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J C Hancox

Publications and source records attributed to J C Hancox.

At least 19 recordsLinked to original sources
PubMed2006

Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine: a case-study in cardiac safety pharmacology.

Drug-induced prolongation of the rate-corrected QT interval (QTCI) on the electrocardiogram occurs as an unwanted effect of diverse clinical and investigational drugs and carries a risk of potentially fatal cardiac arrhythmias. hERG (human ether-à-go-go-related gene) is the gene encoding the alpha-subunit of channels mediating the rapid delayed rectifier K+ current, which plays a vital role in repolarising the ventricles of the heart. Most QTCI prolonging drugs can inhibit the function of recombinant hERG K+ channels, consequently in vitro hERG assays are used widely as front-line screens in cardiac safety-testing of novel chemical entities. In this issue, Rajamani and colleagues report a case of QTCI prolongation with the antidepressant fluoxetine and correlate this with a dual effect of the drug and of its major metabolite norfluoxetine on hERG channels. Both compounds were found to produce an acute inhibition of the hERG channel by pharmacological blockade, but in addition they also were able to disrupt the normal trafficking of hERG protein to the cell membrane. Mutations to a key component of the drug binding site in the S6 region of the channel greatly attenuated channel block, but did not impair disruption of trafficking; this suggests that channel block and drug effects on trafficking were mediated by different mechanisms. These findings add to growing evidence for disruption of hERG channel trafficking as a mechanism for drug-induced long QT syndrome and raise questions as to possible limitations of acute screening methods in the assessment of QTcI prolonging liability of drugs in development.

Antidepressive Agents, Second-Generation↗
PubMed2006

VEGF activates receptor-operated cation channels in human microvascular endothelial cells.

OBJECTIVE: Vascular endothelial growth factor (VEGF) exerts many of its effects by stimulating endothelial calcium influx, but little is known about channels mediating VEGF-induced cation entry. The aim of this study was to measure and characterize for the first time the VEGF-activated cation current in human microvascular endothelial cells (HMVECs). METHODS AND RESULTS: Whole-cell patch-clamp recordings were made from HMVECs. During applied voltage ramps, VEGF activated a current that reversed at 0 mV, was sensitive to gadolinium, and required extracellular cations. Noise analysis yielded a single-channel conductance of 27 pS. The current was not dependent on intracellular calcium stores, and was not blocked by inositol triphosphate (IP3) receptor or serine/threonine kinase inhibition but was partially inhibited by flufenamic acid. A similar current was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analog of diacylglycerol (DAG). To determine whether VEGF could activate recombinant ion channels with similar properties, we investigated the effect of VEGF on Chinese hamster ovary cells cotransfected with VEGFR2 and the canonical transient receptor potential (TRPC) channels, TRPC3 or TRPC6. VEGF induced a similar current to that described above in VEGFR2-TRPC3 and VEGFR2-TRPC6 cells but not in cells transfected with either cDNA alone. CONCLUSIONS: VEGF activates a receptor-operated cation current in HMVECs and OAG can activate directly a similar current in these cells. VEGF is also able to activate heterologously expressed TRPC3/6 channels through VEGFR2.

Animals↗
PubMed2004

Paradoxical effects of insulin on cardiac L-type calcium current and on contraction at physiological temperature.

AIMS/HYPOTHESIS: L-type calcium current (I(Ca,L)) is a major determinant of mammalian cardiac contraction, and data from studies performed at room temperature suggest that this current is stimulated by insulin. This investigation aimed to determine whether or not insulin stimulates cardiac I(Ca,L) at 37 degrees C. METHODS: Isolated guinea pig ventricular myocytes were studied at room temperature and at 37 degrees C. Myocytes were either field stimulated or whole-cell voltage clamped, and cell shortening was measured using video edge detection. RESULTS: Insulin stimulated I(Ca,L) at ambient temperature. However, at 37 degrees C the effect of insulin was to decrease rather than to increase I(Ca,L). This action was concentration dependent and was not associated with voltage shifts in steady-state activation or inactivation properties of I(Ca,L). At 37 degrees C, insulin increased the extent of myocyte contraction despite producing a significant decrease in I(Ca,L) amplitude. CONCLUSIONS/INTERPRETATION: The findings of this study indicate that temperature is a key experimental variable in the study of the physiological actions of insulin. Furthermore, the increase in cardiac cell contraction by insulin at physiological temperature is not due to an increase in I(Ca,L), but is probably due to stimulation of excitation-contraction coupling downstream of I(Ca,L).

Animals↗
PubMed2003

Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine.

4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current (ITO,1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-à-go-go-related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study ITO,1. Under voltage clamp, whole cell HERG current (IHERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 +/- 0.5 mM. Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 mM 4-AP inhibited peak IHERG during an applied action potential clamp waveform by ~59 %. It also significantly prolonged action potentials and inhibited resurgent IK tails from guinea-pig isolated ventricular myocytes, which lack an ITO,1. We conclude that by blocking the alpha-subunit of the IKr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on ITO,1.

4-Aminopyridine↗
PubMed2003

Evidence for a modulatory effect of external potassium ions on ionic current mediated by the cardiac Na+-Ca2+ exchanger.

The aim of this study was to investigate whether or not the activity of the cardiac Na(+)-Ca(2+) exchanger might be directly sensitive to external K(+) concentration ([K(+)](e)). Measurements of whole-cell exchanger current (I(NaCa)) were made at 37 degrees C from guinea-pig isolated ventricular myocytes, using whole-cell patch clamp recording with major interfering conductances blocked. Changing [K(+)](e) from 0 to 5mM significantly reduced both outward and inward exchange currents in a time-dependent manner. Various [K(+)](e) between 1 and 15 mM were tested and the inhibitory effect was observed to be concentration-dependent. At steady-state, 5mM [K(+)](e) decreased the density of Ni(2+)-sensitive current by 52.8+/-4.3% (mean+/-S.E.M., n=6) and of 0Na0Ca-sensitive current by 39.0+/-4.4% (n=5). The possibility that the inhibitory effect of external K(+) on I(NaCa) might wholly or in part be secondary to activation of the sarcolemmal Na(+)-K(+) pump was investigated by testing the effect of K(+) addition in the presence of a high concentration of strophanthidin (500 microM). Ni(2+)-sensitive I(NaCa) was still observed to be sensitive to external K(+) (I(NaCa) decreased by 39.4+/-9.4%, n=4), suggesting that the inhibitory effect could occur independently of activation of the Na(+)-K(+) pump. The effect of external K(+) on I(NaCa) was verified using a baby hamster kidney (BHK) cell line stably expressing the cardiac Na(+)-Ca(2+) exchanger isoform, NCX1. Similar to native I(NaCa), NCX1 current was also suppressed by [K(+)](e). However, [K(+)](e) did not alter current amplitude in untransfected BHK cells. The effect of [K(+)](e) on I(NaCa) could not be attributed to simply adding any monovalent cation back to the external solution, since it was not reproduced by application of equimolar Li(+), Cs(+) and TEA(+). Rb(+), however, could mimic the effect of K(+). Collectively, these data suggest that external K(+) at physiologically and pathologically relevant concentrations might be able to modulate directly the activity of the cardiac Na(+)-Ca(2+) exchanger.

Animals↗
PubMed2002

Comparison of Na(+)/Ca(2+) exchanger current and of its response to isoproterenol between acutely isolated and short-term cultured adult ventricular myocytes.

The Na(+)/Ca(2+) exchanger protein is present in the cell membrane of many tissue types and plays key roles in Ca(2+) homeostasis, excitation-contraction coupling, and generation of electrical activity in the heart. The use of adult ventricular myocyte cell culture is important to molecular biological approaches to study the roles and modulation of the cardiac Na(+)/Ca(2+) exchanger. Therefore, we characterised the functional expression of the exchanger in adult guinea-pig ventricular myocytes maintained in short-term culture (for 4 days) and compared the response of ionic current (I(NaCa)) carried by the exchanger from acutely isolated and Day 4 cells to beta-adrenoceptor activation with isoproterenol (ISO). Functional activity of the exchanger was assessed by measuring I(NaCa) using whole cell patch clamp, under selective recording conditions. I(NaCa) amplitude measured at both +60 and -100mV declined significantly by Day 1 of cell culture, showing a further small decline by Day 4. However, cell surface area (assessed by measuring membrane capacitance) also declined over this time-frame. I(NaCa) normalised to membrane capacitance (I(NaCa) density) did not differ significantly between acutely isolated and cells cultured for 4 days. However, although ISO (1 microM) increased I(NaCa) in acutely isolated myocytes, it exerted no significant effect on I(NaCa) from Day 4 cells. This was not due to an inherent inability of these cells to respond to ISO, as L-type calcium current amplitude from Day 4 cells was increased by ISO to a similar extent as that from acutely isolated cells. Our data suggest that the functional expression of the Na/Ca exchanger is well maintained during short-term culture of adult ventricular myocytes. The lack of response to ISO of I(NaCa) from Day 4 cells suggests: (a) that, despite a well-maintained I(NaCa) density, cultured adult myocytes may not necessarily be suitable for studies of exchanger modulation by some agonists and (b) that there may exist subtle differences between beta-adrenergic regulation of the exchanger protein and of L-type Ca channels.

Adrenergic beta-Agonists↗
PubMed2001

Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.

The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'acquired' prolongation of the QT interval of the electrocardiogram (ECG). This potentially proarrhythmic effect is likely to reflect drug actions on ion channels involved in ventricular action potential repolarisation. In this study, we examined the effects of DISO on potassium channels encoded by HERG, as this K channel type has been implicated in both congenital and acquired long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently transfected with HERG cDNA for subsequent whole cell patch clamp recording. HERG tail currents recorded at -40 mV following test pulses to +30 mV were inhibited in a dose-dependent fashion by DISO concentrations within the clinical range (IC50 = 7.23 +/- 0.72 microM; mean +/- SEM). Experiments with 10 microM DISO indicated that the degree of HERG blockade showed some voltage dependence. Further data obtained using an 'envelope of tails' protocol (pulse potential +40 mV) were consistent with a significant role for open-channel blockade at lower drug concentrations. At higher concentrations it is possible that blockade may have involved drug binding to both resting and open channels. Inhibition of the inactivation-deficient mutant HERG-S631A was comparable to that seen for wild-type HERG. Therefore, channel inactivation was not obligatory for DISO to exert its effect. Native delayed rectifier tail currents from rabbit isolated ventricular myocytes were also inhibited by DISO. We conclude (a) that DISO inhibits HERG encoded potassium channels at clinically relevant concentrations and (b) that this action may constitute the molecular basis for acquired LQTS associated with this drug.

Animals↗
PubMed2001

Anti-adrenergic effect of adenosine on Na(+)-Ca(2+) exchange current recorded from guinea-pig ventricular myocytes.

The Na(+)-Ca(2+) exchanger is a protein present in the cell membrane of many cell types. In heart it plays important roles in Ca homeostasis and ionic current generation. Recently, it has been reported that the beta-adrenergic agonist isoprenaline (ISO) can increase directly Na(+)-Ca(2+) exchanger activity in guinea-pig ventricular myocytes. Adenosine (ADO) exerts anti-adrenergic properties that make it effective against some arrhythmias and the aim of the present study was to determine whether or not ADO can antagonize the direct modulatory effect of ISO on the exchanger.Whole-cell patch clamp measurements of Na(+)-Ca(2+) exchanger current (I(NaCa)) were made from guinea-pig ventricular myocytes, with major interfering currents inhibited. I(NaCa) was measured at 378 degrees C as current sensitive to external nickel (Ni(2+), 10 mM) during an applied descending voltage ramp. ISO (1 microM) significantly increased both inward and outward I(NaCa). This effect was abolished in the presence of ADO (200 microM). ADO alone did not significantly alter the amplitude of I(NaCa). The effect of ADO on the response of I(NaCa) to ISO was mimicked by the A(1)ADO receptor agonist N(6)-cyclopentyladenosine (CPA, 10 microM), whereas the effect of ADO on the response of I(NaCa) to ISO was inhibited by the A(1)ADO receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 microM). These data suggest that the A(1)ADO receptor mediated the response. The anti-adrenergic effects on I(NaCa) of ADO were not affected by the protein kinase C (PKC) inhibitor, chelerythrine (CLT, 1 microM), nor by the nitric oxide (NO) synthase inhibitor, N (G)-nitro-L-arginine methyl ester((L)-NAME, 0.5 mM). Moreover, in the presence of PKC activator phorbol 12-myristate 13-acetate (PMA, 1 microM) or exogenous NO donor sodium nitroprusside (SNP, 100 microM), ISO preserved its stimulatory effect on I(NaCa). However, prior incubation of myocytes with pertussis toxin (PTX, 5 microg ml(-1) did prevent the effect of ADO. The anti-adrenergic effect of ADO on I(NaCa) was mimicked by externally applied carbachol (CCh, 10 microM), a muscarinic receptor agonist. We conclude that ADO antagonized the effect of beta-adrenergic stimulation of I(NaCa) by directly activating inhibitory G-protein (G(i))-linked A(1) receptors in guinea-pig ventricular myocytes. These findings may suggest a novel mechanism by which adenosine exerts some of its antiarrhythmic effects.

Adenosine↗
PubMed2001

Regulation by endothelin-1 of Na+-Ca2+ exchange current (I(NaCa)) from guinea-pig isolated ventricular myocytes.

The cardiac Na+-Ca2+ exchanger participates in Ca homeostasis, and Na+-Ca2+ exchanger-mediated ionic current (I(NaCa)) also contributes to the regulation of cardiac action potential duration. Moreover, I(NaCa) can contribute to arrhythmogenesis under conditions of cellular Ca overload. Although it has been shown that the peptide hormone endothelin-1 (ET-1) can phosphorylate the cardiac Na+-Ca2+ exchanger via protein kinase C (PKC), little is known about the effect of ET-1 on I(NaCa). In order to examine the effects of ET-1 on I(NaCa), whole-cell patch clamp measurements were made at 378C from guinea-pig isolated ventricular myocytes. With major interfering currents inhibited, I(NaCa) was measured as the current sensitive to nickel (Ni; 10mM) during a descending voltage ramp. ET-1 (10 nM) significantly increased I(NaCa) ( approximately 2-fold at -100 mV). Application of a PKC activator (PMA; 1mM: phorbol 12-myristate 13-acetate), mimicked the effect of ET-1. In contrast, the PKC inhibitor chelerythrine (CLT, 1mM) abolished the stimulatory effect of ET-1. An inactive phorbol ester, 4-alpha-phorbol-12,13-didecanoate (4a-PDD, 1mM) had no effect on I(NaCa). Collectively, these data indicate that ET-1 activated I(NaCa) through a PKC-dependent pathway. In additional experiments, isoprenaline (ISO; which has also been reported to activate I(NaCa) ) was applied. The increase in I(NaCa) density with ISO (1mM) was similar to that induced by ET-1 (10nM). When I(NaCa) was pre-stimulated by ET-1, application of ISO elicited no further increase in current and vice versa. ISO also had no additional effect on I(NaCa) when the cells were pretreated with PMA. Application of CLT did not alter the response of I(NaCa) to ISO. We conclude that ET-1 stimulated ventricular I(NaCa) via a PKC-dependent mechanism under our recording conditions. Concentrations of ET-1 and ISO that stimulated I(NaCa) to similar extents when applied separately were not additive when co-applied. The lack of synergy between the stimulatory effects of ET-1 and ISO may be important in protecting the heart from the potentially deleterious consequences of excessive stimulation of I(NaCa).

Adrenergic beta-Agonists↗
PubMed2001

Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes.

The methanesulphonanilide agent dofetilide (UK-68,798) exerts Class III antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (I(Kr)) encoded by HERG. The aim of the present study was to determine whether dofetilide also exhibits Class IV (L-type calcium-channel blocking) effects. L-type calcium current (I(Ca,L)) was measured from rabbit isolated ventricular myocytes, using the whole-cell patch-clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of I(Ca,L) elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nM, 1 microM and 10 microM. I(Ca,L) magnitude was not significantly reduced by any of the concentrations tested (P > 0.05; n = minimum of seven cells per drug concentration). The inactivation time-course of I(Ca,L) was also unaffected by 10 microM dofetilide. Heterologously expressed HERG current (I(HERG)) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 microM dofetilide, with inhibition at 1 microM not significantly different from 100% (P > 0.1). It is concluded that dofetilide produced no I(Ca,L) blocking effects at concentrations up to and exceeding that required for maximal I(HERG) inhibition. The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity.

Animals↗
PubMed2001

Actions of pyrethroid insecticides on sodium currents, action potentials, and contractile rhythm in isolated mammalian ventricular myocytes and perfused hearts.

Pyrethroid insecticides are known to modify neuronal sodium channels, inducing persistent, steady-state sodium current at depolarized membrane potentials. Cardiac myocytes are also rich in sodium channels but comparatively little is known about the effect of pyrethroids on the heart, or on the cardiac sodium channel isoform. In the present study therefore, we determined the actions of type I and type II pyrethroids against rat and guinea pig ventricular myocytes under current and voltage clamp, and on isolated perfused rat hearts. In myocytes, tefluthrin (type I) and fenpropathrin and alpha-cypermethrin (type II) prolonged action potentials and evoked afterdepolarizations. The time course of sodium current (I(Na)) was also prolonged by these compounds. Pyrethroids delayed I(Na) inactivation, when measured under selective conditions as current sensitive to 30 microM tetrodotoxin, by increasing the proportion of slowly inactivating current at the expense of fast inactivating current. Further experiments, focusing on fenpropathrin, revealed that its effects on I(Na) inactivation time course were dose-dependent, and the Na(+) "window-current" was increased in its presence. In unstimulated, isolated hearts perfused with the same pyrethroids, the variability in contraction amplitude increased due to variations in the intervals between heartbeats. These potentially arrhythmogenic changes are consistent with the effects observed at the cellular level. The type I pyrethroid tetramethrin had little effect in any of the preparations. These findings suggest that some pyrethroids possess considerable mammalian cardiac arrhythmogenic potential, the manifestation of which in vivo may depend on the route of exposure.

Action Potentials↗
PubMed2000

Stimulation of Na/Ca exchange by the beta-adrenergic/protein kinase A pathway in guinea-pig ventricular myocytes at 37 degrees C.

We investigated the effect of beta-adrenergic stimulation on Na/Ca exchange in whole-cell patch-clamped guinea-pig ventricular myocytes at 37 degrees C. With ion channel and Na/K pump currents blocked, the Na/Ca exchange current (I(Na-Ca) was measured selectively as membrane current inhibited by 10 mM nickel (Ni) during a voltage ramp applied between +80 and -120 mV. Isoprenaline (1 microM) caused an increase in both inward and outward current generated by the Na/Ca exchange, which was prevented by the beta-adrenoceptor blocker propranolol. These data suggest that isoprenaline caused a receptor-mediated up-regulation of Na/Ca exchange activity. Mimicking beta-adrenoceptor activation, either by stimulation of adenylate cyclase with forskolin or by internal dialysis of cells with cyclic AMP (3':5'-cyclic adenosine monophosphate), also increased I(Na-Ca). Using fluorescence Ca measurement, an increase of internal cAMP was shown to increase the rate of transmembrane Ca transport via the Na/Ca exchange. A selective inhibitor of protein kinase A prevented stimulation of Na/Ca exchange by isoprenaline. These data suggest that the underlying mechanism of stimulation was phosphorylation of the Na/Ca exchange protein by protein kinase A. Isoprenaline did not stimulate I(Na-Ca) when experiments were carried out at 20 degrees C, in contrast to the findings at 37 degrees C. Modulation of Na/Ca exchange by the beta-adrenergic pathway may have important physiological consequences for intracellular Ca regulation and electrical activity during hormonal stimulation, or during sympathetic nerve stimulation.

Adenylyl Cyclases↗
PubMed2000

Gadolinium inhibits Na(+)-Ca(2+) exchanger current in guinea-pig isolated ventricular myocytes.

The trivalent cation, gadolinium (Gd(3+)) is commonly used to inhibit stretch-activated channels. In this report, we show that Gd(3+) also inhibits ionic current (I(NaCa)), carried by the Na(+)-Ca(2+) exchanger protein. Under selective recording conditions, Gd(3+) inhibited both outward and inward I(NaCa) from guinea-pig isolated ventricular myocytes in a dose-dependent manner, with half-maximal inhibition concentrations (IC(50)) of 30.0+/-4.0 microM at +60 mV (Hill-coefficient, h=1.04+/-0.13) and 20.0+/-2.7 microM at -100 mV (h=1.13+/-0.16), respectively (P>0.05, n=5 - 9). Thus, inhibition was not voltage-dependent. The time from Gd(3+) application to steady-state effect was slow compared to the divalent blocker Ni(2+). The slow time course appeared to reflect gradual Gd(3+) accumulation at its binding site on the exchanger, rather than a use-dependent blocking mechanism. This study indicates that for experiments in which Gd(3+) is used, its inhibitory effect on I(NaCa) should be taken into account.

Animals↗
PubMed2000

Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes.

BDF 9198 (a congener of DPI 201 - 106 and BDF 9148) was found to be a positive inotrope on guinea-pig isolated ventricular muscle strips. The effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes were studied using the whole cell patch clamp method. In normal external solution, at 37 degrees C, action potential duration at 50% repolarization (APD(50)) was 167.4+/-8.36 ms (n=37). BDF 9198 produced a concentration-dependent increase in APD(50) (no significant increase at 1x10(-10) M; and APD(50) values of 273.03+/-35.8 ms at 1x10(-9) M; n=6, P<0.01 and 694.7+/-86.3 ms at 1x10(-7) M; P<0.001, n=7). At higher concentrations in the range tested, BDF 9198 also induced early and delayed and after-depolarizations. Qualitative measurements of I(Na) with physiological [Na](o) showed prolongation of the current by BDF 9198, and the appearance of transient oscillatory inward currents at high concentrations. Quantitative recording conditions for I(Na) were established using low external [Na] and by making measurements at room temperature. The current - voltage relation, activation parameters and time-course of I(Na) were similar before and after a partial blocking dose of Tetrodotoxin (TTX, 1 microM), despite a 2 fold difference in current amplitude. This suggests that voltage-clamp during flow of I(Na) was adequately maintained under our conditions. Selective measurements of I(Na) at room temperature showed that BDF 9198 induced a concentration-dependent, sustained component of I(Na) (I(Late)) and caused a slight left-ward shift in the current - voltage relation for peak current. The drug-induced I(Late) showed a similar voltage dependence to peak current in the presence of BDF 9198. Both peak current and I(Late) were abolished by 30 microM TTX and were sensitive to external [Na]. Inactivation of control I(Na) during a 200 ms test pulse to -30 mV followed a bi-exponential time-course. In addition to inducing a sustained current component, BDF 9198 left the magnitude of the fast inactivation time-constant unchanged, but increased the magnitude of the slow inactivation time-constant. Additional experiments with a longer pulse (1 s) raised the possibility that in the presence of BDF 9198, I(Na) inactivation may be comprised of more than two phases. No significant effects of 1x10(-6) M BDF 9198 were observed on the L-type calcium current, or delayed and inward rectifying potassium currents measured at 37 degrees C. It is concluded that the prolongation of APD(50) by BDF 9198 resulted from selective modulation of I(Na). Reduced current inactivation induced a persistent I(Na), increasing the net depolarizing current during the action potential. This action of the drug indicates a potential for 'QT prolongation' of the ECG. The observation of after-depolarizations suggests a potential for proarrhythmia at some drug concentrations.

Action Potentials↗
PubMed2000

Na+-Ca2+ exchange current from rabbit isolated atrioventricular nodal and ventricular myocytes compared using action potential and ramp waveforms.

We measured and compared Na-Ca exchanger current (INa-Ca) from rabbit isolated ventricular and atrioventricular (AV) nodal myocytes, using action potential (AP) and ramp voltage commands. Whole cell patch-clamp recordings were made at 35-37 degrees C; INa-Ca was measured as 5 mM nickel (Ni)- sensitive current with major interfering voltage and calcium-activated currents blocked. In ventricular cells a 2-s descending ramp elicited INa-Ca showing outward rectification and a reversal potential (Erev) of -13.1 +/- 1. 2 mV (n = 12; mean +/- SEM). With a ventricular AP as the voltage command, the profile of INa-Ca followed the applied waveform closely. The current-voltage relation during AP repolarization was almost linear and showed an Erev of -38.3 +/- 5.3 mV (n = 6). As INa-Ca depended on the applied voltage waveform, comparisons between the two cell types utilized the same command waveform (a series of AV nodal APs). In ventricular myocytes this elicited INa-Ca that reversed near -38 mV and was inwardly directed during the pacemaker potential. This command was also applied to AV node cells; mean INa-Ca density at all voltages encompassed by the AP (-70 to +30 mV) did not differ significantly from that in ventricular myocytes (P > 0.05, ANOVA). This finding was confirmed using brief (250 ms) voltage ramp protocols (P > 0.1 ANOVA). These data represent the first direct measurements of AV nodal INa-Ca and suggest that the exchanger may be functionally expressed to similar levels in the two cell types. They may also suggest a possible role for INa-Ca during the pacemaker potential in AV node as inward INa-Ca was observed over the pacemaker potential range even with bulk internal Ca buffered to a low level.

Action Potentials↗
PubMed2000

Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current.

1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic. 2. Long QT syndrome is so-named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents. 3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the 'rapid' cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether-a-go-go-related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram. 4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti-arrhythmics, such as quinidine, non-sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents. 5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K+) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT-prolongation risk of particular agents is important for the clinician.

Action Potentials↗