Abstract 17699: Inositol-1,4,5-Trisphosphate-Mediated Pacemaker Activity in NCX KO Mouse Sinoatrial Nodal Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nidhi Kapoor ◽  
Andrew Tran ◽  
Rui Zhang ◽  
Jeanney Kang ◽  
Joshua I Goldhaber
Keyword(s):  
Action Potentials ◽  
Adrenergic Receptor ◽  
Sinoatrial Node ◽  
Systolic Heart Failure ◽  
Pacemaker Activity ◽  
Ca Channels ◽  
Adult Cardiomyocytes ◽  
Diastolic Depolarization ◽  
Adrenergic Receptor Agonist

Sinoatrial node (SAN) automaticity is due to the interplay of several membrane currents, including the current produced by Na-Ca exchanger (NCX) in response to Ca cycling. Several lines of evidence suggest that inositol-1,4,5-triphosphate receptors (IP 3 Rs) that mobilize [Ca] i are implicated in generation of automaticity in embryonic and adult cardiomyocytes. Increased IP 3 R expression observed in failing heart may predispose to arrhythmias and could contribute to the elevated heart rates associated with systolic heart failure. However, whether IP 3 R signaling influences SAN pacemaking is still controversial, in part due to the confounding influence of periodic Ca flux through the sarcolemma during every beat. To address this concern, we used NCX knockout (KO) SAN cells to study the role of IP 3 signaling on pacemaker activity. In these cells Ca flux across the sarcolemmal membrane is practically eliminated due to NCX ablation and no Ca flux through L-type Ca channels due to lack of action potentials, yet periodic spontaneous waves are still generated by the localized Ca releases (LCRs) of the “Ca clock”. Thus these waves are “uncoupled” from the membrane because there is no NCX to contribute to the diastolic depolarization in response to the release of [Ca] i . We recorded spontaneous Ca oscillations using line scan confocal microscopy in WT and NCX KO SAN cells in the presence of an IP 3 R blocker or during inhibition of phospholipase C (PLC). We found that superfusion with the IP 3 R blocker, 2-APB (2 μm) decreased the frequency of Ca transients in WT SAN cells by 82.6% (n=9, p<0.05) and Ca waves in NCX KO cells by 66% (n=10, p<0.05). Similar results were also obtained on superfusion with the PLC antagonist, U73122 (1 μm). Alternatively, an increase in IP 3 production using the α-1 adrenergic receptor agonist phenylephrine (10 μm) led to an increase in the frequency of Ca transients in WT SAN cells (n=8. P< 0.05) and Ca waves in NCX KO cells (n=9, p <0.05). This effect was blocked on the subsequent additional application of 2-APB. In summary our results indicate that Ca release from IP 3 Rs can modulate Ca oscillation frequency in NCX KO SAN cells and support our hypothesis that IP 3 signaling modulates the Ca cycling processes that regulate pacemaker frequency in the SAN.

Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node

1997 ◽  
Vol 272 (6) ◽  
pp. H2793-H2806 ◽  
Author(s):  
I. Kodama ◽  
M. R. Nikmaram ◽  
M. R. Boyett ◽  
R. Suzuki ◽  
H. Honjo ◽  
...  
Keyword(s):  
Action Potentials ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Pacemaker Activity ◽  
Na Current ◽  
Na Currents ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials ◽  
Rabbit Sinoatrial Node

The effect of block of the L-type Ca2+ current by 2 microM nifedipine and of the Na+ current by 20 microM tetrodotoxin on the center (normally the leading pacemaker site) and periphery (latent pacemaker tissue) of the rabbit sinoatrial node was investigated. Spontaneous action potentials were recorded with microelectrodes from either an isolated right atrium containing the whole node or small balls of tissue (approximately 0.3-0.4 mm in diameter) from different regions of the node. Nifedipine abolished the action potential in the center, but not usually in the periphery, in both the intact sinoatrial node and the small balls. Tetrodotoxin had no effect, on electrical activity in small balls from the center, but it decreased the takeoff potential and upstroke velocity and slowed the spontaneous activity (by 49 +/- 10%; n = 11) in small balls from the periphery. It is concluded that whereas the L-type Ca2- current plays an obligatory role in pacemaking in the center, the Na+ current plays a major role in pacemaking in the periphery.

Endolymphatic sac is involved in the regulation of hydrostatic pressure of cochlear endolymph

2009 ◽  
Vol 297 (5) ◽  
pp. R1610-R1614 ◽  
Author(s):  
Ryuhei Inamoto ◽  
Takenori Miyashita ◽  
Kosuke Akiyama ◽  
Terushige Mori ◽  
Nozomu Mori
Keyword(s):  
Hydrostatic Pressure ◽  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Marked Change ◽  
Endocochlear Potential ◽  
Endolymphatic Sac ◽  
Endolymphatic Pressure ◽  
Adrenergic Receptor Agonist ◽  
Current Potential

To clarify the role of the endolymphatic sac (ES) in the regulation of endolymphatic pressure, the effects of isoproterenol, a β-adrenergic receptor agonist, and acetazolamide, a potent carbonic anhydrase inhibitor, both of which decrease ES direct current potential on cochlear hydrostatic pressure, were examined in guinea pigs. When isoproterenol was applied intravenously, hydrostatic pressures of cochlear endolymph and perilymph were significantly increased with no change in endocochlear potential or the hydrostatic pressure of cerebrospinal fluid. Acetazolamide produced no marked change in the hydrostatic pressure of cochlear endolymph. In ears with an obstructed ES, the action of isoproterenol on the hydrostatic pressure of cochlear endolymph and perilymph was suppressed. These results suggest that the ES may regulate the hydrostatic pressure of the endolymphatic system via the action of the agents such as catecholamines on the ES.

ANP has no postsynaptic effect on autonomic regulation of cardiac pacemaker rate in the rat

1993 ◽  
Vol 265 (6) ◽  
pp. H1983-H1987 ◽  
Author(s):  
D. J. Atchison ◽  
P. S. Pennefather ◽  
U. Ackermann
Keyword(s):  
Salt Solution ◽  
Action Potentials ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Pacemaker Activity ◽  
Physiological Salt Solution ◽  
Sprague Dawley ◽  
Pacemaker Cells ◽  
Frequency Of Action Potentials ◽  
The Right

We studied whether atrial natriuretic peptide (ANP) influences sinoatrial node pacemaker activity or whether it modifies the response to activation of postsynaptic autonomic receptors. Male Sprague-Dawley rats were anesthetized with pentobarbital sodium (45 mg/kg). Their hearts were removed quickly and placed in physiological salt solution. The atria were isolated; the right intra-atrial chamber was exposed to allow intracellular recording from sinoatrial node pacemaker cells. The tissue was placed in a temperature-regulated recording chamber and superfused with warmed oxygenated physiological salt solution. With use of standard microelectrode recording techniques, action potentials were recorded from spontaneously depolarizing cells in the presence of muscarine (62.5–500 nM) or norepinephrine (0.1 and 1.0 microM). Muscarine reduced the frequency of action potentials dose dependently, whereas norepinephrine increased their frequency. The addition of ANP (0.1–100 nM) to the superfusion had no effect on the frequency of action potentials during the superfusion of physiological salt solution or in the presence of either muscarine or norepinephrine. We conclude that ANP does not act on cardiac pacemaker cells to modulate the effect of neurotransmitters.

β-Adrenergic regulation of Na+ uptake by larval zebrafish Danio rerio in acidic and ion-poor environments

2012 ◽  
Vol 303 (10) ◽  
pp. R1031-R1041 ◽  
Author(s):  
Yusuke Kumai ◽  
Mellissa A. R. Ward ◽  
Steve F. Perry
Keyword(s):  
Danio Rerio ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Acidic Water ◽  
Adrenergic Systems ◽  
Β Receptor ◽  
Β Adrenergic Receptors ◽  
Adrenergic Receptor Agonist

The potential role of adrenergic systems in regulating Na+ uptake in zebrafish ( Danio rerio) larvae was investigated. Treatment with isoproterenol (a generic β-adrenergic receptor agonist) stimulated Na+ uptake, whereas treatment with phenylephrine (an α1-adrenergic receptor agonist) as well as clonidine (an α2-adrenergic receptor agonist) significantly reduced Na+ uptake, suggesting opposing roles of α- and β-adrenergic receptors in Na+ uptake regulation. The increase in Na+ uptake associated with exposure to acidic water (pH = 4.0) was attenuated in the presence of the nonselective β-receptor antagonist propranolol or the β1-receptor blocker atenolol; the β2-receptor antagonist ICI-118551 was without effect. The stimulation of Na+ uptake associated with ion-poor water (32-fold dilution of Ottawa tapwater) was unaffected by β-receptor blockade. Translational gene knockdown of β-receptors using antisense oligonucleotide morpholinos was used as a second method to assess the role of adrenergic systems in the regulation of Na+ uptake. Whereas β1- or β2B-receptor knockdown led to significant decreases in Na+ uptake during exposure to acidic water, only β2A-receptor morphants failed to increase Na+ uptake in response to ion-poor water. In support of the pharmacology and knockdown experiments that demonstrated an involvement of β-adrenergic systems in the control of Na+ uptake, we showed that the H+-ATPase-rich (HR) cell, a subtype of ionocyte known to be a site of Na+ uptake, is innervated and appears to express β-adrenergic receptors (propranolol binding sites) at 4 days postfertilization. These data indicate an important role of adrenergic systems in regulating Na+ uptake in developing zebrafish.

scholarly journals Sex differences and the effects of ovariectomy on the β-adrenergic contractile response

2011 ◽  
Vol 301 (3) ◽  
pp. H1127-H1134 ◽  
Author(s):  
Victoria J. McIntosh ◽  
P. Charukeshi Chandrasekera ◽  
Robert D. Lasley
Keyword(s):  
Sex Differences ◽  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Contractile Response ◽  
Receptor Gene ◽  
Male And Female ◽  
Perfused Hearts ◽  
Adrenergic Receptor Agonist ◽  
Adrenergic Receptor Gene

The presence of sex differences in myocardial β-adrenergic responsiveness is controversial, and limited studies have addressed the mechanism underlying these differences. Studies were performed using isolated perfused hearts from male, intact female and ovariectomized female mice to investigate sex differences and the effects of ovarian hormone withdrawal on β-adrenergic receptor function. Female hearts exhibited blunted contractile responses to the β-adrenergic receptor agonist isoproterenol (ISO) compared with males but not ovariectomized females. There were no sex differences in β1-adrenergic receptor gene or protein expression. To investigate the role of adenylyl cyclase, phosphodiesterase, and the cAMP-signaling cascade in generating sex differences in the β-adrenergic contractile response, dose-response studies were performed in isolated perfused male and female hearts using forskolin, 3-isobutyl-1-methylxanthine (IBMX), and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (CPT-cAMP). Males showed a modestly enhanced contractile response to forskolin at 300 nM and 5 μM compared with females, but there were no sex differences in the response to IBMX or CPT-cAMP. The role of the A1 adenosine receptor (A1AR) in antagonizing the β-adrenergic contractile response was investigated using both the A1AR agonist 2-chloro- N6-cyclopentyl-adenosine and A1AR knockout (KO) mice. Intact females showed an enhanced A1AR anti-adrenergic effect compared with males and ovariectomized females. The β-adrenergic contractile response was potentiated in both male and female A1ARKO hearts, with sex differences no longer present above 1 nM ISO. The β-adrenergic contractile response is greater in male hearts than females, and minor differences in the action of adenylyl cyclase or the A1AR may contribute to these sex differences.

The role of calcium in excitation–contraction coupling in crustacean muscle fibers

1982 ◽  
Vol 60 (4) ◽  
pp. 446-458 ◽  
Author(s):  
G. Suarez-Kurtz
Keyword(s):  
Action Potentials ◽  
Muscle Fibres ◽  
Ca Channels ◽  
Mechanical Responses ◽  
Crustacean Muscle ◽  
Ca Uptake ◽  
Intracellular Storage ◽  
Spontaneous Contractions ◽  
Ca Currents

The evidence that calcium (Ca) plays an important role in electrical activity and an essential role in excitation–contraction (E–C) coupling in crustacean muscles is reviewed. These muscles produce graded electrical and mechanical responses to applied depolarizations. Removal of Ca from the bath solution eliminates both responses. Addition of Ba2+ or Sr2+ to Ca-free saline restores membrane electrogenesis, and all-or-none action potentials can be induced. With Sr2+ vigorous contractions are produced, whereas Ba action potentials evoke minimal or no tension, showing that rapid depolarization of the membrane potential is not sufficient per se for E–C coupling in crab and barnacle muscle. Several inorganic (e.g., multivalent cations) and organic (e.g., aminoglycoside antibiotics) which block membrane Ca channels block electrogenesis and contraction. However, the "Ca antagonists" verapamil and D600 also block Ca uptake at intracellular storage sites, resulting in spontaneous contractions and the delayed relaxation of small contractions associated with residual Ca currents. The evidence that the Ca which enters the fibres needs to release Ca from intracellular storage sites to produce contractions is detailed and discussed. Finally, a model for E–C coupling is discussed. This model includes the sites and mechanisms of action for several chemicals which modify E–C coupling in crustacean muscle fibres.

Sign in / Sign up

Export Citation Format

Share Document