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S Nattel

Publications and source records attributed to S Nattel.

At least 109 records · Page 6Linked to original sources
PubMed1996

Protein kinase C activates ATP-sensitive K+ current in human and rabbit ventricular myocytes.

Mediators involved in ischemia preconditioning such as adenosine and norepinephrine, can activate protein kinase C (PKC), and a variety of observations suggest that both PKC and ATP-sensitive K+ current (I (KATP) play essential roles in ischemic preconditioning. PKC is therefore a candidate to link receptor binding to I(KATP) activation, but it has not been shown whether and how PKC can activate I(KATP) in the heart. The present study was designed to determine whether PKC can activate I(KATP) in rabbit and human ventricular myocytes. Under conditions designed to minimize Na+ and Ca2+ currents, dialysis of rabbit ventricular myocytes with pipette solutions containing reduced [ATP] elicited I(KATP)++, with a 50% effective concentration (EC50)of 260 micromol/L. In cells that failed to show I (KATP) under control conditions, superfusion with 1 micromol/L phorbol 12,13-didecanoate (PDD) elicited I(KATP) in a fashion that depended on pipette [ATP], with an [ATP] EC 50 of 601 micromol/L. PDD-induced I(KATP) activation was concentration dependent, with an EC 50 of 7.1 nmol/L. The highly selective PKC inhibitor bisindolylmaleimide totally prevented I(KATP) activation by PDD, and in blinded experiments, 1 micromol/L PDD elicited I(KATP) in eight of nine cells, whereas its non-PKC-stimulating analogue 4 alpha-PDD failed to elicit I(KATP) in any of the five cells tested (P = .003). Similar experiments were conducted in human ventricular myocytes and showed that 0.1 micromol/L PDD elicited I( KATP) at pipette [ATP] of 100 and 400 micromol/L (five of five cells at each concentration) but not at 1 mmol/L [ATP] (none of five cells). We conclude that PKC activates I(KATP) in rabbit and human ventricular myocytes by reducing channel sensitivity to intracellular ATP. This finding has potentially important implications for understanding the mechanisms of ischemic preconditioning.

Adenosine Triphosphate↗
PubMed1996

Evidence for two components of delayed rectifier K+ current in human ventricular myocytes.

Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.

4-Aminopyridine↗
PubMed1996

Adrenergic modulation of ultrarapid delayed rectifier K+ current in human atrial myocytes.

The ultrarapid delayed rectifier K+ current (IKur) in human atrial cells appears to correspond to Kv1.5 cloned channels and to play an important role in human atrial repolarization. Kv1.5 channels have consensus sites for phosphorylation by protein kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of IKur in human atrial myocytes. Isoproterenol increased IKur in a concentration-dependent manner, with significant effects at concentrations as low as 10 nmol/L. The effects of isoproterenol were reversible by washout or by the addition of propranolol (1 mumol/L). Isoproterenol's effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membrane-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect on IKur when the protein kinase A inhibitor peptide, PKI(6-22)amide, was included in the pipette solution; in a separate set of experiments in which isoproterenol alone increased IKur by 45 +/- 9% relative to control, subsequent superfusion with isoproterenol in the presence of the protein kinase inhibitor H-7 failed to alter IKur. In contrast to isoproterenol, phenylephrine (in the presence of propranolol to block beta-adrenegic effects) induced a concentration-dependent inhibition of IKur, with significant effects observed at concentrations as low as 10 mumol/L. The inhibitory actions of phenylephrine were reversed by the addition of prazosin and prevented by coadministration with a highly selective inhibitor of protein kinase C, bisindolylmaleimide. These results indicate that beta-adrenergic stimulation enhances, whereas alpha-adrenergic stimulation inhibits, IKur and suggest that these actions are mediated by protein kinase A and protein kinase C, respectively. The modulation of IKur by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmias.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Mechanisms of ischemic preconditioning in rat hearts. Involvement of alpha 1B-adrenoceptors, pertussis toxin-sensitive G proteins, and protein kinase C.

BACKGROUND: Ischemic preconditioning attenuates the effects of subsequent sustained ischemia by a mechanism involving adenosine and G proteins in several species. Adenosine is not involved in ischemic preconditioning of rat hearts, the mechanisms of which are poorly understood. METHODS AND RESULTS: Reduction of isometric tension development was used as an index of the effects of ischemia in isolated, Langendorff-perfused rat hearts. Two 5-minute periods of ischemia followed by 10 minutes of reperfusion attenuated the reduction of developed tension caused by 30 minutes of ischemia and 15 minutes of reperfusion. Pretreatment with pertussis toxin (PTX), depletion of norepinephrine stores with reserpine, or blockade of alpha 1-adrenoceptors with prazosin prevented the effects of ischemic preconditioning. Whereas alpha 1B-receptor blockade with chloroethylclonidine blocked ischemic preconditioning, alpha 1A-receptor blockade with 5-methylurapadil had no effect. The alpha-adrenergic agonist phenylephrine mimicked the effects of ischemic preconditioning in a concentration-dependent manner, and pretreatment with PTX prevented the action of maximally effective concentrations of phenylephrine. The protein kinase C activator phorbol 12-myristate 13-acetate mimicked and the protein kinase C inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine and bisindolylmaleimide prevented ischemic preconditioning. CONCLUSIONS: Ischemic preconditioning in isolated, perfused rat hearts is caused by stimulation of alpha 1B-adrenoceptors by endogenous catecholamines through the activation of protein kinase C via a PTX-sensitive G protein. The PTX-sensitive inhibitory protein Gi, which can be activated by adenosine, muscarinic agonists, and alpha 1-adrenoceptor agonists, may play a central role in ischemic preconditioning mediated by protein kinase C across a broad range of species.

Animals↗
PubMed1995

Determinants and mechanisms of flecainide-induced promotion of ventricular tachycardia in anesthetized dogs.

BACKGROUND: Class IC antiarrhythmic agents such as flecainide are known to have potentially significant ventricular proarrhythmic actions, but the underlying mechanisms are incompletely understood. While some studies have reported proarrhythmia in both healthy dogs and dogs that previously have had a myocardial infarction (MI), there are no published, controlled studies comparing proarrhythmia in healthy dogs vs in dogs with MI. In addition, the concentration dependence of proarrhythmia is unknown and the electrophysiological changes associated with proarrhythmia are not well established. METHODS: We administered successive loading and maintenance infusions of flecainide until ventricular tachyarrhythmia or death occurred in 13 healthy dogs and 19 dogs with 72-hour-old MIs (MI dogs). Ventricular proarrhythmia, defined as reproducible ventricular tachycardia absent under control conditions and occurring in the presence of flecainide, was observed in 4 of 13 healthy dogs (31%) and 15 of 19 MI dogs (79%, P = .02), and drug-induced spontaneous ventricular tachycardia occurred in 8 of 19 MI dogs but in no healthy dogs (P = .007). Activation data at the time of proarrhythmia were available for 11 MI dogs and provided evidence for reentry in 9, with a complete epicardial reentry circuit identified in 4 dogs and a partial circuit in 5. While flecainide slowed ventricular conduction in both the longitudinal and transverse directions, there were no significant differences between overall drug-induced conduction changes in MI dogs compared with healthy dogs. However, in 7 MI dogs for whom activation data were available during ventricular pacing at concentrations comparable to those causing proarrhythmia, flecainide induced a new arc of block in 6 of 7, whereas an arc of block was never observed in the absence of proarrhythmia. Conduction block was induced transverse to fiber orientation in a rate-dependent fashion and was caused by a regionally-specific effect of the drug. No differences were noted between refractory periods proximal and distal to the site of block. CONCLUSIONS: Prior MI strongly predisposes dogs to flecainide proarrhythmia, which occurs in the majority of such dogs in a concentration-related way. In most cases, activation data suggest that anisotropic reentry around a localized arc of rate-dependent transverse conduction block underlies proarrhythmia. These results provide insights into the conditions and mechanisms underlying the ability of flecainide to promote the occurrence of ventricular tachycardia.

Animals↗
PubMed1995

Contribution of ATP-sensitive potassium channels to the electrophysiological effects of adenosine in guinea-pig atrial cells.

1. Adenosine caused dose-dependent action potential abbreviation in multicellular guinea-pig atrial preparations, an action antagonized by glyburide (IC50, 31 microM) in both physiological and low-chloride superfusate. 2. When 5 mM ATP was included in pipettes for whole-cell voltage clamp of isolated guinea-pig atrial myocytes, adenosine (10 microM) increased the holding current at -40 mV from 41 +/- 8 to 246 +/- 31 pA (mean +/- S.E.M., P < 0.01), and glyburide (20 microM) returned the holding current to 69 +/- 11 pA (P < 0.01 vs. adenosine alone). Acetylcholine (10 microM) also increased the holding current, but its effects were not altered by glyburide. 3. Both adenosine and acetylcholine induced an additional current component in response to 500 ms voltage steps. Glyburide partially inhibited the adenosine-induced current, but did not alter the effect of acetylcholine. In the presence of maximally effective acetylcholine concentrations, adenosine increased membrane conductance (P < 0.01), although to a lesser extent than in the absence of acetylcholine. 4. Single K+ channel activity was seen in only one of eight cell-attached patches in the absence of adenosine or acetylcholine (0.5 mM Ba2+ in bath and pipette solutions). With acetylcholine (10 microM) in the pipette, inwardly rectifying channels (conductance, 41 +/- 5 pS) were seen in five of six patches. With adenosine (10 microM) in the pipette, single-channel activity was seen in twelve of fourteen patches with two populations of channels, one similar to that induced by acetylcholine and another higher-conductance channel (72 +/- 5 pS) that showed less inward rectification. Glyburide (20 microM) suppressed the high-conductance channel (68 +/- 2 pS) leaving a single channel type with a conductance of 36 +/- 5 pS and strong inward rectification. 5. We conclude that K+ATP channels contribute to the electrophysiological actions of adenosine on guinea-pig atrium in the presence of physiological intracellular ATP levels, and may therefore play a role in the cardiac electrophysiological effects of adenosine in the absence of myocardial ischaemia.

Acetylcholine↗
PubMed1995

Long-term risk stratification with dipyridamole imaging.

This study was undertaken to assess the reliability of clinical parameters and dipyridamole-thallium 201 images for predicting the occurrence of future cardiac events (nonfatal myocardial infarction or cardiac death). Dipyridamole myocardial perfusion imaging is routinely performed in patients who have possible or known coronary disease and a low exercise tolerance. A total of 753 patients underwent clinical assessment and semiquantitative dipyridamole-201TI imaging and were followed up as outpatients. Patients who underwent coronary revascularization during the follow-up period were excluded from the study because the decision to intervene would have been based at least in part on the test itself. There were 82 cardiac events and 54 noncardiac deaths, and 11 patients were lost to follow-up after a mean follow-up of 15 months. With use of a quantitative index reflecting the amount of jeopardized myocardium, patients could be stratified by dipyridamole imaging into subsets with coronary morbidity and mortality rates ranging from 1% to 89%, (p = 0.0001). When clinical and scintigraphic variables were subjected to backward stepwise logistic regression analysis, the significant predictors of cardiac events were the jeopardized myocardium index by scintigraphy (p < 0.0001), left ventricular hypertrophy on the electrocardiogram (p = 0.0009), and transient dipyridamole-induced left ventricular cavitary dilatation (p = 0.0073). Quantitative dipyridamole-201TI imaging appears to be a powerful predictor of future cardiac events in patients with coronary disease and a low exercise tolerance and is a potentially useful contributor to risk-profile assessment and to the treatment of these patients.

Aged↗
PubMed1995

Newer developments in the management of atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. Unlike reentrant supraventricular tachycardia and malignant ventricular tachyarrhythmias, for which highly effective and safe nonpharmacologic therapies are available, the treatment of AF remains controversial and often problematic. Whereas electrical cardioversion restores sinus rhythm in most patients with AF, the maintenance of sinus rhythm often requires membrane-active antiarrhythmic drugs that may increase mortality by inducing ventricular proarrhythmia. The control of ventricular response rate, often associated with oral anticoagulation to prevent thromboembolic complications, is an alternative strategy in AF management. The relative efficacy and risks of these strategies and their respective role in different patient subgroups remain to be established. This article focuses on newer developments in the management of AF, including prospects for improved methods to maintain sinus rhythm, newer approaches to rate control, controversies regarding the use of oral anticoagulation, and novel nonpharmacologic therapies. These newer developments may lead over the next 10 years to a revolution in the management of AF as profound as that produced over the last 10 years by nonpharmacologic therapy of other arrhythmias.

Adrenergic beta-Antagonists↗
PubMed1995

Idiopathic atrial fibrillation in dogs: electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide.

OBJECTIVES: This study sought to determine the mechanisms of idiopathic atrial fibrillation and the atrial antifibrillatory action of flecainide in dogs. BACKGROUND: In a small subset of dogs, sustained atrial fibrillation can be readily induced in the absence of vagal tone. The electrophysiologic mechanisms underlying this ability to sustain atrial fibrillation, and of flecainide action on the arrhythmia, are unknown. METHODS: Six dogs with inducible sustained atrial fibrillation were studied before and after flecainide administration and compared with a control group of 10 dogs. RESULTS: Dogs with atrial fibrillation differed in displaying more shortening of the atrial refractory period with increased rate, resulting in a significantly shorter refractory period and wavelength for reentry at rapid rates, and in increased regional dispersion in refractoriness. Activation maps during sustained fibrillation showed a mean (+/- SE) of 6.3 +/- 0.4 coexistent zones of reentry, compatible with short wavelengths, whereas in control dogs activation during self-limited atrial fibrillation was better organized, and the number of reentrant circuits was smaller. Quantitative analysis demonstrated significantly greater inhomogeneity of activation during atrial fibrillation in dogs with atrial fibrillation than in control animals. Flecainide terminated atrial fibrillation by increasing the duration and homogeneity of atrial refractoriness at rapid rates, thereby reducing the number of reentry circuits and the heterogeneity of activation. CONCLUSIONS: The ability of atrial fibrillation to sustain itself resulted from enhanced rate-dependent shortening of atrial refractoriness and increased regional heterogeneity. Flecainide reversed these changes and restored sinus rhythm. These results suggest potential mechanisms of idiopathic atrial fibrillation and are pertinent to understanding the clinical actions of flecainide.

Action Potentials↗
PubMed1995

Is cardiac migraine a clinical entity?

Chest pain because of a disorder of the coronary circulation is assumed to be ischemic in nature. Irrespective of the underlying pathophysiological mechanism, it is accepted that all routes lead to myocardial ischemia in the pathway to anginal pain. The authors describe a patient with a history of vasoactive disorders including migraine, asthma, documented variant angina with prolonged episodes of chest pain, and scintigraphic evidence of inferior and posterior wall ischemia during exercise and ergonovine testing in the absence of significant underlying stenoses. Remarkably, severe retrosternal chest pain, ST segment depression in multiple leads, and relative increased uptake in the inferior and posterior walls on Tc-99m sestamibi tomographic images developed during pharmacologic coronary vasodilatation with dipyridamole, leading the authors to speculate as to the possible existence of a nonischemic chest pain syndrome caused by coronary vasodilatation either in association with variant angina or as a separate entity.

Angina Pectoris, Variant↗
PubMed1995

Role of chloride currents in repolarizing rabbit atrial myocytes.

Rabbit atrial cells manifest a prominent transient outward K+ current (Ito1), but this current recovers slowly from inactivation and is unlikely to be important at physiological rates (3-5 Hz). Depolarization of rabbit atrial cells also elicits a transient Ca(2+)-dependent outward Cl- current (Ito2). To compare the relative magnitude of these transient outward currents at various rates, we applied whole cell voltage-clamp techniques to isolated rabbit atrial myocytes. Whereas peak Ito1 exceeded Ito2 at slow rates (0.1 Hz), Ito1 was strongly reduced as rate was increased (by 97 +/- 2%, mean +/- SE, at 4 Hz), while Ito2 was slightly reduced (by 28 +/- 4%, 4 Hz). The reversal potential of transient outward tail currents at 0.07 Hz was -49 +/- 9 mV, while at 2.5 Hz the reversal potential became -18 +/- 7 mV (calculated Cl- reversal potential -18 mV). The addition of the Cl- transport blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; 150 microM) or the replacement of external Cl- with methanesulfonate inhibited a large part of the transient outward current elicited by depolarization at 4 Hz. DIDS and Cl- replacement increased action potential duration in both single rabbit atrial cells and multicellular rabbit atrial preparations. We conclude that the Ca(2+)-dependent Cl- current is substantially larger than the transient K+ current at physiological rates in the rabbit and is likely to play a more important role in action potential repolarization than the latter current in this tissue in vivo.

4-Aminopyridine↗
PubMed1995

Comparative mechanisms of 4-aminopyridine-resistant Ito in human and rabbit atrial myocytes.

The cardiac transient outward current (Ito) has been shown in several species to consist of two components: 1) a 4-aminopyridine (4-AP)-sensitive component (Ito1) and 2) a 4-AP-resistant component (Ito2). In rabbits, Ito2 is a Ca(2+)-dependent Cl- current [ICl(Ca)]; similar mechanisms have been suggested to underlie Ito2 in human atrium. We used whole cell patch-clamp techniques to define the mechanism of Ito2 (defined as the component resistant to 5 mM 4-AP) in human atrial myocytes, with parallel experiments performed in rabbit atrial cells. In rabbit atrium, Ito2 activated more slowly than Ito1 and had a bell-shaped current-voltage of Ito with properties similar to Ito2 in the rabbit, and a similar component recorded with pipette K+ replaced by Cs+ was suppressed by the substitution of methanesulfonate for Cl- in the superfusate. In human cells, a 4-AP-resistant Ito2 was recorded at a depolarizing pulse frequency of 1 Hz, but not at 0.1 Hz. Ito2 activated rapidly and inactivated earlier than Ito1, whereas its I-V relation was linear like that of Ito1. Ryanodine had no effect on human atrial Ito. When K(+)-free pipette solutions were used, no Ito was recorded in 30 human atrial myocytes, and external Cl- replacement with methanesulfonate failed to reveal an Ito. In 13 human myocytes, isoproterenol increased ICa but failed to activate an Ito compatible with ICl(Ca). Whereas caffeine suppressed human atrial Ito, it also suppressed Ito1 [in the presence of 200 microM Cd2+ to block ICa and 5 mM intracellular ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid to buffer intracellular Ca2+] in both human and rabbit atrium, indicating an action unrelated to Ca(2+)-triggered Ca2+ release. In conclusion, we were unable to demonstrate the presence of ICl(Ca) in human atrial myocytes, and the 4-AP-resistant component of Ito appeared to be due to 4-AP unblocking.

4-Aminopyridine↗
PubMed1995

Alpha-adrenergic control of volume-regulated Cl- currents in rabbit atrial myocytes. Characterization of a novel ionic regulatory mechanism.

alpha-Adrenergic stimulation is known to play a role in cardiac arrhythmogenesis and to modulate a variety of cardiac K+ currents. The effects of alpha-adrenergic stimulation on Cl- currents are largely unknown. Many cardiac cell types show a volume-sensitive Cl- current induced by cell swelling (ICl.swell). The present experiments were designed to assess the potential alpha-adrenergic modulation of ICl.swell in rabbit atrial myocytes. ICl.swell was induced with the use of a hypotonic superfusate, under conditions designed to prevent currents carried by K+, Na+, and Ca2+ ions. A basal Cl- current (ICl.b) was observed under isotonic conditions in 128 of 150 cells (85%), had the same dependency on [Cl-]o as ICl.swell, and was reduced by cell shrinkage induced by hypertonic superfusion, suggesting that ICl.b is carried by the same volume-sensitive Cl- conductance as ICl.swell. Phenylephrine produced a concentration-dependent and near-complete inhibition of ICl.b and ICl.swell, with EC50 values of 86 +/- 5 and 72 +/- 7 (mean +/- SEM) mumol/L, respectively, at +20 mV. Norepinephrine (administered in the presence of 1 mumol/L propranolol) also inhibited ICl.b and ICl.swell, with EC50 values of 2.6 +/- 0.1 and 2.8 +/- 0.4 mumol/L, respectively. The concentration-response curve for phenylephrine was shifted significantly (P < .001) to the right by the alpha 1-adrenoceptor antagonist prazosin and by the alpha 1A-receptor antagonists (+)-niguldipine and 5-methylurapidil but was unaltered by the alpha 1B-receptor antagonist chloroethylclonidine (100 mumol/L). Inhibition of protein kinase C (PKC) with staurosporine, H-7, or 18-hour preincubation with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) blocked the effects of phenylephrine on ICl.swell, and the highly selective PKC inhibitor bisindolylmaleimide blocked the effects of norepinephrine on ICl.swell and ICl.b. Both PMA and 1-oleoyl-2-acetylglycerol inhibited ICl.swell in a concentration-dependent fashion. In blinded studies, the phorbol ester phorbol 12,13-didecanoate (PDD) reduced ICl.swell by 91 +/- 3%; its inactive analogue 4 alpha-PDD had no effect (mean change, 3 +/- 1%). Preincubation with pertussis toxin (PTX) prevented the actions of phenylephrine on ICl.swell, indicating a role for a PTX-sensitive guanine nucleotide-binding (G) protein. We conclude that alpha-adrenergic agonists inhibit volume-sensitive Cl- currents in rabbit atrial cells by interacting with an alpha 1A-adrenoceptor mechanism that is coupled to PKC via a PTX-sensitive G protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1995

Voltage- and time-dependent block by perhexiline of K+ currents in human atrium and in cells expressing a Kv1.5-type cloned channel.

Perhexiline maleate is an antianginal drug that has been shown to have antiarrhythmic effects in humans. To examine whether some of these clinical observations could be caused by block of cardiac K+ channels, we examined the effects of perhexiline on a rapidly activating delayed rectifier K+ channel (Kv1.5) cloned from human heart and stably expressed in human embryonic kidney cells as well as a corresponding K+ current (the ultra-rapid delayed rectifier, IKur) in human atrial myocytes. With the use of inside-out macropatches, we found that perhexiline inhibited Kv1.5 current in a time- and voltage-dependent manner with an IC50 value of 1.5 x 10(-6) M at +50 mV. Perhexiline reduced Kv1.5 tail current amplitude and slowed its decay relative to control. These data are consistent with blockade of open channels, probably from the intracellular surface. Perhexiline (3 microM) also blocked IKur in human atrial myocytes. The block that was observed was both time- and voltage-dependent in qualitatively similar ways to block of Kv1.5 channels. However, the time-dependent block of IKur by perhexiline was somewhat slower and its voltage-dependence steeper relative to its effects on Kv1.5. These data indicate that perhexiline blocks both cloned and native human cardiac K+ channels. Blockade of one or more types of voltage-dependent K+ channels may explain some of the electrophysiological effects of perhexiline observed in humans.

Atrial Function↗
PubMed1995

Effects of flecainide, quinidine, and 4-aminopyridine on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes.

Antiarrhythmic drugs prevent atrial reentrant arrhythmias by prolonging atrial action potential duration and refractoriness. The ionic mechanisms by which antiarrhythmic drugs alter human atrial repolarization are poorly understood. The present study was designed to assess the concentration-, voltage-, time- and frequency-dependent effects of the antiarrhythmic agents quinidine and flecainide, as well as of the K+ channel blocker 4-aminopyridine, on the calcium-independent transient outward current (Ito1) and the ultrarapid delayed rectifier current (IKur) in isolated human atrial myocytes. Quinidine and flecainide blocked Ito1 at clinically relevant concentrations. Block of Ito1 by quinidine was use and frequency dependent, whereas block by flecainide was frequency independent, and 4-aminopyridine showed use-dependent unblocking. Depolarizing prepulses enhanced flecainide block and reduced 4-aminopyridine block in a fashion suggesting a preferential interaction with the inactivated state for flecainide and with the resting, closed state for 4-aminopyridine. Quinidine block depended on the potential of a depolarizing test pulse in a fashion suggesting open channel block. All three drugs accelerated channel inactivation during depolarization at 1 Hz and failed to block Ito1 during initial current rise, with block appearing with time constants of 6.3 +/- 1.2 msec for flecainide, 14.5 +/- 4.2 msec for quinidine and 3.0 +/- 0.9 msec for 4-aminopyridine at 16 degrees C, suggesting a role for channel opening in block development. Quinidine blocked IKur at clinical concentrations, whereas flecainide had no effect on IKur. Quinidine block of IKur was voltage dependent, with part of the voltage dependence attributable to open-channel block and the remainder compatible with a blocking site within the voltage field at a position subject to 23% of the total electrical field. Quinidine's blocking actions on IKur were similar to those previously reported for block of a cardiac K+ channel clone of the Shaker family (Kv1.5), for which IKur is believed to be the equivalent native current. These results indicate that flecainide and quinidine block Ito1, and quinidine blocks IKur, in human atrial myocytes in a state-dependent fashion. Because drug effects are manifest at clinically relevant concentrations, and Ito1 and IKur have been shown to be potentially important currents in human atrial repolarization, these findings are relevant to understanding the ionic mechanisms underlying the clinical antiarrhythmic properties of these drugs.

4-Aminopyridine↗