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Vol. 283, Issue 2, 478-487, 1997
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto 390, Japan
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Abstract |
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 Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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We investigated the effects of a neuropeptide, pituitary adenylate cyclase-activating polypeptide- (PACAP) 27, on the sinoatrial nodal pacemaker activity and the mechanisms for the cardiac effects of PACAP-27 in the autonomically decentralized heart of the anesthetized dog. PACAP-27 (0.01-0.3 nmol) injected into the sinus node artery increased followed by decreased sinus rate. PACAP-27 (0.1 and 0.3 nmol) caused atrial fibrillation spontaneously. After atropine, PACAP-27 never decreased but only increased sinus rate as did vasoactive intestinal peptide. However, propranolol did not affect the negative and positive chronotropic effects. Tetrodotoxin but not hexamethonium abolished the negative chronotropic response to PACAP-27 in atropine nontreated dogs, and tetrodotoxin also inhibited the positive chronotropic response by 34% in atropine-treated dogs. In atropine- and propranolol-treated dogs, positive chronotropic responses to PACAP-27 were inhibited by PACAP-(6-27), a PACAP receptor antagonist but not by vasoactive intestinal peptide (10-28), a vasoactive intestinal peptide receptor antagonist. These results indicate that PACAP-27 causes the negative chronotropic effect through the postganglionic parasympathetic nerve activation and it produces the positive chronotropic effect mediated by PACAP receptors with an activation of non-adrenergic, nonvasoactive intestinal peptide-ergic nerves at least in part in the dog heart. Atropine and tetrodotoxin abolished atrial fibrillation induced by PACAP-27 but other blockers did not. These results suggest that neurally released acetylcholine induced by PACAP-27 participates in the induction of atrial fibrillation.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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PACAP
is a newly discovered neuropeptide isolated originally from the ovine
hypothalamus (Miyata et al., 1989
). PACAP is widely distributed in the brain, testis, adrenal gland and gut (Arimura et al., 1991). PACAP acts as a neurotransmitter, a
neuromodulator or a neurotrophic factor in the central nervous system
(Arimura and Shinoda, 1995). However, the precise mechanism of PACAP on peripheral organs including the heart, has not been defined. PACAP is
present in two molecular forms with 38 (PACAP-38) and 27 (PACAP-27) amino acid residues and its N-terminal (1-28) sequence is 68% homologous with VIP (Miyata et al., 1990). PACAP increases
and IP3 mediated by type I, II and III PACAP
receptors and type II and III PACAP receptors are identical with type I
and II VIP receptors, respectively (Shivers et al., 1991;
Ishihara et al., 1992; Lutz et al., 1993;
Spengler et al., 1993; Harmar and Lutz, 1994).
PACAP produced positive inotropic and lusitropic effects in the
isolated neonatal pig heart (Ross-Ascuitto et al., 1993). An
i.v. injection of PACAP increased heart rate in the anesthetized cat
(Minkes et al., 1992) and the conscious rat (Gardiner
et al., 1994), and increased followed by decreased heart
rate in anesthetized dogs (Ishizuka et al., 1992). Recently,
we observed that PACAP-38 increased followed by decreased heart rate in
isolated and perfused dog atria (Yonezawa et al., 1996) and
in anesthetized dogs (Hirose et al., 1997) when PACAP-38 was
administered to the branch of the coronary artery to the SA nodal
region, "sinus node artery." We briefly reported that PACAP-38
decreased heart rate mediated by activation of parasympathetic nerves
and sensitized the atrial fibrillation induced by ACh injection in
anesthetized dog hearts (Hirose et al., 1997). However,
there are little available reports in the heart that determine the
mechanism of the cardiac responses to PACAP. Thus, we tried to
investigate the chronotropic responses to PACAP-27 in the anesthetized
dog heart when a substance was given into the sinus node artery. In the
preliminary experiments, we observed that PACAP-27 was more potent than
PACAP-38 and that at high doses PACAP-27 consistently caused atrial
fibrillation.
It is well known that ACh induces atrial fibrillation when it is
released by activation of vagus nerves or it is applied exogenously in
mammalian hearts (Lewis et al., 1921; Goldenberg and
Rothberger, 1934). However, there is no available report that an
endogenous substance except ACh itself causes atrial fibrillation
although aconitine (Scherf et al., 1948), hypertonic
solution (Chiba et al., 1969) and mechanical interventions
(Rothberger and Winterberg, 1910) can cause atrial fibrillation.
Therefore, first, we verified that PACAP-27 causes atrial fibrillation
in the anesthetized dog heart. Then, to elucidate the mechanism of the
biphasic chronotropic effects and the induction of atrial fibrillation
induced by PACAP-27, we analyzed PACAP-27-induced responses using
pharmacological key drugs including PACAP receptor and VIP receptor
antagonists in the autonomically decentralized heart of the open-chest
anesthetized dog. To determine the direct chronotropic response, we
injected substances directly into the sinus node artery in the
anesthetized dog heart (Hashimoto et al., 1968).
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The animal experiments were approved by the Shinshu University School of Medicine Animal Studies Committee.
Preparation
Forty-three mongrel dogs of either sex, weighing 10 to 28 kg,
were anesthetized with sodium pentobarbital (35 mg/kg i.v.). A tracheal
cannula was inserted and intermittent positive-pressure ventilation was
started by a respirator (Harvard Apparatus, Millis, MA, model 607) with
room air. The chest was opened transversely at the fifth intercostal
space. Cervical vagus nerves were isolated bilaterally via a midline
neck incision and crashed with tight ligature. Each stellate ganglion
was isolated and crashed at its junction with the ansa subclavia. These
maneuvers remove almost all tonic neural activity to the heart (Levy
et al., 1966).
A bipolar electrode was placed on the base of the epicardial surface of the right atrium near the SA node to record electrical activity. Sinus rate was measured and displayed on an oscillograph (Nihon Kohden, Tokyo, Japan, model RTA-1200). The systemic arterial blood pressure was recorded from the left femoral artery by a pressure transducer. The left femoral vein was cannulated for drug injection and for physiological saline infusion to adjust spontaneous fluid losses. To stimulate the intracardiac parasympathetic nerve fibers to the SA nodal region, a bipolar electrode, 1.5 mm interelectrode distance, was placed on the fat pad overlying the right atrial side of the junctions of the pulmonary veins and connected to a stimulator (Nihon Kohden, SEN 7103). This parasympathetic nerve stimulation was applied at 30 Hz with 0.05 msec or less pulse duration and a voltage of 10 V for 30 sec.
The direct perfusion of the sinus node artery was prepared by the
method of Hashimoto et al. (Hashimoto et al.,
1968). A polyethylene tubing (o.d. 2.2 mm) was tapered to fit a
cannula, the tip of which had an outer diameter of 0.5 to 1 mm. A
rubber tubing was connected to the shank of the cannula for the purpose
of injecting drug solutions. The dorsal right atrial artery so called
sinus node artery was carefully isolated from its origin and cannulated with the cannula. Then, it was perfused with heparinized blood from the
right femoral artery. The perfusion pressure could be maintained
constant at 90 mmHg by means of shunting the excess blood to the blood
reservoir through a pneumatic resistance which was placed in parallel
with the perfusion system. The perfusion blood flow rate was measured
in the extracorporeal circuit of the perfusion system by an
electromagnetic flowmeter (Nihon Kohden, MFV-2100). Sodium heparin (500 USP units/kg i.v.) was administered at the beginning of the perfusion
and 200 USP units/kg were given subsequently at 1-hr intervals.
Experimental Protocol
SA nodal pacemaker activity.
We carried out four series of
experiments after 30 min stabilization from the surgical procedures. In
the first series, to examine the effects of PACAP-27 and VIP on the SA
nodal pacemaker activity, we studied the changes in sinus rate in
response to PACAP-27 (0.01-0.3 nmol, n = 6) or VIP
(0.003-0.03 nmol, n = 5) injected into the sinus node
artery of the autonomically decentralized hearts in the open-chest,
anesthetized dogs. Enough recovery time (usually 1 hr after injection
of PACAP-27) has been allowed to avoid the effects of the former
injection of PACAP-27 on the effects of the following injection of
PACAP-27, that is, "tachyphylaxis." PACAP presents tachyphylaxis in
neonatal pig hearts (Ross-Ascuitto et al., 1993).
Atrial Fibrillation. When PACAP-27 at 0.1 or 0.3 nmol was injected into sinus node artery, it usually caused spontaneous atrial fibrillation. Thus, we investigated the incidence of the atrial fibrillation induced by PACAP-27 in autonomically decentralized, open-chest anesthetized dogs. First, we examined the incidence of atrial fibrillation induced by PACAP-27 (0.01-0.3) in the absence of a blocker (n = 6) and in the presence of atropine (0.7 µmol/kg i.v., n = 5) or propranolol (3.4 µmol/kg i.v., n = 6). Second, we studied the effects of hexamethonium (1 µmol, n = 5), TTX (30 nmol, n = 5), phentolamine (355 nmol, n = 3) and PACAP-(6-27) (10 nmol, n = 5) injected into the sinus node artery on the incidence of the PACAP-27-induced atrial fibrillation. Additionally, to test whether intracardiac parasympathetic stimulation induces atrial fibrillation, we stimulated the intracardiac parasympathetic nerves to the SA nodal region at a frequency of 30 Hz for 30 sec in five autonomically decentralized hearts. The pulse duration of the stimulation was selected to evoke similar decreases in sinus rate induced by PACAP-27.
Drugs
Drugs were mixed fresh for each experiment. Pituitary adenylate
cyclase-activating polypeptide 27 (human) (PACAP-27, Peptide Institute
Inc., Osaka, Japan), vasoactive intestinal peptide (human, porcine)
(VIP, Peptide Institute Inc.), vasoactive intestinal peptide 10-28
(human, porcine, rat) (VIP-(10-28), Peninsula Labo. Inc., Belmont, CA)
and pituitary adenylate cyclase-activating polypeptide 6-27 (human,
ovine, rat) (PACAP-(6-27), Peninsula Labo. Inc.) were dissolved in
distilled water and kept frozen at -20°C as stock solutions, and
diluted immediately before use. Acetylcholine chloride (ACh, Daiichi,
Tokyo, Japan), atropine sulfate (Wako Pure Chemicals, Tokyo, Japan),
hexamethonium bromide (Yamanouchi, Tokyo, Japan), TTX (Wako Pure
Chemicals), norepinephrine hydrochloride (Sankyo, Tokyo, Japan),
nicotine bitartrate (Tokyo Kasei Kogyo, Tokyo, Japan) and propranolol
hydrochloride (Sigma Chemical Co., St Louis, MO) were dissolved and
diluted in 0.9% NaCl. Drugs were injected into the sinus node artery
through a rubber tube by a microsyringe (Terumo Co., Tokyo, Japan) or
the left femoral vein. The amount of drug solution injected into the sinus node artery was 0.01 ml in a period of 4 sec, because 0.01 ml of
0.9% NaCl has no effect on the SA nodal pacemaker activity (Hashimoto
et al., 1968).
Statistical Analysis
All data were shown as the maximum change in response to each drug and expressed as mean ± S.E.M. The biphasic chronotropic responses to PACAP-27 were determined at the same phase before and after the treatment with each blocker. To assess the potency of the PACAP-27 and VIP for the increases in sinus rate, the negative log doses causing an increase in sinus rate by 50 beats/min were determined. An analysis of variance with Bonferroni's test was used for the statistical analysis of multiple comparisons of data. Student's t-test for unpaired data was used for comparison between the two groups. Fishers' exact test was used for comparison with the incidence of atrial fibrillation. P < 0.05 were considered statistically significant.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effects of PACAP-27 and VIP on SA nodal pacemaker activity.
PACAP-27 at a dose of 0.03 nmol produced a biphasic effect on sinus
rate characterized by an initial increase followed by decrease in sinus
rate, when it was injected into the sinus node artery of an
autonomically decentralized heart in the open-chest anesthetized dog
(fig. 1A). The negative chronotropic
response to PACAP-27 reached to the maximum level approximately 2 min
after the injection. However, VIP at a dose of 0.03 nmol only increased sinus rate (fig. 1B). When we increased a dose of PACAP-27 to 0.3 nmol,
PACAP-27 decreased atrial cycle length from 500 to 400 msec at 10 sec
after the PACAP-27 injection (fig. 2A and
B) and at 30 sec after the injection, it prolonged the cycle length to 840 msec followed by suddenly and spontaneously induced atrial fibrillation (fig. 2C).
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Effects of propranolol and atropine on a biphasic response to PACAP-27. After propranolol at 3.4 µmol/kg i.v. was given, it abolished the increases (68 ± 9.4 beats/min) in sinus rate in response to norepinephrine at 0.3 or 1 nmol into the sinus node artery of six dogs (table 1I). However, the biphasic effects of PACAP-27 (0.01-0.3 nmol) in propranolol treated dogs were not significantly different from those in nontreated dogs (fig. 3A; table 1I).
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Effects of tetrodotoxin and hexamethonium.
To determine
whether the responses to PACAP-27 are mediated through neural
activation, we examined the effects of TTX on the chronotropic
responses to PACAP-27. TTX at 30 nmol injected into the sinus node
artery abolished the negative chronotropic response to 0.1 nmol of
PACAP-27 (P < .01), and it caused only a positive response in
five hearts (fig. 4A; table 1III). TTX
rather augmented the initial increase in sinus rate when the response
was determined at the same phase before and after treatment with TTX.
TTX also abolished the negative chronotropic response to stimulation of the parasympathetic nerves to the SA nodal region (fig. 4A; table 1III).
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Effects of a high dose of PACAP-27.
To investigate whether the
chronotropic responses to PACAP-27 cause tachyphylaxis, we studied
effects of PACAP-27 at a dose of 0.1 nmol on the chronotropic responses
to PACAP-27 at a dose of 0.03 nmol, ACh at 3 nmol and norepinephrine at
0.3 nmol. PACAP-27 at 0.03 nmol and norepinephrine increased sinus
rate, whereas ACh decreased sinus rate as shown figure
6A. One hour later, 0.1 nmol of PACAP-27
injected into the sinus node artery caused a biphasic effects. After
returning to the pre-drug basal level, the second injection of PACAP-27
at 0.03 nmol only produced the negative chronotropic effect, whereas
the chronotropic responses to norepinephrine and ACh were not changed
(fig. 6A). Summarized data from five dogs are shown in figure 6B and
table 1V. The positive chronotropic responses to 0.03 nmol of PACAP-27
were reversed to the negative one and the negative responses were
potentiated (P < .05) by pretreatment with 0.1 nmol of PACAP-27,
while the responses to ACh and norepinephrine were not affected
significantly.
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Effects of PACAP-(6-27) and VIP-(10-28).
When we examined
the effects of PACAP-(6-27) on the negative chronotropic response to
PACAP-27, PACAP-(6-27) at 10 nmol in five dogs did not affect the
decreases in sinus rate in response to 0.3 nmol of PACAP-27 (fig.
7B; Table 1VI). The negative response was
determined just before the induction of atrial fibrillation.
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A pharmacological analysis of the PACAP-27-induced atrial fibrillation. PACAP-27 in doses of 0.1 and 0.3 nmol induced atrial fibrillation in a dose-dependent manner (P < .01) in six dogs (table 3). PACAP-27 at 0.3 nmol caused atrial fibrillation in all six dogs. The atrial fibrillation evoked by PACAP-27 continued 3 min or more and then spontaneously terminated. The longest duration of the atrial fibrillation was 54 min.
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Effects of PACAP-27 on flow rate of the sinus node artery.
PACAP-27 in doses of 0.01 to 0.3 nmol increased the perfused blood flow
in a dose-dependent manner (P < .005) in six hearts as shown in
figure 9. Control flow rate for 6 dogs to
the sinus node artery is 4 ± 1.3 ml/min.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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PACAP-27 on SA nodal pacemaker activity.
PACAP-27 in doses of
0.01 to 0.3 nmol caused a biphasic dose-dependent chronotropic effect
in the autonomically decentralized dog heart (figs. 1 and 3). PACAP-27
increased sinus rate to more than 180 beats/min in atropine-treated dog
hearts and the order of the potency for the positive chronotropic
response to PACAP-27, PACAP-38, VIP and norepinephrine is VIP > PACAP-27 > norepinephrine > PACAP-38 in the dog heart
(Yonezawa et al., 1996; Hirose et al., 1997).
PACAP-38 at 1 nmol increased sinus rate by 20% followed by decreased
sinus rate by 20%, respectively, in the anesthetized dog heart (Hirose
et al., 1997). Thus, the negative chronotropic response to
PACAP-27 was much greater than that to PACAP-38 and PACAP-27 at a high
dose (0.3 nmol) sometimes caused sinus arrest transiently. ACh at 3 nmol or more into the sinus node artery induced sinus arrest in the
autonomically decentralized dog hearts. Therefore, it is suggested that
PACAP-27 is a very potent endogenous substance on the heart
rhythmicity.
).
A high dose of PACAP-27 did not inhibit the negative chronotropic
response to a low dose of PACAP-27, indicating that the negative
response to PACAP-27 did not present tachyphylaxis (fig. 6).
Additionally, a PACAP receptor antagonist, PACAP-(6-27) did not
inhibit the negative chronotropic response to PACAP-27, although the
blocker attenuated the increases in sinus rate (figs. 7 and 8; table
1). Thus, we suggest that the release of ACh evoked by PACAP-27 is
mediated by the PACAP receptors which are different from the
PACAP-(6-27)-sensitive PACAP receptors although other unknown
mechanisms may exist including direct effects independent of PACAP
receptors, e.g., direct ACh release or direct muscarinic
receptor activation by PACAP-27. In the distal colon of the rat, a
PACAP antagonist, PACAP-(6-38) inhibited the muscle relaxation induced
by electrical field stimulation (Kishi et al., 1996).
However, PACAP-(6-38) did not affect the positive as well as negative
chronotropic responses to PACAP-38 in the isolated, perfused dog atrium
(Yonezawa et al., 1996).
Neither propranolol injected into the sinus node artery did affect the
increase in sinus rate in response to PACAP-27 in atropine-treated dogs
nor intravenous treatment with propranolol affected the biphasic effects of PACAP-27 in nonatropine treated dogs (fig. 3; table 2),
indicating that the positive chronotropic response to PACAP-27 is not
mediated through beta adrenoceptors in the dog heart.
However, a high dose of PACAP-27 attenuated the positive chronotropic
response to a low dose of PACAP-27 (fig. 6; table 1) and PACAP-(6-27) inhibited the positive chronotropic response to PACAP-27 but not to VIP
(figs. 7 and 8; table. 2). However, VIP-(10-28) inhibited the positive
chronotropic response to VIP but not to PACAP-27 (fig. 8; table 2).
From these results, therefore, we suggest that PACAP-27 increases sinus
rate mediated by PACAP receptors that are different from VIP receptors
in the dog heart.
PACAP-27 and PACAP-38 cause several effects mediated through three
types of PACAP receptors (Harmar and Lutz, 1994). The type I PACAP
receptor is subdivided into two subtypes on the basis of binding
studies. PACAP1A receptors bind PACAP-27 with slightly higher affinity
than PACAP-38, although PACAP1B receptors bind PACAP-38 with high
affinity and PACAP-27 with low affinity. The type I PACAP receptor is
coupled to adenylate cyclase and phospholipase C (Spengler et
al., 1993). The type II PACAP receptor is identical with the type
I VIP receptor (Ishihara et al., 1992; Sreedharan et
al., 1995). The type II PACAP receptor binds PACAP-27, PACAP-38 and VIP with similar affinities (Shivers et al., 1991) and
is coupled to only adenylate cyclase (Ishihara et al., 1992;
Spengler et al., 1993). The third type of receptor is
identical to the type II VIP receptor (Lutz et al., 1993)
and three neuropeptides activate the type II VIP receptor with the same
rank order as for stimulation of cAMP production in the cAMP reporter
LVIP cells (Usdin et al., 1994). Therefore, we suggest that
the positive chronotropic response to PACAP-27 is mediated by type I
PACAP receptors, probably PACAP1A or PACAP1A-like receptors in the dog heart. However, we need further studies including the receptor binding
study and measurements of cAMP and IP3 in the dog
heart, because the type I PACAP receptor mRNA was expressed abundantly in the brain, but there was little expression in peripheral tissues (Spengler et al., 1993; Hashimoto et al., 1993).
In our study, tetrodotoxin attenuated the positive chronotropic
responses to PACAP-27 by 34% in atropine-treated dogs (fig. 5; table
2). These results in addition to other our results suggest that
PACAP-27 neurally increases sinus rate in part and the neural activation is nonadrenergic and non-VIP-ergic in the dog heart. From
our results, however, we could not define which receptors mediated the
tetrodotoxin-sensitive positive response to PACAP-27.
Atrial fibrillation induced by PACAP-27.
In our study, we
first demonstrated that PACAP-27 injected into the sinus node artery
caused atrial fibrillation in the autonomically decentralized heart of
the open-chest anesthetized dog (fig. 2; table 3). The atrial
fibrillation induced by PACAP-27 was abolished by atropine and TTX but
not hexamethonium (tables 3 and 4), indicating that the
PACAP-27-induced ACh release from intracardiac parasympathetic nerves
participates in an induction of atrial fibrillation in the dog heart.
It is well known that vagus stimulation and other cholinomimetic drugs
evoke atrial fibrillation in anesthetized dog hearts (Lewis et
al., 1921). However, in the autonomically decentralized dog heart,
vagus stimulation caused sinus arrest but not induce atrial
fibrillation (Furukawa et al., 1996). ACh in doses of 3 to
30 nmol injected into sinus node artery also hardly caused atrial
fibrillation (Hirose et al., 1997). In addition, when we
stimulated the intracardiac parasympathetic nerves to the SA nodal
region for 30 sec, the stimulation decreased sinus rate more than did
PACAP-27, but did not cause atrial fibrillation in our present study.
Therefore, the PACAP-27-induced ACh release mainly affects the
induction of atrial fibrillation but we cannot neglect other mechanisms
may be involved in that of atrial fibrillation in the dog heart.
). Sympathetic stimulation also
shortens atrial refractory period in the anesthetized dog (Zipes
et al., 1974; Takei et al., 1991). The shortening
atrial refractory period is related to the augmentation of the
relaxation after the increase in tissue cAMP mediated by
beta adrenoceptors. Additionally, simultaneous stimulation
of the sympathetic and parasympathetic nerves additively shortens the
atrial refractory period in anesthetized dog hearts (Takei et
al., 1991). Under sympathetic tone, thus, atrial fibrillation
induced by ACh occurs easier (Hashimoto et al., 1968). In
our study, propranolol tended to decrease the incidence of the atrial
fibrillation induced by PACAP-27 (table 3). However, propranolol
affected neither the positive nor negative chronotropic responses to
PACAP-27 (fig. 3; tables 1 and 2). Thus, it is unlikely that
beta adrenergic mechanism participates in the
PACAP-27-induced atrial fibrillation. PACAP-38 induced a biphasic
inotropic and chronotropic responses in isolated perfused dog atria,
and those cardiac responses were not inhibited by propranolol (Yonezawa
et al., 1996). In addition, i.v. injection of propranolol
did not change the basal sinus rate in our study, indicating that
circulatory catecholamines hardly affected the induction of atrial
fibrillation in the autonomically decentralized heart of the
anesthetized dog. In our study, we applied a high dose of propranolol
(3.4 µmol/kg, i.v.). Thus, it is likely that
Na+ channel blocking effects of propranolol, so
called membrane stabilizing action (Davis and Temte, 1968), related to
decrease the induction of atrial fibrillation induced by PACAP-27,
although beta adrenoceptor blocking effects might be
involved.
However, phentolamine administered into the SA node artery did not
decrease the incidence of the PACAP-27-induced atrial fibrillation (table 4). The positive cardiac responses to alpha
adrenoceptor agonists were not inhibited by alpha
adrenoceptor antagonists in isolated dog atria (Chiba, 1977).
Furthermore, alpha adrenoceptors exist in the dog heart but
alpha adrenoceptor-mediated responses are not determined
(Endoh et al., 1991). Therefore, alpha
adrenoceptors may not relate to the induction of atrial fibrillation
induced by PACAP-27 in the dog heart.
A PACAP receptor antagonist, PACAP-(6-27) did not attenuate the
incidence of PACAP-27-induced atrial fibrillation (table 4), although
it partly inhibited the positive chronotropic response to PACAP-27
(fig. 8; table 2). These results suggest that PACAP-(6-27)-sensitive PACAP receptors do not mainly act on the induction of atrial
fibrillation in the dog heart, but they may support in part the
induction of atrial fibrillation.
Thus, our results suggest that the PACAP-27-induced ACh release from
intracardiac parasympathetic nerves but not adrenergic mechanism mainly
participates in the induction of atrial fibrillation in the
autonomically decentralized dog heart, although we cannot neglect other
mechanisms, which induce positive chronotropic responses to PACAP-27,
participate in the induction of atrial fibrillation. PACAP-27 increases
cAMP in several tissues (Miyata et al., 1989; Spengler
et al., 1993; Tong et al., 1993). IBMX, a
nonspecific phosphodiesterase inhibitor, augmented the increase in left
ventricular dP/dtmax in response to PACAP in neonatal pig hearts
(Ross-Ascuitto et al., 1993). Thus, PACAP-27 might increase
tissue cAMP and shorten the atrial refractory period in the dog atrial
muscles. We need further studies to define the precise mechanisms of
the induction of atrial fibrillation induced by PACAP-27, especially
the relationship between atrial fibrillation and mechanisms causing
positive chronotropic responses to PACAP-27, in the heart.
It has been suggested that the positive inotropic and lusitropic
effects of PACAP are useful as a cardiotonic agent (Ascuitto et
al., 1996). However, PACAP has several actions in addition to the
hormonal actions (Arimura et al., 1995). Furthermore, in our
study, we demonstrated that PACAP acts on the peripheral nervous system
as well as on the heart and it induces atrial fibrillation. Although
many reports suggest a role for PACAP in humans (Kimura et
al., 1990; Shen et al., 1992; Guijarro et
al., 1995; Suda et al., 1991), further studies with
PACAP are still needed before clinical application.
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Footnotes |
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Accepted for publication July 25, 1997.
Received for publication February 5, 1997.
1 This work was supported in part by Ministry of Education, Science, and Culture, Japan, Scientific Research Grant-in-Aid 08670105.
Send reprint requests to: Dr. Y. Furukawa, Department of Pharmacology, Shinshu University School of Medicine, Matsumoto 390, Japan.
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Abbreviations |
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ACh, acetylcholine;
IP3, inositol
1,4,5-trisphosphate;
PACAP, pituitary adenylate cyclase-activating
polypeptide;
SA, sinoatrial;
TTX, tetrodotoxin;
VIP, vasoactive
intestinal peptide;
cAMP, cyclic adenosine 3
,5-monophosphate.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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,
n = 6) and after (
, n = 6) treatment with propranolol at 3.4 µmol/kg i.v. in the
autonomically decentralized heart of the anesthetized dog. B, Positive
chronotropic responses to PACAP-27 (
) in doses of 0.003 to 0.03 nmol in five nonblockade dogs.
Vertical bars show S.E.M. Control sinus rate before propranolol
treatment in six dogs was 121 ± 8.3 (mean ± S.E.M.)
beats/min and it was not significantly different from the sinus rates
of other experimental groups.
