamide, and UK 14,304 were dissolved in 99.8% dimethyl
sulfoxide, and further dilutions were made with perfusion buffer. At
the concentration used (ie, 0.1%), dimethyl sulfoxide had no effect on
any preparation in these studies. N-0861 was dissolved in 95% ethanol.
Other drugs were dissolved in water.
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Norepinephrine Overflow From Isolated Hearts Subjected to Ischemia and Reperfusion
The cumulative norepinephrine overflow during the 45-minute reperfusion of isolated guinea pig hearts subjected to global ischemia for 20 minutes rose from an undetectable level to 798±60 pmol/g (mean±SEM, n=5). Most of the norepinephrine was released in the first 10 minutes of reperfusion (Fig 1
, inset). During reperfusion, there
was also a marked increase in histamine overflow. In the first 2
minutes, histamine overflow into the coronary effluent
increased fourfold (5.1±1.0 pmol/g per minute) over the
preischemic level (1.2±0.2 pmol/g per minute) and then
declined to approximately twofold (2.4±0.4 pmol/g per minute) in the
following 4 minutes (n=5).
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Ischemia/Reperfusion, Norepinephrine Overflow,
and Its Pharmacological Modulation: Effects of
Norepinephrine Neuronal Reuptake Blockers and
Na+-H+ Exchange
Inhibitors
Desipramine (10 nmol/L), a blocker of norepinephrine
neuronal reuptake, suppressed norepinephrine overflow
during reperfusion after 20-minute global ischemia in isolated
guinea pig hearts (Fig 1
). The
Na+-H+ exchanger
inhibitor EIPA (10 µmol/L) also markedly decreased
norepinephrine overflow caused by
ischemia/reperfusion (Fig 1). In the absence of drugs, the
incidence of ventricular fibrillation during reperfusion
was 100%. In contrast, no fibrillation occurred in hearts perfused
with desipramine or EIPA.
Ischemia/Reperfusion, Norepinephrine Overflow,
and Its Pharmacological Modulation: Effects of Histamine
H3-Receptor Agonists
The selective histamine
H3-receptor agonist imetit
(0.1 µmol/L) markedly decreased (50%) norepinephrine
overflow during reperfusion after 20-minute global ischemia in
isolated guinea pig hearts (Fig 2A). The selective
histamine H3-receptor antagonist thioperamide
(0.3 µmol/L) did not by itself affect norepinephrine
overflow during reperfusion; however, thioperamide prevented the
inhibitory effect of imetit (Fig 2A). Since both EIPA and
imetit attenuated norepinephrine overflow during
reperfusion, we tested whether H3-receptor stimulation
might be coupled to inhibition of the Na+-H+
exchanger. For this, we evaluated the effects of subthreshold
concentrations of EIPA and imetit added in combination. As shown in Fig
2B, neither imetit at 10 nmol/L nor EIPA at 3 µmol/L
affected
norepinephrine overflow. In combination, however, both
compounds significantly decreased norepinephrine overflow
(by 25%) during reperfusion.
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Ischemia/Reperfusion, Norepinephrine Overflow,
and Its Pharmacological Modulation: Effects of
2-Adrenoceptor Agonists and
Antagonists
The 2-adrenoceptor agonist UK 14,304 (10
µmol/L)
significantly potentiated (by 30%) norepinephrine overflow
during reperfusion after 20-minute global ischemia in isolated
guinea pig hearts (Fig 3A). The
2-adrenoceptor antagonist yohimbine (1
µmol/L) prevented the potentiating effect of UK 14,304. Furthermore,
yohimbine by itself markedly decreased norepinephrine
overflow (by 50%) and so did two other 2-adrenoceptor
antagonists: rauwolscine (1 µmol/L), which is
structurally similar to yohimbine, and idazoxan (10 µmol/L), which is
unrelated to yohimbine (Fig 3A); the inhibition with
rauwolscine
and idazoxan was 30% and 40%, respectively. Shown in Fig 3B is
the
finding that subthreshold concentrations of yohimbine (30 nmol/L) and
EIPA (3 µmol/L), which by themselves did not influence
norepinephrine overflow, significantly attenuated
norepinephrine overflow (by 35%) when added in
combination.
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Ischemia/Reperfusion, Norepinephrine Overflow,
and Its Pharmacological Modulation: Effects of Adenosine
A1-Receptor Activation and Blockade
The selective adenosine
A1-receptor agonist
CPA (0.1 µmol/L) markedly decreased norepinephrine
overflow (by 75%) during reperfusion after 20-minute global
ischemia in isolated guinea pig hearts (Fig 4A).
The selective adenosine A1-receptor
antagonist N-0861 (5 µmol/L) prevented the
inhibitory effect of CPA. Furthermore, N-0861 by itself
enhanced norepinephrine overflow by 40%. Shown in Fig 4B
is the finding that subthreshold concentrations of CPA (3 nmol/L) and
EIPA (3 µmol/L), which by themselves did not influence
norepinephrine overflow, significantly attenuated it (by
35%) when added in combination.
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Effects of H3-Receptor, 2-Adrenoceptor,
and A1-Receptor Ligands on Reperfusion
Arrhythmias
After 20-minute global ischemia, ventricular
fibrillation invariably occurred in all control hearts at the beginning
of reperfusion and persisted for 3.05±0.74 minutes (n=14). The
effects
of H3-receptor, 2-adrenoceptor, and
A1-receptor ligands on the incidence of
ventricular fibrillation are presented in Fig 5. The selective
histamine H3-receptor
agonist imetit (0.1 µmol/L) decreased the incidence of
ventricular fibrillation by 50%. This effect was prevented
by the selective H3-receptor antagonist
thioperamide (0.3 µmol/L, Fig 5A). As shown in Fig
5B and 5C, the
2-adrenoceptor antagonist yohimbine (1
µmol/L) and the selective adenosine A1-receptor
agonist CPA (0.1 µmol/L) each prevented the occurrence of
ventricular fibrillation. The effect of yohimbine was
counteracted by the concomitant administration of the
2-adrenoceptor agonist UK 14,304 (10 µmol/L, Fig
5B),
whereas the effect of CPA was abolished by the selective
adenosine A1-receptor antagonist N-0861
(5 µmol/L).
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Shown in Fig 6 is the relationship
between
norepinephrine overflow and duration of
ventricular fibrillation in 51 hearts subjected to
20-minute global ischemia followed by 45-minute reperfusion
either in the absence or in the presence of various drugs. It is
evident that the arrhythmia lasted progressively longer as the
norepinephrine overflow increased. Moreover, agents that
increased norepinephrine release by 50%, either via
2-adrenoceptor stimulation or adenosine
A1-receptor blockade, more than doubled the duration of
ventricular fibrillation. In contrast, agents that
stimulate histamine H3- and adenosine
A1-receptors or block 2-adrenoceptors,
norepinephrine neuronal uptake (uptake1), and
Na+-H+ exchanger all decreased
norepinephrine release and shortened or abolished
ventricular fibrillation.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Our data clearly indicate that histamine H3-receptor activation attenuates carrier-mediated norepinephrine release caused by protracted myocardial ischemia and suggest that this effect may be associated with an inhibition of the Na+-H+ exchanger in sympathetic nerve endings. Analogous to histamine H3-receptor activation,
2-adrenoceptor blockade and adenosine
A1-receptor stimulation also attenuated
carrier-mediated norepinephrine release, most likely by
inhibiting the Na+-H+ exchanger. Whatever the
pharmacological agent used to positively or negatively modulate
norepinephrine release, we consistently found that
as the norepinephrine overflow increased or decreased from
control levels, reperfusion arrhythmias became more or less
severe, respectively, thus implicating norepinephrine
release as a major cause of reperfusion arrhythmias.
We found that subjecting isolated guinea pig hearts to global
ischemia for 20 minutes greatly augmented
norepinephrine overflow during reperfusion. Depending on
the length of the ischemic episode, different mechanisms are
likely to mediate the enhancement in norepinephrine
release. Relatively short ischemic periods (ie, 10 minutes)
are thought to augment norepinephrine exocytosis from
adrenergic nerves.3 With longer-lasting
ischemia (ie, 20 minutes), metabolically
deprived ion pumps fail and H+ accumulates in sympathetic
nerve endings, leading to a compensatory activation of the
Na+-H+ antiporter and intracellular
Na+ accumulation.3 4 This, coupled
with a
decreased vesicular storage of norepinephrine and its
consequent accumulation in the axoplasm, causes a reversal of
uptake1, such that norepinephrine is
actively carried out of the sympathetic nerve terminal
(carrier-mediated norepinephrine
release).3 4 5 With more protracted
ischemia (ie,
>30 minutes), cell lysis occurs, and norepinephrine leaks
out of the neurons.3
Having previously demonstrated that histamine H3-receptors
attenuate the enhancement in norepinephrine exocytosis,
which occurs after 10-minute global ischemia,2 we
have now assessed whether H3-receptor activation modifies
the marked increase in norepinephrine overflow that follows
20-minute global ischemia and is accompanied by severe
reperfusion arrhythmias. That a reversal of the neuronal
norepinephrine uptake was the cause of this release was
verified by the finding that the norepinephrine transport
inhibitor desipramine blocked the increase in overflow (see
Fig 1). If enhanced exocytosis had been the mechanism involved
in the
increased release of norepinephrine in these studies, then
desipramine would have potentiated norepinephrine
overflow.2 Moreover, that an activation of the
Na+-H+ exchanger created the conditions that
favored a reversal of the neuronal uptake was demonstrated by our
finding that the antiporter inhibitor EIPA blocked the
increase in norepinephrine overflow (see Fig 1). Notably,
desipramine and EIPA each prevented the occurrence of reperfusion
arrhythmias. The fact that a marked attenuation of
norepinephrine release coincided with the absence of
arrhythmias implicates norepinephrine as a major
cause of reperfusion arrhythmias. Indeed, we found that the
severity of reperfusion arrhythmias was directly associated
with an increase in norepinephrine overflow (see Fig 6).
The selective histamine-H3 receptor agonist imetit9 markedly attenuated the increase in norepinephrine release that occurred during reperfusion after 20-minute global ischemia and that was due to the reversal of uptake1. Because the selective H3-receptor antagonist thioperamide10 prevented the effects of imetit, our findings indicate that activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release. These modulatory receptors are most likely located on sympathetic nerve endings, since their presence can be directly demonstrated in isolated adrenergic terminals (ie, cardiac synaptosomes).1 As to the mechanism of the H3-receptor–mediated inhibition of norepinephrine release in the setting of protracted myocardial ischemia, our data suggest an association between H3-receptor activation and Na+-H+ antiport inhibition. Indeed, we found that subthreshold concentrations of imetit and EIPA acted synergistically to significantly reduce norepinephrine release when added in combination.
We also found that activation of adenosine
A1-receptors markedly attenuated norepinephrine
release, whereas their inhibition potentiated it. Furthermore,
subthreshold concentrations of the adenosine
A1-receptor agonist CPA and the antiporter
inhibitor EIPA markedly inhibited
norepinephrine overflow when added in combination (see Fig 4B).
Thus, it is possible that the adenosine
A1-receptor–induced inhibition of carrier-mediated
norepinephrine release involves an antagonism of the
Na+-H+ exchanger, similar to what we postulate
for the histamine H3-receptor.
The hypothesis that the H3-receptor–mediated
inhibition of carrier-mediated norepinephrine release
involves a decrease in the Na+-H+ exchanger
activity is further supported by our findings with selective ligands
for 2-adrenoceptors. Indeed, 2-receptor
activation, which has been previously associated with a stimulation of
the Na+-H+ exchanger,11 enhanced
norepinephrine release. This action was inhibited by
2-adrenoceptor blockade (see Fig 3A). Moreover,
2-adrenoceptor blockade by itself inhibited the
norepinephrine overflow caused by
ischemia/reperfusion, an indication that
norepinephrine released in this condition activates
prejunctional 2-adrenoceptors and thus the antiporter.
Indeed, subthreshold concentrations of the
2-adrenoceptor blocker yohimbine and the antiporter
inhibitor EIPA markedly inhibited
norepinephrine overflow when added in combination (see Fig 3B).
To date, very little is known regarding the transductional mechanisms
involved in the effects mediated by histamine H3-receptors.
In a gastric epithelial tumor cell line, activation of
H3-receptors was tied to the inhibition of
phosphoinositide metabolism.12
It is conceivable that during prolonged myocardial ischemia,
H3-receptor activation may also lead to the inhibition of
phosphoinositide turnover in sympathetic nerve endings,
which would result in a decrease in protein kinase C activity and
inhibition of the Na+-H+ antiporter. Inasmuch
as selective adenosine A1-agonists reportedly
inhibit phosphoinositide turnover in neural
tissue,13 adenosine A1-receptors could
also attenuate carrier-mediated norepinephrine release
by inhibiting the antiporter. Conversely, the stimulation of
norepinephrine release by 2-adrenoceptor
activation, and its inhibition by 2-adrenoceptor
blockade, could be explained by the reported
2-adrenoceptor–induced stimulation of the
antiporter.11
During reperfusion, there was a marked increase in the overflow of
histamine into the coronary effluent. Accordingly, we would
have assumed H3-receptors to be activated by the
endogenous ligand, similar to what we had previously
observed in hearts subjected to 10-minute global
ischemia.2 However, the H3-receptor
antagonist thioperamide did not by itself potentiate
norepinephrine overflow after 20-minute global
ischemia (see Fig 2A), suggesting a lack of
H3-receptor activation. The finding that thioperamide
potentiated exocytotic,2 but not carrier-mediated,
norepinephrine overflow could be interpreted as an
indication that two subsets of H3-receptors, with different
affinities and perhaps transductional mechanisms, may be involved in
the modulation of exocytotic and carrier-mediated
norepinephrine release. The first subset could be coupled
to N-type Ca2+ channels via a pertussis
toxin–sensitive Gi/Go
protein,14 whereas the other could be coupled to the
Na+-H+ exchanger via a G protein,
phospholipase
C, and phosphoinositide turnover.
Accordingly, we hypothesize that high-affinity H3-receptors inhibit the enhanced norepinephrine exocytosis after 10-minute global ischemia. After 20-minute global ischemia, these receptors become desensitized as a result of the more prolonged histamine release. Thus, only nonactivated low-affinity H3-receptors would remain available for stimulation by selective H3-agonists. No potentiation of carrier-mediated norepinephrine release occurred with selective H3-receptor antagonists, because according to this hypothesis, low-affinity H3-receptors would not be occupied by endogenous histamine. Nevertheless, imetit, which has a 60-fold higher affinity for the H3-receptor than does histamine,9 is still able to bind to the low-affinity H3-receptors and inhibit norepinephrine release. The existence of two H3-receptor subtypes has indeed been proposed in other tissues.15 16 Whether these receptor subtypes exist in cardiac adrenergic nerve terminals and whether they may operate via distinct signal transduction mechanisms remain to be determined.
H3-receptor activation markedly reduced the incidence of
ventricular fibrillation during reperfusion and greatly
shortened its duration in the remaining cases, demonstrating that these
modulatory receptors mitigate the dysfunctional consequences of
prolonged myocardial ischemia. Moreover,
2-adrenoceptor blockade and adenosine
A1-receptor activation prevented reperfusion
arrhythmias. Because all of these antiarrhythmic effects
coincided with a marked reduction in norepinephrine
overflow, our findings highlight the importance of nonexocytotic
norepinephrine release17 in the generation of
reperfusion arrhythmias.
Activation of adenosine A1-receptors with CPA
caused a greater inhibition of norepinephrine release than
did activation of H3-receptors with imetit (compare Figs
2A and 4A). Also, the effect of CPA in
combination with EIPA was greater
than that of imetit in combination with EIPA (compare Figs 2B
and 4B).
This could be interpreted to suggest that adenosine plays a
more important role than histamine in negatively modulating
carrier-mediated norepinephrine release in protracted
ischemia/reperfusion, possibly because high-affinity
H3-receptors have become desensitized in these conditions.
Nevertheless, the availability of low-affinity
H3-receptors would still enable the use of potent
H3-agonists for the prevention of reperfusion
arrhythmias.
Indeed, although H3- and adenosine
A1-receptor stimulation, as well as
2-adrenoceptor blockade, reduced carrier-mediated
norepinephrine release, H3-receptor stimulation
may be more advantageous than adenosine A1-receptor
activation or 2-adrenoceptor blockade. Unlike
adenosine A1-receptor stimulation,18
H3-receptor activation has no negative chronotropic and
dromotropic effects. Furthermore, H3-receptors modulate
both exocytotic2 and carrier-mediated
norepinephrine release associated with acute and protracted
myocardial ischemia, respectively. In contrast,
2-adrenoceptor blockade inhibits carrier-mediated
norepinephrine release but enhances
norepinephrine exocytosis.2
Thus, we have found a very strong correlation between the amount of norepinephrine release and the severity of reperfusion arrhythmias. We have previously reported the presence of H3-receptors on sympathetic nerve endings in the human heart.1 Furthermore, others have demonstrated carrier-mediated norepinephrine release in ischemic human heart specimens.5 Collectively, these findings may further the development of novel pharmacological means to reduce reperfusion arrhythmias in the clinical setting.
In conclusion, histamine H3-receptor activation attenuates both exocytotic1 2 14 and carrier-mediated norepinephrine release associated with acute and protracted myocardial ischemia, respectively. The mechanisms of action are likely to differ. Inhibition of exocytosis probably involves a decreased Ca2+ entry via N-type channels,14 whereas inhibition of carrier-mediated norepinephrine release probably involves an antagonism of the Na+-H+ exchanger.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-34215 and HL-46403. Dr Imamura was a Fellow of the American Heart Association, New York City Affiliate, Inc.
Received September 13, 1995; accepted December 5, 1995.
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