C-type natriuretic peptide inhibits ANP secretion and  atrial dynamics in perfused atria: NPR-B-cGMP signaling

The purpose of the present experiments was to define the role of C-type natriuretic peptide (CNP) in the regulation of atrial secretion of atrial natriuretic peptide (ANP) and atrial stroke volume. Experiments were performed in perfused beating and nonbeating quiescent atria, single atrial myocytes, and atrial membranes. CNP suppressed in a dose-related fashion the increase in atrial stroke volume and ANP secretion induced by atrial pacing. CNP caused a right shift in the positive relationships between changes in the secretion of ANP and atrial stroke volume or translocation of the extracellular fluid (ECF), which indicates the suppression of atrial myocytic release of ANP into the paracellular space. The effects of CNP on the secretion and contraction were mimicked by 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). CNP increased cGMP production in the perfused atria, and the effects of CNP on the secretion of ANP and atrial dynamics were accentuated by pretreatment with an inhibitor of cGMP phosphodiesterase, zaprinast. An inhibitor of the biological natriuretic peptide receptor (NPR), HS-142-1, attenuated the effects of CNP. The suppression of ANP secretion by CNP and 8-BrcGMP was abolished by a depletion of extracellular Ca2+ in nonbeating atria. Natriuretic peptides increased cGMP production in atrial membranes with a rank order of potency of CNP > BNP > ANP, and the effect was inhibited by HS-142-1. CNP and 8-BrcGMP increased intracellular Ca2+ concentration transients in single atrial myocytes, and mRNAs for CNP and NPR-B were expressed in the rabbit atrium. From these results we conclude that atrial ANP release and stroke volume are controlled by CNP via NPR-B-cGMP mediated signaling, which may in turn act via regulation of intracellular Ca2+.

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Distinct roles for L- and T-type Ca2+ channels in regulation of atrial ANP release

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.6.h2879 ◽

2000 ◽

Vol 279 (6) ◽

pp. H2879-H2888 ◽

Cited By ~ 18

Author(s):

Jin Fu Wen ◽

Xun Cui ◽

Jin Sub Ahn ◽

Suhn Hee Kim ◽

Kyung Hwan Seul ◽

...

Keyword(s):

Stroke Volume ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Pulse Pressure ◽

Extracellular Fluid ◽

Intracellular Ca ◽

Continuous Presence ◽

The Relationship ◽

Rabbit Atria ◽

Ca2 Channels

Atrial secretion of atrial natriuretic peptide (ANP) has been shown to be regulated by atrial workload. Although modulating factors for the secretion of ANP have been reported, the role for intracellular Ca2+ on the secretion of ANP has been controversial. The purpose of the present study was to define roles for L- and T-type Ca2+ channels in the regulation of ANP secretion in perfused beating rabbit atria. BAY K 8644 (BAY K) increased atrial stroke volume and pulse pressure. BAY K suppressed ANP secretion and ANP concentration in terms of extracellular fluid (ECF) translocation concomitantly with an increase in atrial dynamics. BAY K shifted the relationship between ANP secretion and ECF translocation downward and rightward. These results indicate that BAY K inhibits myocytic release of ANP. In the continuous presence of BAY K, diltiazem reversed the effects of BAY K. Diltiazem alone increased ANP secretion and ANP concentration along with a decrease in atrial dynamics. Diltiazem shifted relationships between ANP secretion and atrial stroke volume or ECF translocation leftward. The T-type Ca2+ channel inhibitor mibefradil decreased atrial dynamics. Mibefradil inhibited ANP secretion and ANP concentration in contrast with the L-type Ca2+ channel inhibitor. These results suggest that activation of L- and T-type Ca2+ channels elicits opposite effects on atrial myocytic release of ANP.

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Atrial pressure, distension, and pacing frequency in ANP secretion in isolated perfused rabbit atria

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.260.1.r39 ◽

1991 ◽

Vol 260 (1) ◽

pp. R39-R46 ◽

Cited By ~ 5

Author(s):

K. W. Cho ◽

K. H. Seul ◽

S. H. Kim ◽

K. M. Seul ◽

G. Y. Koh

Keyword(s):

Electrical Stimulation ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Atrial Pressure ◽

Atrial Pacing ◽

Atrial Myocytes ◽

Volume Changes ◽

Series Of Experiments ◽

The Relationship ◽

Rabbit Atria

It has been suggested in this laboratory that the principal stimulus for the secretion of atrial natriuretic peptide (ANP) is the reduction of atrial distension and that the secretion of ANP is dependent on both atrial reduction volume and reduction frequency. To investigate the relationship among the changes in atrial pressure, distension, pacing frequency, and ANP secretion, we performed a series of experiments in the isolated perfused rabbit atria. Increase in atrial pressure without changes in transmural pressure and thus without volume changes did not raise immunoreactive ANP (irANP) secretion. Atrial distension without changes in intracavitary atrial pressure increased irANP secretion with the reduction. Electrical stimulation with atrial distension resulted in an increase in irANP secretion in proportion to pacing frequency. Incremental response of irANP secretion to electrical stimulation was accentuated by increasing atrial distension. Neither atrial pacing without distension nor distension without pacing raised irANP secretion. These results suggest that the direct and principal stimulus for irANP secretion in response to atrial pacing and distension is the length shortening of atrial myocytes and that the incremental response of irANP secretion to increasing pacing frequency is the result of an increase in frequency of the length shortening of atrial myocytes.

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Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00079.2012 ◽

2012 ◽

Vol 302 (11) ◽

pp. H2310-H2320 ◽

Cited By ~ 56

Author(s):

Vyacheslav M. Shkryl ◽

Joshua T. Maxwell ◽

Timothy L. Domeier ◽

Lothar A. Blatter

Keyword(s):

Sarcoplasmic Reticulum ◽

Cellular Level ◽

Release Mechanism ◽

Atrial Myocytes ◽

Restitution Curve ◽

Intracellular Ca ◽

Cardiac Alternans ◽

Kinetics Of ◽

Beating Frequency

Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death. At the cellular level, Ca2+ alternans appears as cytosolic Ca2+ transients of alternating amplitude at regular beating frequency. Cardiac alternans is a multifactorial process but has been linked to disturbances in intracellular Ca2+ regulation. In atrial myocytes, we tested the role of voltage-gated Ca2+ current, sarcoplasmic reticulum (SR) Ca2+ load, and restitution properties of SR Ca2+ release for the occurrence of pacing-induced Ca2+ alternans. Voltage-clamp experiments revealed that peak Ca2+ current was not affected during alternans, and alternans of end-diastolic SR Ca2+ load, evaluated by application of caffeine or measured directly with an intra-SR fluorescent Ca2+ indicator (fluo-5N), were not a requirement for cytosolic Ca2+ alternans. Restitution properties and kinetics of refractoriness of Ca2+ release after activation during alternans were evaluated by four different approaches: measurements of 1) the delay (latency) of occurrence of spontaneous global Ca2+ releases and 2) Ca2+ spark frequency, both during rest after a large and small alternans Ca2+ transient; 3) the magnitude of premature action potential-induced Ca2+ transients after a large and small beat; and 4) the efficacy of a photolytically induced Ca2+ signal (Ca2+ uncaging from DM-nitrophen) to trigger additional Ca2+ release during alternans. The results showed that the latency of global spontaneous Ca2+ release was prolonged and Ca2+ spark frequency was decreased after the large Ca2+ transient during alternans. Furthermore, the restitution curve of the Ca2+ transient elicited by premature action potentials or by photolysis-induced Ca2+ release from the SR lagged behind after a large-amplitude transient during alternans compared with the small-amplitude transient. The data demonstrate that beat-to-beat alternation of the time-dependent restitution properties and refractory kinetics of the SR Ca2+ release mechanism represents a key mechanism underlying cardiac alternans.

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Angiotensin-(1–7) stimulates high atrial pacing-induced ANP secretion via Mas/PI3-kinase/Akt axis and Na+/H+ exchanger

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00608.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. H1365-H1374 ◽

Cited By ~ 32

Author(s):

Amin Shah ◽

Rukhsana Gul ◽

Kuichang Yuan ◽

Shan Gao ◽

Young-Bin Oh ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Renin Angiotensin System ◽

Cardiovascular Effects ◽

Chronic Administration ◽

Atrial Pacing ◽

Potential Candidate ◽

Dependent Manner ◽

Intracellular Ca

Angiotensin-(1–7) [ANG-(1–7)], one of the bioactive peptides produced in the renin-angiotensin system, plays a pivotal role in cardiovascular physiology by providing a counterbalance to the function of ANG II. Recently, it has been considered as a potential candidate for therapeutic use in the treatment of various types of cardiovascular diseases. The aim of the present study is to explain the modulatory role of ANG-(1–7) in atrial natriuretic peptide (ANP) secretion and investigate the functional relationship between two peptides to induce cardiovascular effects using isolated perfused beating rat atria and a cardiac hypertrophied rat model. ANG-(1–7) (0.01, 0.1, and 1 μM) increased ANP secretion and ANP concentration in a dose-dependent manner at high atrial pacing (6.0 Hz) with increased cGMP production. However, at low atrial pacing (1.2 Hz), ANG-(1–7) did not cause changes in atrial parameters. Pretreatment with an antagonist of the Mas receptor or with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), or nitric oxide synthase blocked the augmentation of high atrial pacing-induced ANP secretion by ANG-(1–7). A similar result was observed with the inhibition of the Na+/H+ exchanger-1 and Ca2+/calmodulin-dependent kinase II (CaMKII). ANG-(1–7) did not show basal intracellular Ca2+ signaling in quiescent atrial myocytes. In an in vivo study using an isoproterenol-induced cardiac hypertrophy animal model, an acute infusion of ANG-(1–7) increased the plasma concentration of ANP by twofold without changes in blood pressure and heart rate. A chronic administration of ANG-(1–7) increased the plasma ANP level and attenuated isoproterenol-induced cardiac hypertrophy. The antihypertrophic effect was abrogated by a cotreatment with the natriuretic peptide receptor-A antagonist. These results suggest that 1) ANG-(1–7) increased ANP secretion at high atrial pacing via the Mas/PI3K/Akt pathway and the activation of Na+/H+ exchanger-1 and CaMKII and 2) ANG-(1–7) decreased cardiac hypertrophy which might be mediated by ANP.

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Role of JNK in hypertonic activation of Cl−-dependent Na+/H+ exchange in Xenopus oocytes

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.6.c1978 ◽

2001 ◽

Vol 281 (6) ◽

pp. C1978-C1990 ◽

Cited By ~ 29

Author(s):

Greg G. Goss ◽

Lianwei Jiang ◽

David H. Vandorpe ◽

Dawn Kieller ◽

Marina N. Chernova ◽

...

Keyword(s):

Xenopus Oocytes ◽

Rank Order ◽

Inhibitory Effect ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Intracellular Ca ◽

Transport Inhibitors ◽

Amiloride Derivatives ◽

Acid Loading

In the course of studying the hypertonicity-activated ion transporters in Xenopus oocytes, we found that activation of endogenous oocyte Na+/H+ exchange activity (xoNHE) by hypertonic shrinkage required Cl−, with an EC50 for bath [Cl−] of ∼3 mM. This requirement for chloride was not supported by several nonhalide anions and was not shared by xoNHE activated by acid loading. Hypertonicity-activated xoNHE exhibited an unusual rank order of inhibitory potency among amiloride derivatives and was blocked by Cl− transport inhibitors. Chelation of intracellular Ca2+ by injection of EGTA blocked hypertonic activation of xoNHE, although many inhibitors of Ca2+-related signaling pathways were without inhibitory effect. Hypertonicity activated oocyte extracellular signal-regulated kinase 1/2 (ERK1/2), but inhibitors of neither ERK1/2 nor p38 prevented hypertonic activation of xoNHE. However, hypertonicity also stimulated a Cl−-dependent increase in c-Jun NH2-terminal kinase (JNK) activity. Inhibition of JNK activity prevented hypertonic activation of xoNHE but not activation by acid loading. We conclude that hypertonic activation of Na+/H+ exchange in Xenopusoocytes requires Cl− and is mediated by activation of JNK.

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Mechanical basis of ANP secretion in beating atria: atrial stroke volume and ECF translocation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.5.r1129 ◽

1995 ◽

Vol 268 (5) ◽

pp. R1129-R1136 ◽

Cited By ~ 9

Author(s):

K. W. Cho ◽

S. H. Kim ◽

C. H. Kim ◽

K. H. Seul

Keyword(s):

Stroke Volume ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Extracellular Fluid ◽

Field Stimulation ◽

Atrial Volume ◽

Atrial Rate ◽

Mechanical Basis ◽

Rabbit Atria ◽

Peak Value

To investigate the mechanism by which an increase in pacing frequency or distension increases the secretion of atrial natriuretic peptide (ANP), the changes in atrial volume during contraction (atrial stroke volume), transmural transport of the extracellular fluid (ECF), and ANP secretion were quantified in the beating perfused rabbit atria. The atrium was stimulated by transmural field stimulation or by atrial distension induced by an increase in intraatrial pressure. Atrial stretch and incremental increases in pacing frequency up to 2 Hz activated the secretion of ANP coincident with an increase in atrial stroke volume and the transendocardial translocation of the ECF. These results showed positive relationships between changes in the secretion of ANP and the atrial stroke volume or the translocation of the ECF. The translocation of the ECF was also positively correlated with the change in atrial stroke volume. The accentuated secretion of ANP and translocation of the ECF waned at higher stimulating rates to show a peak value. Even under this condition, the secretion of ANP was a function of the translocation of the ECF. These data suggest that the increases in atrial stroke volume and translocation of ECF are fundamental factors in the ANP stimulation in response to atrial stretch and increases in atrial rate.

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Regulation of ANP secretion by cardiac Na+/Ca2+ exchanger using a new controlled atrial model

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00408.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. R31-R40

Author(s):

Kyung Hwan Seul ◽

Jeong Hee Han ◽

Keum Yee Kang ◽

Sung Zoo Kim ◽

Suhn Hee Kim

Keyword(s):

Stroke Volume ◽

Atrial Natriuretic Peptide ◽

Interstitial Fluid ◽

Driving Forces ◽

Physiological Role ◽

Physical Factor ◽

Systolic Volume ◽

End Systolic Volume ◽

Intracellular Ca

The myocardial interstitium is important in regulating cardiac function. Between the atrial lumen and the pericardial space are transmural pathways, and movement of interstitial fluid (ISF) through these pathways is one of the main driving forces regulating translocation of substances from the interstitium into the blood. To define how ISF translocation from the interstitial space into the luminal space is regulated by each component of atrial hemodynamics, we devised a new rabbit atrial model in which each physical parameter could be controlled independently. Using this system, we also defined the physiological role of the cardiac Na+/Ca2+ exchanger on secretion of atrial natriuretic peptide (ANP) by depletion of extracellular Na+ ([Na+]o). Increases in stroke volume and atrial end-systolic volume increased ISF translocation and ANP secretion. However, an increase in atrial rate did not influence ISF translocation but, rather, increased ANP secretion. Gradual depletion of [Na+]o caused gradual increases in ANP secretion and intracellular Ca2+([Ca2+]i), which were blocked in the presence of Ca2+-free buffer and Ni2+, but not in the presence of KB-R7943, diltiazem, mibefradil, caffeine, or monensin. Amiloride and its analog blocked an increase in ANP secretion but not an increase in [Ca2+]i by [Na+]o depletion. Therefore, we suggest that ANP secretion and ISF translocation may be differently controlled by each physical factor. These results also suggest that the increase in ANP secretion in response to [Na+]o depletion may involve inhibition of Na+/Ca2+ and Na+/H+ exchangers but not an increase in [Ca2+]i.

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Plasmodium falciparum Guanylyl Cyclase-Alpha and the Activity of Its Appended P4-ATPase Domain Are Essential for cGMP Synthesis and Blood-Stage Egress

mBio ◽

10.1128/mbio.02694-20 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Stephanie D. Nofal ◽

Avnish Patel ◽

Michael J. Blackman ◽

Christian Flueck ◽

David A. Baker

Keyword(s):

Plasmodium Falciparum ◽

Cyclic Gmp ◽

Guanylyl Cyclase ◽

Blood Stage ◽

Atpase Domain ◽

Content Type ◽

Cgmp Production ◽

Cgmp Signaling ◽

Cgmp Synthesis

ABSTRACT Guanylyl cyclases (GCs) synthesize cyclic GMP (cGMP) and, together with cyclic nucleotide phosphodiesterases, are responsible for regulating levels of this intracellular messenger which mediates myriad functions across eukaryotes. In malaria parasites (Plasmodium spp), as well as their apicomplexan and ciliate relatives, GCs are associated with a P4-ATPase-like domain in a unique bifunctional configuration. P4-ATPases generate membrane bilayer lipid asymmetry by translocating phospholipids from the outer to the inner leaflet. Here, we investigate the role of Plasmodium falciparum guanylyl cyclase alpha (GCα) and its associated P4-ATPase module, showing that asexual blood-stage parasites lacking both the cyclase and P4-ATPase domains are unable to egress from host erythrocytes. GCα-null parasites cannot synthesize cGMP or mobilize calcium, a cGMP-dependent protein kinase (PKG)-driven requirement for egress. Using chemical complementation with a cGMP analogue and point mutagenesis of a crucial conserved residue within the P4-ATPase domain, we show that P4-ATPase activity is upstream of and linked to cGMP synthesis. Collectively, our results demonstrate that GCα is a critical regulator of PKG and that its associated P4-ATPase domain plays a primary role in generating cGMP for merozoite egress. IMPORTANCE The clinical manifestations of malaria arise due to successive rounds of replication of Plasmodium parasites within red blood cells. Once mature, daughter merozoites are released from infected erythrocytes to invade new cells in a tightly regulated process termed egress. Previous studies have shown that the activation of cyclic GMP (cGMP) signaling is critical for initiating egress. Here, we demonstrate that GCα, a unique bifunctional enzyme, is the sole enzyme responsible for cGMP production during the asexual blood stages of Plasmodium falciparum and is required for the cellular events leading up to merozoite egress. We further demonstrate that in addition to the GC domain, the appended ATPase-like domain of GCα is also involved in cGMP production. Our results highlight the critical role of GCα in cGMP signaling required for orchestrating malaria parasite egress.

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