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Query: UNIPROT:Q96S42 (nodal)
 22,877 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine has potent cardiac electrophysiologic effects including a negative chronotropic action on the sinus node and a predominant negative dromotropic action on the AV node. The latter property has mainly led to the use of adenosine as antiarrhythmic agent for the acute management of paroxysmal supraventricular tachycardia (PSVT) mediated by a reentrant mechanism involving the AV node. The effects of adenosine are dose-dependent and of very short duration since the half-life is less than 10s. The efficacy rates for termination of AV reentrant tachycardias were found to be 35% with 3 mg, 60-70% with 6 mg, 80% with 9 mg, and 90-95% with 12 mg adenosine. The AV nodal depressant effects of adenosine have also been used for determining the mechanism of wide QRS tachycardias for differentiating supraventricular tachyarrhythmias with aberrant conduction from ventricular tachycardia. Adenosine either terminates or slows almost all types of supraventricular tachyarrhythmias or it leads to unmasking of the underlying mechanism such as atrial flutter with aberrant conduction. One form of ventricular tachycardia, the idiopathic type originating from the right ventricular outflow tract can usually be terminated with adenosine due to its cAMP-mediated mechanism. Adenosine is helpful to detect or to increase preexcitation which is important for planning a catheter ablation procedure since the preexcitation pattern allows to localize the accessory pathway. Since the action of adenosine usually does not alter the accessory pathway conduction it is also useful for control ablation efficacy noninvasively in terms of antegrade conduction and during ventricular pacing for the retrograde conduction. Further evaluation and research is necessary for better understanding of adenosine action on the human atrial electrophysiology since it provokes atrial fibrillation in some patients, and of adenosine action on the different pathways in AV nodal reentrant tachycardias and some accessory pathways with decremental (AV nodal-like) conduction properties.
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PMID:[Exogenous adenosine as an anti-arrhythmia agent]. 906 65

The ionic mechanisms underlying the negative dromotropic effect of adenosine were studied in calcium-tolerant myocytes isolated from the region of the rabbit atrioventricular (AV) node. Action potentials and membrane currents were recorded by using the whole cell patch clamp technique. Adenosine (1 to 50 microM) abolished the spontaneous activity of AV node myocytes with hyperpolarization of the membrane potential. Voltage clamp experiments showed that adenosine induced an inwardly rectifying, time-independent potassium current. These effects were antagonized by 8-cyclopentyl-1,3-dipropylxanthine and produced by ribose 5-phosphate isomerase A, indicating that they were mediated by the A1 adenosine receptor. Adenosine also had a small direct inhibitory action on the inward calcium current (ICa) but had a more marked indirect action following stimulation of the calcium current by isoprenaline. The isoprenaline-induced increase in ICa was abolished in the presence of adenosine 10 microM. In cells pretreated with the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the isoprenaline-induced increase in ICa was not reduced by the addition of adenosine. Coincubation of the cells with L-NAME plus L-arginine (the endogenous substrate of nitric oxide synthase) restored the adenosine-induced attenuation of ICa. A membrane permeable analogue of cGMP, 8Br cGMP, an inhibitor of cGMP-stimulated phosphodiesterase, prevented the antiadrenergic effect of adenosine. These results suggest that adenosine activates guanylyl cyclase following the production of nitric oxide, and the subsequent stimulation of phosphodiesterase enhances the breakdown of isoprenaline-elevated cAMP leading to a reduction in the stimulated ICa. In conclusion, the important ionic mechanisms of the actions of adenosine on AV nodal cells are a direct effect, with activation of a potassium conductance and an indirect antiadrenergic effect on ICa, which is mediated by nitric oxide production and phosphodiesterase stimulation.
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PMID:Ionic mechanisms of the effect of adenosine on single rabbit atrioventricular node myocytes. 944

Effects of acetylcholine (ACh) on the L-type calcium current were examined in isolated atrioventricular nodal cells that exhibited spontaneous contractions. ACh (0.1 to 10 microM) inhibited basal calcium current dose-dependently. This inhibition was eliminated by dialysis with 8Br cAMP or cAMP-dependent kinase inhibitory peptide. Both extracellular N-ethylmaleimide 50 microM and intracellular GDPssS 0.2 mM abolished the ACh effect. Dialysis with cGMP or NG-monomethyl-L-arginine did not significantly affect ACh inhibition of basal calcium current. Similarly, cGMP-dependent protein kinase inhibitor KT5823 (1 microM) and the type II phosphodiesterase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (30 microM) did not attenuate the ACh effect. Therefore, ACh inhibits the basal calcium current in the atrioventricular node mainly by suppressing cAMP synthesis through the inhibitory GTP-binding protein.
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PMID:Muscarinic inhibition of basal L-type calcium current in pacemaker cells from the rabbit atrioventricular node. 944 1

The role of nitric oxide in the autonomical regulation of atrioventricular (AV) spontaneous action potentials and L-type calcium current (ICa-L) in isolated single AV nodal cells from rabbit heart was examined by using the whole cell patch clamp technique, immunohistochemical staining and single cell reverse transcription polymerase chain reaction analysis. The nitric oxide donor 3-morpholino-sydnonimine (SIN-1) (0.1 mmol/L) suppressed the beta-agonist isoproterenol- (1 mumol/L) stimulated increase in ICa-L and decreased the frequency and amplitude of spontaneous action potentials. In cells in which ICa-L had been previously attenuated by the muscarinic agonist carbamylcholine (CCh, 1 mumol/L), SIN-1 had no additive effect. Intracellular dialysis with the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA, 0.5 mmol/L) blocked CCh- but not SIN-1-induced ICa-L attenuation. However, intracellular dialysis with methylene blue (20 mumol/L), which inhibits nitric oxide-mediated activation of guanylyl cyclase and cGMP production blocked the effects of both CCh and SIN-1 on ICa-L. In these cells, neither L-NMMA nor methylene blue affected the CCh-activated potassium current (IK(ACh)). Internal dialysis with cGMP (10 mumol/L) significantly inhibited isoproterenol-stimulated ICa-L without affecting IK(ACh). In AV nodal cells internally perfused with either a nonhydrolyzable cAMP analogue, 8-Br-cAMP (0.5 mmol/L), or a high concentration of cAMP (0.5 mmol/L), CCh did not inhibit ICa-L but still activated IK(ACh). CCh-induced ICa-L attenuation could be abolished or quickly reversed by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (20 mumol/L) but not by milrinone (5 mumol/L), which only inhibits the cGMP-inhibited phosphodiesterase isozyme (PDE3). Immunohistochemical staining identified the presence of the endothelial constitutive nitric oxide synthase (NOS3) in both single AV node cells in vitro and in cryostat sections of AV node tissue in situ. These results demonstrate that endogenous nitric oxide is involved in the muscarinic cholinergic attenuation of ICa-L in AV nodal cells; the mechanism likely involves the cGMP-stimulated phosphodiesterase.
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PMID:Nitric oxide regulation of atrioventricular node excitability. 944 2

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.
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PMID:Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G. 1096 24

The use of full agonists of the A(1)-adenosine receptor (A(1)-ADOR) as antiarrhythmic agents is limited by their actions to cause high-grade atrioventricular (AV) block, profound bradycardia, atrial fibrillation, and vasodilation. It may be possible to avoid these undesired actions by use of partial agonists. We determined the effects of CVT-2759, a potential partial agonist of A(1)-ADORs, on guinea pig hearts. CVT-2759 (0.1-100 microM) increased the S-H interval of the isolated heart from 45 +/- 1 to 60 +/- 3 ms (P < 0. 01) with a half-maximal effect at 3.1 microM. CVT-2759 did not cause second-degree AV block. CVT-2759 significantly attenuated the actions of the full agonists N(6)-cyclopentyladenosine and adenosine. CVT-2759 caused a moderate slowing of atrial rate by </=13% and did not shorten the durations of either the atrial or the ventricular monophasic action potential. Coronary conductance was increased by CVT-2759 only at concentrations >10 microM. In contrast, CVT-2759 was a full agonist to decrease cAMP content of rat adipocytes and Fischer rat thyroid line 5 cells. Results of radioligand binding assays indicated that CVT-2759 stabilized a high-affinity, G protein-coupled state of the A(1)-ADOR in membranes prepared from rat adipocytes but not in membranes prepared from the guinea pig brain. The results suggest that a weak A(1)-ADOR agonist, such as CVT-2759, may be useful to slow AV nodal conduction and thereby ventricular rate without causing AV block, bradycardia, atrial arrhythmias, or vasodilation.
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PMID:A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts. 1112 49

Adenosine-induced slowing of atrioventricular nodal conduction is a rate-dependent process that is potentiated by the A(1)-adenosine receptor allosteric enhancer, PD 81,723. The ionic mechanisms underlying these phenomena were investigated in guinea pig isolated hearts and single atrial myocytes by measuring the atrium-to-His bundle (A-H) interval and using patch-clamp recordings, respectively.A decrease in atrial cycle length from 300 to 190 ms decreased the concentration of adenosine needed to cause atrioventricular nodal block from 7.8 +/- 1.0 to 2.6 +/- 0.7 micromol/L (P < 0.001). Ba(2+) (100 micromol/L), a selective blocker of the adenosine-activated inward rectifier K(+) current I(K,ADO) in the atrioventricular node, failed to abolish this rate-dependent effect of adenosine. PD 81,723 (5 micromol/L) potentiated the negative dromotropic effect of adenosine even after I(K,ADO) was blocked by Ba(2+) and after attenuation of I(Ca,L) by adenosine was prevented by 8-Br-cAMP (1.5 mmol/L). In atrial myocytes, adenosine augmented a time- and voltage-dependent K(+) current (Ado-I(K)). Ado-I(K) was more sensitive to adenosine than I(K,ADO) (EC(50) values, 0.8 versus 1.4 micromol/L, P < 0.01). PD 81,723 blocked I(K,ADO), but potentiated Ado-I(K). Ado-I(K) was insensitive to Ba(2+) (P = 0.98), whereas it was blocked by chromanol 293B (5 micromol/L, P < 0.001). Unlike I(K,ADO), Ado-I(K) increased during rapid stimulation of myocytes (P < 0.001). Adenosine augments a time- and voltage-dependent K(+) current, Ado-I(K). The pharmacological and kinetic properties of Ado-I(K) are consistent with it playing an important role in the negative dromotropic effect of adenosine at lower concentrations of the nucleoside, at fast heart rates and in the presence of PD 81,723.
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PMID:Potentiation of the negative dromotropic effect of adenosine by rapid heart rates: possible ionic mechanism. 1211 Oct 39

The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.
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PMID:Pacemaker channel dysfunction in a patient with sinus node disease. 1275 Apr 3

Endogenous opioids and nitric oxide (NO) are recognized modulators of cardiac function. Enkephalins and inhibitors of NO synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that NO systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cGMP pathway. Microdialysis probes were inserted into the SA node, and they were perfused with nonselective (Nomega-nitro-l-arginine methyl ester) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate l-arginine. Introduction of MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of l-arginine and not by d-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor S-nitroso-N-acetyl-penicillamine, the protein kinase G activator 8-bromo-cGMP, or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals.
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PMID:Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node. 1288 Dec 16

Local, rhythmic, subsarcolemmal Ca2+ releases (LCRs) from the sarcoplasmic reticulum (SR) during diastolic depolarization in sinoatrial nodal cells (SANC) occur even in the basal state and activate an inward Na(+)-Ca2+ exchanger current that affects spontaneous beating. Why SANC can generate spontaneous LCRs under basal conditions, whereas ventricular cells cannot, has not previously been explained. Here we show that a high basal cAMP level of isolated rabbit SANC and its attendant increase in protein kinase A (PKA)-dependent phosphorylation are obligatory for the occurrence of spontaneous, basal LCRs and for spontaneous beating. Gradations in basal PKA activity, indexed by gradations in phospholamban phosphorylation effected by a specific PKA inhibitory peptide were highly correlated with concomitant gradations in LCR spatiotemporal synchronization and phase, as well as beating rate. Higher levels of basal PKA inhibition abolish LCRs and spontaneous beating ceases. Stimulation of beta-adrenergic receptors extends the range of PKA-dependent control of LCRs and beating rate beyond that in the basal state. The link between SR Ca2+ cycling and beating rate is also present in vivo, as the regulation of beating rate by local beta-adrenergic receptor stimulation of the sinoatrial node in intact dogs is markedly blunted when SR Ca2+ cycling is disrupted by ryanodine. Thus, PKA-dependent phosphorylation of proteins that regulate cell Ca2+ balance and spontaneous SR Ca2+ cycling, ie, phospholamban and L-type Ca2+ channels (and likely others not measured in this study), controls the phase and size of LCRs and the resultant Na(+)-Ca2+ exchanger current and is crucial for both basal and reserve cardiac pacemaker function.
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PMID:High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. 1651 72


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