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Vol. 286, Issue 1, 70-76, July 1998
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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There are no available data on the direct effect of C-type natriuretic peptide (CNP) and brain natriuretic peptide (BNP) on the myocardial contractility in mammalian hearts. Thus we studied the inotropic and chronotropic effects of CNP-22 and BNP-32 compared with those of atrial natriuretic peptide (ANP)-28 using the isolated, blood-perfused canine right atrial or left ventricular preparations. CNP increased the atrial contractile force in a dose-dependent manner with a small increase in sinus rate in isolated atria, whereas neither ANP nor BNP changed atrial force and rate. CNP but not BNP also increased the ventricular contractile force in isolated ventricles. Pretreatment with a high dose (3 nmol) of CNP attenuated the positive inotropic response to CNP at a low dose (1 nmol) but not to norepinephrine. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142-1, inhibited the increases in atrial contractile force and sinus rate in response to CNP, but it did not affect the positive cardiac responses to norepinephrine. Propranolol did not block the positive cardiac responses to CNP. 3-Isobutyl-1-methylxanthine in rates of 0.6 to 1.3 µmol/min attenuated the CNP-induced positive inotropic responses, when it potentiated the positive inotropic response to norepinephrine. On the other hand, parasympathetic nerve stimulation attenuated the positive cardiac responses to CNP and norepinephrine. These results demonstrate that CNP increases myocardial contractile force with a small increase in sinus rate mediated by guanylyl cyclase-linked natriuretic peptide receptors, probably type B receptors in the dog heart, and suggest that the positive inotropic response to CNP is influenced by the cyclic adenosine 3',5'-monophosphate-dependent signal transduction.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The
natriuretic peptide family is made up of three distinct peptides: ANP,
BNP and CNP. These peptides are thought to play an important role in
cardiovascular homeostasis (Brown et al., 1993
). ANP is a
28-amino-acid peptide that is secreted from atria and acts as a cardiac
hormone with a variety of biological actions including natriuresis,
diuresis, vasorelaxation and inhibition of renin and aldosterone
secretion (Nakao et al., 1992). BNP is a 32-amino-acid
peptide that shares structural and biological similarity to ANP and is
a novel cardiac hormone which is synthesized in and secreted from the
ventricle and atria (Mukoyama et al., 1991; Ogawa et
al., 1991).
CNP is a newly identified 22-amino-acid peptide that demonstrates
structural similarity to the cardiac hormones ANP and BNP (Komatsu
et al., 1991). This peptide is distributed widely within the
vascular endothelium (Espiner, 1994) and may play a role in the
regulation of vascular tone (Clavell et al., 1993).
Additionally, CNP mRNA has been detected in the rat heart (Vollmar
et al., 1993), and the existence of CNP has been
demonstrated in the human ventricle (Wei et al., 1993).
Both ANP and BNP function biologically via NPR-A that is
highly expressed in endothelial cells (Koller et al., 1991).
CNP functions via NPR-B that is highly expressed in vascular
smooth muscles. All three peptides are cleared and degraded
intracellularly by NPR-C (Koller et al., 1991). mRNA
transcripts for these three receptors were all detectable in the rat
and human heart (Nunez et al., 1992). Therefore, all three
natriuretic peptides may have a potential role in cardiac function
modulation.
Recently, Beaulieu et al. (1996) observed that CNP but not
ANP increased sinus rate in anesthetized and isolated dog hearts and
that its positive chronotropic effect was not blocked by prazosin, atropine, indomethacin, losartan, cimetidine or mepyramine. However, no
report is available on the effects of CNP and BNP on myocardial contractility and whether the positive chronotropic response to CNP is
mediated by natriuretic peptide receptors. Therefore, in this study, we
investigated the direct effects of CNP and BNP as well as ANP on the
atrial and ventricular contractility and SA nodal pacemaker activity in
the isolated, blood-perfused right atrial and left ventricular
preparations of the dogs. We observed the positive inotropic and
chronotropic responses to CNP. Thus, to determine whether the positive
cardiac responses to CNP are mediated by guanylyl cyclase-linked
natriuretic receptors, we examined the effects of HS-142-1 on the
positive cardiac responses to CNP in the isolated right atrial
preparations. HS-142-1 is an inhibitor of the guanylyl cyclase-linked
natriuretic peptide receptors, i.e., NPR-A and NPR-B
(Matsuda and Morishita, 1993). We also studied the effects of a
phosphodiesterase inhibitor, IBMX, and intracardiac parasympathetic
nerve stimulation on the positive cardiac responses to CNP to
investigate whether the positive cardiac responses to CNP interacts
with the cAMP-dependent signal transduction.
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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.
Isolated, blood-perfused dog heart preparations.
Isolated
right atria and left ventricles were obtained from 22 dogs (weighing
9-15 kg) anesthetized with sodium pentobarbital (35 mg/kg i.v.). Each
preparation was perfused with heparinized arterial blood from a second,
support dog. The details of these preparations have been described
earlier (Chiba et al., 1975; Chiba, 1976).
). The
femoral arterial blood pressure, heart rate derived from lead II of the
electrocardiogram of the support dog and the rate of blood flow to the
preparation were monitored simultaneously.
Experimental protocols. We carried out three series of experiments after 30 min stabilization. In the first series, to examine the direct effects of ANP, BNP and CNP on the SA nodal pacemaker activity, atrial contractility and ventricular contractility, we studied the changes in sinus rate and atrial contractile force in response to ANP (1-30 nmol, n = 3), BNP (1-30 nmol, n = 3), CNP (0.1-3 nmol, n = 6) and norepinephrine (0.1, 0.3 or 1 nmol, n = 6) in the isolated, blood-perfused right atrium and the changes in the ventricular contractile force in response to BNP (1-30 nmol, n = 3), CNP (0.1-10 nmol, n = 6) and norepinephrine (0.1, 0.3 or 1 nmol, n = 6) in the isolated, blood-perfused left ventricle. Additionally, to investigate whether the cardiac responses to CNP cause tachyphylaxis, we studied the effects of CNP at 3 nmol (n = 5) on the positive cardiac responses to CNP at 1 nmol and norepinephrine at 0.1, 0.3 or 1 nmol in isolated right atrial preparations. The responses to CNP were obtained 2 and 30 min after the high dose of CNP.
In the second series, to determine whether the cardiac responses to CNP are mediated by natriuretic peptide receptors, we studied the effects of a natriuretic peptide receptor antagonist, HS-142-1 (2 mg, n = 5) on the positive cardiac responses to CNP (1 nmol) and norepinephrine (0.1, 0.3 or 1 nmol) in the isolated right atrium. The responses to CNP were obtained 2 and 30 min after HS-142-1 treatment. Additionally, to study whether the responses to CNP are mediated by adrenergic mechanism, we examined the effects of propranolol (30 nmol, n = 5) on the positive cardiac responses to CNP (1 nmol) and norepinephrine (0.1 nmol) in the isolated right atrium. The responses to CNP were observed 2 min after propranolol. In the third series, to determine whether the cardiac responses to CNP are influenced by phosphodiesterase inhibition, we examined the effects of IBMX, a nonspecific phosphodiesterase inhibitor, on the positive cardiac responses to CNP (1 nmol, n = 5) and norepinephrine (0.1, 0.3 or 1 nmol, n = 5) in the atrial preparations. IBMX in low (0.06-0.13 µmol/min) or high rates (0.6-1.3 µmol/min) was infused into the sinus node artery. The responses to CNP were observed 2 min after IBMX infusion started. To examine whether acetylcholine released by stimulation of vagal nerves attenuates the positive cardiac responses to CNP, we also studied the effects of intracardiac parasympathetic nerve stimulation on the positive cardiac responses to CNP (1 nmol) and norepinephrine (0.1 or 0.3 nmol) in five isolated perfused right atria. Enough recovery time (usually 30 min after injection of CNP) was allowed to prevent the effects of the former injection of CNP from affecting the next injection of CNP through the experiment.Drugs.
Drugs were mixed fresh for each experiment. Atrial
natriuretic peptide-28 (human) (ANP-28, Peptide Institute Inc., Osaka, Japan), brain natriuretic peptide-32 (human) (BNP-32, Peptide Institute
Inc.) and C-type natriuretic peptide-22 (human) (CNP-22, Peptide
Institute Inc.) were dissolved in distilled water, kept frozen at
20°C as stock solutions and diluted immediately before use. A
nonpeptide natriuretic peptide receptor antagonist, HS-142-1, which
was a generous gift of Y. Matsuda at Tokyo Research Laboratories, Kyowa
Hakko Kogyo Co, Ltd, Tokyo, Japan, was dissolved in distilled water
before use. Norepinephrine hydrochloride (Sankyo, Tokyo, Japan),
propranolol hydrochloride (Sigma, St Louis, MO) and IBMX (Aldrich,
Milwaukee, WI) were dissolved and diluted in 0.9% NaCl. Drugs were
injected or infused into the sinus node artery or the anterior
descending branch of the left coronary artery through a rubber tube by
a microsyringe. The amount of drug solution injected was 0.01 to 0.03 ml during a 4-sec period.
Statistical analysis. All data were presented as percent changes from the respective control and expressed as mean ± S.E. 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. P < .05 was 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 ANP, BNP and CNP on the SA nodal pacemaker activity and myocardial contractility. When CNP (0.3-3 nmol) was injected into the sinus node artery of an isolated, blood-perfused right atrium, CNP increased the sinus rate and atrial contractile force dose dependently (fig. 1A). Figure 2 summarizes data of the effects of ANP, BNP, CNP and norepinephrine on the isolated right atrial preparation. CNP (0.1-3 nmol) increased the sinus rate (P < .05) and atrial contractile force (P < .01). On the other hand, ANP and BNP did not affect the sinus rate and atrial contractility significantly even when the doses of peptides were increased to 30 nmol. The threshold dose for the positive inotropic effect of CNP was 0.1 nmol. The percentage increases in atrial force in response to CNP were greater than those in sinus rate. The chronotropic and inotropic responses to norepinephrine were characterized for comparison with the responses to peptides.
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Effects of HS-142-1 and propranolol on the positive cardiac responses to CNP. To investigate whether the positive inotropic and chronotropic responses to CNP were mediated by guanylyl cyclase-linked natriuretic peptide receptors, we studied the effects of HS-142-1 (2 mg) on the positive inotropic and chronotropic responses to CNP (1 nmol) and norepinephrine (0.1-1 nmol) in five isolated right atria. HS-142-1 blocked the positive inotropic response to CNP (P < .001) but not to norepinephrine (fig. 5). When CNP was rechallenged 30 min after HS-142-1 treatment, it caused increases in atrial contractile force similar to those before HS-142-1. HS-142-1 abolished the small positive chronotropic response to CNP (table 1, part II). HS-142-1 did not affect the basal sinus rate and atrial contractility in the isolated atria.
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Effects of IBMX and intracardiac parasympathetic stimulation on positive cardiac responses to CNP. We investigated whether the positive inotropic and chronotropic responses to CNP interact with the cAMP-dependent signal transduction. Low infusion rates (0.06-0.13 µmol/min) of IBMX increased the sinus rate by 22 ± 6.2 beats/min (17 ± 4.9%) and atrial contractile force by 0.8 ± 0.1 g (28 ± 5.2%) from the control levels in five dog atria. High infusion rates (0.6-1.3 µmol/min) of IBMX also increased the sinus rate by 65 ± 10.1 beats/min (55 ± 7.6%) and atrial contractile force by 4.6 ± 0.9 g (135 ± 16.2%) in another five atria. Two minutes later, the sinus rate and contractile force reached the steady-state levels that were maintained during IBMX infusion. IBMX at low rates did not affect the positive inotropic response to CNP, whereas it potentiated (P < .001) the positive inotropic response to norepinephrine (fig. 6A). However, IBMX at high rates attenuated (P < .001) the positive inotropic response to CNP, but it still potentiated the positive inotropic response to norepinephrine (fig. 6B). Neither low rates nor high rates of IBMX significantly affect the positive chronotropic responses to CNP and norepinephrine significantly (table 1, parts III and IV).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Cardiac effects of natriuretic peptides.
We demonstrated in
the present study that CNP directly and dose-dependently increased
atrial and ventricular contractile forces in isolated, blood-perfused
dog heart preparations (figs. 1, 2 and 3). Our results also showed that
the positive inotropic response to CNP was much greater than the
positive chronotropic response to CNP, whereas norepinephrine increased
the sinus rate and myocardial contractile force to a similar degree
(fig. 2). Other cardiotonic peptides such as vasoactive intestinal
peptide, pituitary adenylyl cyclase-activating polypeptide and glucagon
increased sinus rate more than atrial contractile force in comparison
with those effects of norepinephrine in isolated perfused right atrial
preparations of the dog (Furukawa et al., 1986; Karasawa
et al., 1990; Yonezawa et al., 1996). It is
suggested, therefore, that CNP and its analogs may be very useful
cardiotonic agents. On the other hand, BNP did not affect the atrial
and ventricular contractility as well as sinus rate in the present
study (figs. 2B and 3), although BNP is a cardiac hormone that is
synthesized in and secreted from the ventricle (Mukoyama et
al., 1991; Ogawa et al., 1991). In addition, ANP that
is secreted from atria had no effect on the atrial contractility and
sinus rate (fig. 2A). Therefore, ANP and BNP may not have a potential
role as a paracrine hormone in cardiac contractility and sinus rate in
the dog heart.
have shown that CNP circulates in low
picomolar concentrations in canine plasma. The isolated atrial preparation used in the present study was perfused with arterial blood
from a support dog. However, when HS-142-1, a natriuretic peptide
receptor blocker, was injected into the sinus node artery of the
isolated atrial preparation, it did not affect the basal sinus rate and
atrial contractility in this preparation. Therefore, endogenous CNP may
not have a potential role on cardiac function in physiological states.
Mechanisms for the CNP-induced positive inotropic and chronotropic
responses.
In the present study, we demonstrated that a high dose
of CNP attenuated the increases in atrial contractility and sinus rate in response to a low dose of CNP but not norepinephrine (fig. 4).
HS-142-1 blocked the positive cardiac responses to CNP (fig. 5 and
table 1, part II). HS-142-1 is a specific natriuretic peptide receptor
antagonist. The affinity cross-linking study demonstrated that
HS-142-1 specifically abolished the labeling of the 135 kdalton band
which was derived from the labeling of the guanylyl cyclase-linked natriuretic peptide receptors (Matsuda and Morishita, 1993). However, HS-142-1 had no effect on the labeling of the 60 kdalton band which
was derived from the guanylyl cyclase-free receptors, i.e., NPR-C (Matsuda and Morishita, 1993). HS-142-1 inhibited cGMP
production stimulated by ANP, BNP and CNP with almost equal potency in
PC12 cells (Matsuda and Morishita, 1993). From the present results, therefore, we suggest that CNP increases the myocardial contractile force and sinus rate mediated by the guanylyl cyclase-linked
natriuretic peptide receptors but not by the guanylyl cyclase-free
receptors in the dog heart.
described ligand specificity
of the two different subtypes of guanylyl cyclase-linked natriuretic peptide receptors, i.e., NPR-A and NPR-B. NPR-A has high
affinity for ANP and BNP, whereas NPR-B binds only CNP with high
affinity. Dose-response curves for stimulation of guanylyl cyclase of
NPR-A and NPR-B demonstrated that both ANP and BNP could stimulate
NPR-A effectively, and that BNP was approximately 10-fold less potent than ANP (Koller and Goeddel, 1992). In contrast, CNP did not increase
intracellular cGMP significantly in cells expressing NPR-A. In
NPR-B-expressing cells, only CNP could stimulate cGMP production
effectively (Koller and Goeddel, 1992). In the present study, we
demonstrated that CNP caused the positive inotropic and chronotropic
effects, whereas ANP and BNP had no effects on the cardiac
contractility and sinus rate (figs. 1, 2 and 3). Therefore, it is
likely that the positive inotropic and chronotropic effects of CNP are
mediated by NPR-B in the dog heart. On the other hand, propranolol did
not affect the positive inotropic and chronotropic responses to CNP,
which indicates that the cardiac responses to CNP are not mediated
through beta adrenoceptors in the dog heart.
Most of the biological activities of the natriuretic peptides are
thought to be mediated by intracellular accumulation of cGMP through
the activation of particulate guanylyl cyclase (Inagami, 1989; Song
et al., 1988). NPR-A and NPR-B are members of the family of
receptor guanylyl cyclases. Our present results demonstrated that the
positive inotropic response to CNP was mediated by NPR-B, which
suggests that the increase in the production of cGMP induced by CNP may
cause the positive inotropic response to CNP, although we did not
determine changes in tissue cGMP and cAMP concentrations. Several cGMP
effectors, namely, cGs-PDE (type II PDE), cGi-PDE (type III PDE) and
G-kinase have been reported in vertebrate heart cells (Lohmann et
al., 1991). Physiologically relevant targets of cGMP action in
mammalian hearts include cGi-PDE and G-kinase (Lohmann et
al., 1991). cGi-PDE is a dominant isozyme regulating intracellular
cAMP in the heart of many species (Rapundalo et al., 1989;
Beavo and Reifsynder, 1990; Bohm et al., 1991). Ono and
Trautwein (1991) reported that cGMP further increased L-type calcium
current activated by isoproterenol, forskolin or intracellular dialysis
with cAMP in guinea-pig ventricular cells. They suggested that
inhibition of cGMP-sensitive PDE induced by cGMP increased tissue cAMP
and that cGMP, as an intrinsic inhibitor for cGi-PDE, had a regulatory
function under physiological conditions. cGMP also has been reported to
increase both L-type calcium current and myocardial contractility in
single beat cells of guinea-pig ventricular myocytes (Shirayama and
Pappano, 1996). On the other hand, Kumar et al. (1997)
suggested that cGMP increased the basal L-type calcium current mediated
by G-kinase-dependent phosphorylation of calcium channels in newborn
rabbit ventricular cells. Our present results demonstrated that the
high infusion rates of IBMX (0.6-1.3 µmol/min) decreased the
positive inotropic response to CNP. When 0.6 to 1.3 µmol/min of IBMX
attenuated the positive inotropic response to CNP, intra-arterial
concentrations of IBMX were approximately 60 to 130 µM. This
concentration is about 5- to 10-fold greater than the IBMX
concentrations that inhibit type I to IV PDEs in guinea-pig isolated
ventricular myocytes (Bethke et al., 1992). Therefore, it is
conceivable that cGMP increased by CNP could not act on cGi-PDE further
after infusion of IBMX at high rates, because cGi-PDE already had been
inhibited by high rates of IBMX in the isolated atrium. In addition, we
demonstrated that when we investigated the effect of intracardiac
parasympathetic nerve stimulation on the positive cardiac responses to
CNP and norepinephrine, parasympathetic nerve stimulation attenuated
the positive cardiac responses to these substances (fig. 7). Furukawa
et al. (1989) reported that IBMX and norepinephrine-induced
positive cardiac responses were depressed by parasympathetic nerve
stimulation in isolated dog atria. Lindemann and Watanabe (1985)
reported that acetylcholine attenuated the increase in cAMP,
phospholamban phosphorylation and calcium uptake produced by IBMX in
guinea-pig ventricles, and suggested that cholinomimetics inhibited
cAMP-dependent effects at a site or sites in the cAMP cascade distal
the catalytic unit of adenylyl cyclase. Therefore, the cAMP-dependent
signal transduction may be involved in the positive cardiac responses to CNP.
However, sodium nitroprusside markedly elevated atrial cGMP levels but
produced little or no functional change (Diamond et al.,
1977; Taniguch et al., 1979; Endoh and Yamashita, 1981). Sodium nitroprusside had no effect on cardiac contractility in isolated, blood-perfused dog heart preparations (Chiba et
al., 1982). In addition, there is no report of the positive
inotropic effect of ANP in the heart, although several reports
demonstrate that ANP activates a receptor containing particulate
guanylyl cyclase activity and increases cGMP in isolated rabbit and rat cardiac myocytes (Cramb et al., 1987; Neyses and Vetter,
1989). Therefore, further studies and measurements of tissue cGMP and cAMP levels are needed to demonstrate the intracellular mechanisms for
the positive inotropic response to CNP in the dog heart, because it is
not clear if all of the CNP-induced action can be explained by a
cGMP-mediated mechanism.
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Acknowledgments |
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We thank Dr. Y. Matsuda and Dr. S. Nakanishi (Tokyo Research Laboratories, Kyowa Hakko Kogyo Co, Ltd, Tokyo, Japan) for kindly providing HS-142-1.
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Footnotes |
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Accepted for publication March 20, 1998.
Received for publication October 9, 1997.
1 This work was supported by Ministry of Education, Science, and Culture, Japan, Scientific Research Grant-in-Aid 09670090.
Send reprint requests to: Y. Furukawa, M.D., Department of Pharmacology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
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Abbreviations |
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ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; IBMX, 3-isobutyl-1-methylxanthine; NPR-A, natriuretic peptide type-A receptor; NPR-B, natriuretic peptide type-B receptor; NPR-C, clearance receptor; cAMP, cyclic adenosine 3',5'-monophosphate; cGMP, cyclic guanosine 3',5'-monophosphate; cGs-PDE, cGMP-stimulated phosphodiesterase; cGi-PDE, cGMP-inhibited phosphodiesterase; G-kinase, cGMP-dependent protein kinase, SA node, sinoatrial node.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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-adrenergic stimulation of phospholamban phosphorylation and Ca2+ transport in guinea pig ventricles.
J Biol Chem
260:
13122-13129-adrenergic effect on Ca2+ current in guinea-pig ventricular cells.
J Physiol
443:
387-404.This article has been cited by other articles:
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