Cardiac Action Potential Duration Research Articles

Keeping the heart going: a new role for KATP channels

Heart failure is a major cause of death in Western societies. It is usually precipitated by an increased haemodynamic load against which the heart must pump, such as that caused by narrowing of the aorta. For reasons still not understood, some individuals are more susceptible to heart failure. The issue of how the heart adapts to changes in ventricular pressure load is therefore of considerable significance. The paper by Yamada et al. (2006) in this issue of The Journal of Physiology reveals that KATP channels are involved in adaptation to ventricular pressure load and protect against heart failure. KATP channels serve as metabolic sensors that translate changes in cell metabolism into changes in electrical activity. In the heart, KATP channels are normally closed but they open in response to various forms of cardiac stress, including ischaemia, physical exertion, stress hormones such as adrenaline, and mineralocorticoid-induced hypertension (Kane et al. 2005). Opening of KATP channels leads to membrane hyperpolarization and shortening of the cardiac action potential, thereby reducing contractility. In this way, KATP channels serve to reduce calcium influx and ATP consumption at times of metabolic stress. Because the membrane resistance is very high during the plateau of the cardiac action potential, opening of as few as 1% of the KATP channels in the cell can halve the cardiac action potential duration (Faivre & Findlay, 1990). Cardiac KATP channels are composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR2A) subunits. Both contribute to metabolic regulation, with ATP blocking the channel via binding to Kir6.2 and Mg-nucleotides opening it via interaction with SUR2A. The sulphonylurea receptor also confers sensitivity to a variety of drugs, including the sulphonylureas for which it was named. Genetic deletion of Kir6.2 results in the total loss of functional cardiac KATP channels, as both types of subunit are required to form a functional channel. Mice lacking KATP channels due to knockout of Kir6.2 (Kir6.2-KO mice) have previously been shown to exhibit enhanced sensitivity to several forms of cardiac stress, including ischaemia and sympathetic stimuli. Yamada et al. (2006) now use Kir6.2-KO mice to explore the role of cardiac KATP channels in heart failure. In wild-type mice, no change in action potential duration or energetic handling was observed in response to ventricular pressure overload induced by transverse aortic constriction. In contrast, Kir6.2-KO mice showed an abnormal prolongation of the cardiac action potential that resulted in elevation of intracellular Ca2+ and ATP depletion. Similar effects were found in wild-type mice when KATP channels were inhibited with the sulphonylurea glyburide. Within hours of aortic constriction, Kir6.2-KO mice developed biventricular congestive heart failure, characterized by decreased cardiac function, fluid retention, progressive sinus bradycardia and atrio-ventricular conduction block. After 48 h, about half of them were dead. However, wild-type animals showed no evidence of increased mortality or heart failure. Surviving Kir6.2-KO animals exhibited compromised cardiac function and myocardial hypertrophy, which were associated with up-regulation of the transcription factors MEF2 and NF-AT. Precisely how ventricular pressure overload results in opening of KATP channels remains unclear. One possibility is that channels are activated by mechanical stretch of the ventricle wall. In support of this idea, previous studies have shown that KATP channels in atrial myocytes are opened by cell swelling, leading to action potential shortening (Van Wagoner, 1993; Saegusa et al. 2005). Furthermore, disruption of the actin network, as might occur in response to stretch, leads to cardiac KATP channel activation (Terzic & Kurachi, 1996). Thus it seems reasonable to speculate that ventricular KATP channels are activated by stretch, but this remains to be established. In conclusion, Yamada et al. (2006) demonstrate a new functional role for the KATP channel in the heart: protection against left ventricular pressure overload and congestive heart failure. A second intriguing suggestion is that KATP channels may be involved in regulation of gene expression, via their ability to regulate calcium influx. Finally, the discovery that cardiac KATP channels are involved in the response to ventricular overload may have therapeutic implications. Many patients with type 2 diabetes are treated with sulphonylureas. Some of these drugs preferentially block pancreatic β-cell KATP channels, whereas others, like glyburide, block both cardiac and pancreatic β-cell KATP channels. This suggests that sulphonylureas should be administrated with care in patients affected by type 2 diabetes if they also suffer from left ventricle pressure overload. Furthermore, it raises the question of whether K+ channel openers might be helpful in congestive heart failure.

EMF-1: Repolarization Alternans as a Novel Mechanism of Calcium-Mediated Arrhythmogenesis in Heart Failure

The vast majority of sudden cardiac deaths (SCD) occur in patients with ventricular contractile dysfunction (i.e. heart failure). However, the mechanisms linking mechanical to electrophysiological dysfunction in the heart are unclear. Impaired calcium (Ca) cycling is the most striking abnormality of failing myocytes and is most directly responsible for contractile dysfunction; yet it remains unclear how this influences susceptibility to arrhythmias. Repolarization alternans (R-ALT, beat-to-beat alternation of cardiac cellular action potential duration), manifest clinically as T wave alternans, is closely associated with susceptibility to SCD.

Long QT 1 Mutation KCNQ1A344VIncreases Local Anesthetic Sensitivity of the Slowly Activating Delayed Rectifier Potassium Current

Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to investigate whether the LQT1 mutation A344V in the S6 region of KCNQ1, at a position corresponding to the local anesthetic binding site in HERG, may render drug insensitive KCNQ1 channels into a toxicologically relevant target of these pharmacologic agents. This may suggest that LQTS constitutes not only a nonspecific but also a specific pharmacogenetic risk factor for anesthesia. The authors examined electrophysiologic and pharmacologic properties of wild-type and mutant KCNQ1 channels. The effects of bupivacaine, ropivacaine, and mepivacaine were investigated using two-electrode voltage clamp and whole cell patch clamp recordings. The mutation A344V induced voltage-dependent inactivation in homomeric KCNQ1 channels and shifted the voltage dependence of KCNQ1/KCNE1 channel activation by +30 mV. The mutation furthermore increased the sensitivity of KCNQ1/KCNE1 channels for bupivacaine 22-fold (KCNQ1wt/KCNE1: IC50 = 2,431 +/- 582 microM, n = 20; KCNQ1A344V/KCNE1: IC50 = 110 +/- 9 microM, n = 24). Pharmacologic effects of the mutant channels were dominant when mutant and wild-type channels were coexpressed. Simulation of cardiac action potentials with the Luo-Rudy model yielded a prolongation of the cardiac action potential duration and induction of early afterdepolarizations by the mutation A344V that were aggravated by local anesthetic intoxication. The results indicate that certain forms of the LQTS may constitute a specific pharmacogenetic risk factor for regional anesthesia.

Dynamics and Cardiac Arrhythmias

Cardiac arrhythmias, characterized by single or multiple reentrant circuits, represent a dynamic phenomenon in an excitable medium. In this review, we provide a brief overview of how cardiac action potential duration restitution, conduction velocity restitution, and intracellular calcium cycling regulate the dynamics of action potential excitation and wave propagation in relation to the genesis and maintenance of cardiac arrhythmias.

Effects of transmural electrical heterogeneities and electrotonic interactions on the dispersion of cardiac repolarization and action potential duration: A simulation study

It has been shown in the literature that myocytes isolated from the ventricular walls at various intramural depths have different action potential durations (APDs). When these myocytes are embedded in the ventricular wall, their inhomogeneous properties affect the sequence of repolarization and the actual distribution of the APDs in the entire wall. In this article, we implement a mathematical model to simulate the combined effect of (a) the non-homogeneous intrinsic membrane properties (in particular the non-homogeneous APDs) and (b) the electrotonic currents that modulate the APDs when the myocytes are embedded in the ventricular myocardium. In particular, we study the effect of (a) and (b) on the excitation and repolarization sequences and on the distribution of APDs in the ventricles. We implement a Monodomain tissue representation that includes orthotropic anisotropy, transmural fiber rotation and homogeneous or heterogeneous transmural intrinsic membrane properties, modeled according to the phase I Luo–Rudy membrane ionic model. Three-dimensional simulations are performed in a cartesian slab with a parallel finite element solver employing structured isoparametric trilinear finite elements in space and a semi-implicit adaptive method in time. Simulations of excitation and repolarization sequences elicited by epicardial or endocardial pacing show that in a homogeneous slab the repolarization pathways approximately follow the activation sequence. Conversely, in the heterogeneous cases considered in this study, we observed two repolarization wavefronts that started from the epi and the endocardial faces respectively and collided in the thickness of the wall and in one case an additional repolarization wave starting from an intramural site. Introducing the heterogeneities along the transmural epi-endocardial direction affected both the repolarization sequence and the APD dispersion, but these effects were clearly discernible only in transmural planes. By contrast, in planes parallel to epi- and endocardium the APD distribution remained remarkably similar to that observed in the homogeneous model. Therefore, the patterns of the repolarization sequence and APD dispersion on the epicardial surface (or any other intramural surface parallel to it) do not reveal the uniform transmural heterogeneity.

A new toxin from the sea anemone Condylactis gigantea with effect on sodium channel inactivation

A new peptide toxin exhibiting a molecular weight of 5043 Da (av.) and comprising 47 amino acid residues was isolated from the sea anemone Condylactis gigantea. Purification of the peptide was achieved by a multistep chromatographic procedure monitoring its strong paralytic activity on crustacea (LD 50 approx. 1 μg/kg). Complete sequence analysis of the toxic peptide revealed the isolation of a new member of type I sea anemone sodium channel toxins containing the typical pattern of the six cysteine residues. From 11 kg of wet starting material, approximately 1 g of the peptide toxin was isolated. The physiological action of the new toxin from C. gigantea CgNa was investigated on sodium currents of rat dorsal root ganglion neurons in culture using whole-cell patch clamp technique ( n = 60 ). Under current clamp condition (CgNa) increased action potential duration. This effect is due to slowing down of the TTX-S sodium current inactivation, without modifying the activation process. CgNa prolonged the cardiac action potential duration and enhanced contractile force albeit at 100-fold higher concentrations than the Anemonia sulcata toxin ATXII. The action on sodium channel inactivation and on cardiac excitation-contraction coupling resemble previous results with compounds obtained from this and other sea anemones [Shapiro, B.I., 1968. Purification of a toxin from tentacles of the anemone C. gigantea. Toxicon 5, 253–259; Pelhate, M., Zlotkin, E., 1982. Actions of insect toxin and other toxins derived from the venom of scorpion Androtonus australis on isolated giant axons of the cockroach Periplaneta americana. J. Exp. Biol. 97, 67–77; Salgado, V., Kem, W., 1992. Actions of three structurally distinct sea anemone toxins on crustacean and insect sodium channels. Toxicon 30, 1365–1381; Bruhn, T., Schaller, C., Schulze, C., Sanchez-Rodriquez, J., Dannmeier, C., Ravens, U., Heubach, J.F., Eckhardt, K., Schmidtmayer, J., Schmidt, H., Aneiros, A., Wachter, E., Béress, L., 2001. Isolation and characterization of 5 neurotoxic and cardiotoxic polypeptides from the sea anemone Anthopleura elegantissima. Toxicon, 39, 693–702]. Comprehensive analysis of the purified active fractions suggests that CgNa may represent the main peptide toxin of this sea anemone species.

The D3-dopaminergic Agonist 7-hydroxy-dipropylaminotetralin (7-OH-DPAT) Increases Cardiac Action Potential Duration and Blocks Human Ether-a-go-go-related Gene K+ Channel

The D3-dopaminergic agonist (+/-) 7-hydroxy-dipropylaminotetralin (7-OH-DPAT) prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced the upstroke velocity of the action potential of rabbit sinoatrial node cells. These effects were not mediated by D3-dopaminergic receptors. In cat Purkinje fibers, the drug increased action potential duration. In voltage-clamped cat ventricular myocytes, 7-OH-DPAT blocked the rapid component of the delayed rectifier potassium current, IKr. This effect was corroborated in experiments studying the effect of the drug on human Ether-a-go-go-related Gene channels expressed in Xenopus oocytes and in HEK293 cells. We conclude that the direct electrophysiologic effects of 7-OH-DPAT on cardiac tissues are caused by the blockade of the rapid component of the delayed rectifier potassium current, IKr.

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

Multiple components of cardiac Na current play a role in determining electrical excitation in the heart. Recently, the role of nonequilibrium components in controlling cardiac action potential plateau duration, and their importance in regulating the occurrence of afterdepolarizations and arrhythmias have garnered more attention. In particular, late Na current (late I(Na)) has been shown to be important in LQT2 and LQT3 arrhythmias. Class III agents like dofetilide, clofilium, and sotalol, which can all cause a drug-induced form of LQT2, significantly lengthen action potential duration at 50% and 90% repolarization in isolated rabbit Purkinje fibers, and can initiate the formation of early afterdepolarizations, and extra beats. These actions can lead to the development of a serious ventricular tachycardia, torsades de pointes, in animal models and patients. However, pretreatment with agents that block late I(Na), like lidocaine, mexiletine, and RSD1235, a novel mixed ion channel blocker for the rapid pharmacologic conversion of atrial fibrillation, significantly attenuates the prolonging effects of Class III agents or those induced by ATX-II, a specific toxin that delays Na channel inactivation and amplifies late I(Na) greatly, mimicking LQT3. The Na channel block caused by lidocaine and RSD1235 can be through the open or inactivated states of the channel, but both equivalently inhibit a late component of Na current (I(Na)), recorded at 22 degrees C using whole-cell patch clamp of Nav 1.5 expressed in HEK cells. These protective actions of lidocaine, mexiletine, and RSD1235 may result, at least in part, from their ability to inhibit late I(Na) during action potential repolarization, and inhibition of the inward currents contributing to EAD and arrhythmia formation.

Left ventricular muscle band (VMB): thoughts on its physiologic and clinical implications☆

Although the ventricular muscle band (VMB) is formed by one continuous band of myocardium and there is some evidence to suggest that it may contract sequentially along its course from the right ventricle, through the septum, then along its basoapical left ventricular spiral, the structure is not activated in this sequence. Activation as programmed by the fully developed Purkinje system proceeds broadly and directly from endocardium to epicardium and from apex to base. Although not activated sequentially along its course, the band may still contract and relax sequentially if there is a progressive lengthening of the contraction duration in association with a nonuniform lengthening of the cardiac fiber action potential (repolarization) duration. Also, the systolic and diastolic functions of the band should be considered as part of a complex, integrated electromechanical system in which the activation is programmed to ensure optimal function.

DITPA restores the repolarizing potassium currents Itof and Iss in cardiac ventricular myocytes of diabetic rats

Diabetes Mellitus (DM) can produce an increase in the cardiac action potential duration and QT interval that can be associated with sudden death. These cardiac effects are due to a region-specific decrease in repolarizing outward K + currents. Some authors have suggested that the proarrhythmic effects of diabetes can be due to diabetes-induced hypothyroidism. Thus, we have examined the effect of the thyroid hormone analog diiodothyropropionic acid (DITPA) on calcium-independent outward potassium currents in ventricular myocytes from diabetic rats. Sustained ( I ss) and fast transient outward ( I tof) K + currents were recorded using the whole-cell configuration of the patch-clamp technique. Myocytes were enzymatically isolated from the free wall of the right ventricle, and the epicardial and endocardial layers of the left ventricle of healthy, diabetic and DITPA-treated diabetic rats. Circulating thyroid hormones were measured by electrochemiluminescence. DITPA-treatment of diabetic rats restored I tof and I ss current densities in cardiac myocytes from the three regions studied, but did not alter current densities in myocytes of control rats. T 3 and T 4 levels were reduced by diabetes, and DITPA-treatment increased circulating T 3 levels. T 3-treatment of diabetic rats also restored current densities to control values. However, direct incubation of diabetic myocytes with DITPA did not restore current densities. In summary, DITPA-treatment of diabetic rats restored the potassium current ( I tof and I ss) densities in myocytes from all ventricular regions.

Control of Electrical Alternans in Canine Cardiac Purkinje Fibers

Alternation in the duration of consecutive cardiac action potentials (electrical alternans) may precipitate conduction block and the onset of arrhythmias. Consequently, suppression of alternans using properly timed premature stimuli may be antiarrhythmic. To determine the extent to which alternans control can be achieved in cardiac tissue, isolated canine Purkinje fibers were paced from one end using a feedback control method. Spatially uniform control of alternans was possible when alternans amplitude was small. However, control became attenuated spatially as alternans amplitude increased. The amplitude variation along the cable was well described by a theoretically expected standing wave profile that corresponds to the first quantized mode of the one-dimensional Helmholtz equation. These results confirm the wavelike nature of alternans and may have important implications for their control using electrical stimuli.

Inhibition of cardiac HERG potassium channels by antidepressant maprotiline

Many drugs block delayed rectifier K + channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether- a-go-go-related gene ( HERG) K + channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC 50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 μM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.

Block of hERG Channels by Berberine

Berberine prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude. Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current, I(Kr) and I(Ks). Here we have studied the effects of berberine on hERG (I(Kr)) and KCNQ1/KCNE1 (I(Ks)) channels expressed in HEK-293 cells and Xenopus oocytes. In HEK-293 cells, the IC50 for berberine was 3.1 +/- 0.5 microM on hERG compared with 11 +/- 4% decreases on KCNQ1/KCNE1 channels by 100 microM berberine. Likewise in oocytes, hERG channels were more sensitive to block by berberine (IC50 = 80 +/- 5 microM) compared with KCNQ1/KCNE1 channels (approximately 20% block at 300 microM). hERG block was markedly increased by membrane depolarization. Mutation to Ala of Y652 or F656 located on the S6 domain, or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine. An inactivation-deficient mutant hERG channel (G628C/S631C) was also blocked by berberine. Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists.

Phosphorylation of the A-kinase-anchoring Protein Yotiao Contributes to Protein Kinase A Regulation of a Heart Potassium Channel

Regulation of the heart by the sympathetic nervous system, fundamental to the physiological response to stress and exercise, requires coordinated phosphorylation of multiple downstream molecular targets, including the I(Ks) (slowly activating potassium current) channel. Sympathetic nervous system stimulation increases intracellular cAMP for which targeted regulation is directed in large part by distinct scaffold or anchoring proteins. Yotiao is an A-kinase-anchoring protein (AKAP) that recruits the cyclic AMP-dependent protein kinase (protein kinase A (PKA)) and protein phosphatase 1 to the carboxyl terminus of the I(Ks) channel to form a molecular complex and control its phosphorylation state, crucial to the cardiac cellular response to sympathetic nervous system stimulation. Here we report that Yotiao itself is a substrate for PKA phosphorylation, and we identify a Yotiao amino-terminal (N-T) residue (Ser-43) that is PKA-phosphorylated in response to beta-adrenergic receptor stimulation. The replacement of Ser-43 by Ala ablates the PKA phosphorylation of N-T Yotiao and markedly diminishes the functional response of the wild type and pseudo-phosphorylated I(Ks) channel to cAMP but neither prevents the PKA phosphorylation of KCNQ1 nor its binding to Yotiao. These results suggest, for the first time, a critical role for the PKA phosphorylation of an AKAP in the functional regulation of an ion channel protein and postphosphorylation allosteric modulation of the I(Ks) channel by Yotiao.

Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1+minK channels

Both spironolactone (SP) and its main metabolite, canrenoic acid (CA), prolong cardiac action potential duration and decrease the Kv11.1 (HERG) current. We examined the effects of SP and CA on cardiac hKv1.5, Kv4.3 and Kv7.1+minK channels that generate the human I(Kur), I(to1) and I(Ks), which contribute to the control of human cardiac action potential duration.hKv1.5 currents were recorded in stably transfected mouse fibroblasts and Kv4.3 and Kv7.1 + minK in transiently transfected Chinese hamster ovary cells using the whole-cell patch clamp. SP (1 microM) and CA (1 nM) inhibited hKv1.5 currents by 23.2 +/- 3.2 and 18.9 +/- 2.7%, respectively, shifted the midpoint of the activation curve to more negative potentials and delayed the time course of tail deactivation.SP (1 microM) and CA (1 nM) inhibited the total charge crossing the membrane through Kv4.3 channels at +50 mV by 27.1 +/- 6.4 and 27.4 +/- 5.7%, respectively, and accelerated the time course of current decay. CA, but not SP, shifted the inactivation curve to more hyperpolarised potentials (V(h)-37.0 +/- 1.8 vs -40.8 +/- 1.6 mV, n = 10, P < 0.05).SP (10 microM) and CA (1 nM) also inhibited Kv7.1 + minK currents by 38.6 +/- 2.3 and 22.1 +/- 1.4%, respectively, without modifying the voltage dependence of channel activation. SP, but not CA, slowed the time course of tail current decay.CA (1 nM) inhibited the I(Kur) (29.2 +/- 5.5%) and the I(to1) (16.1 +/- 3.9%) recorded in mouse ventricular myocytes and the I(K) (21.8 +/- 6.9%) recorded in guinea-pig ventricular myocytes.A mathematical model of human atrial action potentials demonstrated that K(+) blocking effects of CA resulted in a lengthening of action potential duration, both in normal and atrial fibrillation simulated conditions. The results demonstrated that both SP and CA directly block hKv1.5, Kv4.3 and Kv7.1 + minK channels, CA being more potent for these effects. Since peak free plasma concentrations of CA ranged between 3 and 16 nM, these results indicated that blockade of these human cardiac K(+) channels can be observed after administration of therapeutic doses of SP. Blockade of these cardiac K(+) currents, together with the antagonism of the aldosterone proarrhythmic effects produced by SP, might be highly desirable for the treatment of supraventricular arrhythmias.

Toxicity studies with pure trans-capsaicin delivered to dogs via intravenous administration

Previous toxicology and pharmacology studies have reported variable acute cardiac effects of capsaicin, primarily involving hypotension and bradycardia. However, these studies have suffered from two important limitations. First, the capsaicin tested has been derived from pepper plant extracts, which is likely to display varying degrees of purity and possibly diverse impurity profiles. Second, post-dosing follow-up was generally limited to three or fewer days. Therefore, the objective of the studies reported here was to test the cardiac and other target organ toxicity potential of pure, synthetic trans-capsaicin (the only naturally occurring stereoisomer of capsaicin) when delivered via intravenous administration to dogs either acutely or for 14 days. Taken together, results from these two studies indicate that pure trans-capsaicin—even when delivered directly into the systemic circulation at high dose levels—is rapidly eliminated, induces transient tachycardia and hypertension, does not alter the duration of cardiac action potentials, and causes only very minimal organ toxicities. The different toxicity profiles of pure trans-capsaicin reported here and chili pepper extracts previously reported suggest that the purity and source of capsaicin should be an important consideration for toxicological evaluations.

Risperidone-induced action potential prolongation is attenuated by increased repolarization reserve due to concomitant block of ICa,L

The neuroleptic risperidone is an effective blocker of the rapidly activating component of the delayed rectifier current (I(Kr)) and hence is expected to prolong cardiac action potential duration (APD). However, unlike with other typical I(Kr) blockers we failed to demonstrate a marked prolongation of late repolarization with risperidone. It is hypothesized that the APD-prolonging effect of risperidone is masked by the high repolarization reserve due to the prominent delayed rectifier currents I(Kr) and I(Ks) in guinea pig papillary muscle. Action potentials and force of contraction were recorded in isolated guinea pig papillary muscles. L-type calcium current I(Ca,L) and I(Kr) were measured using the standard patch clamp technique in single ventricular cardiomyocytes. Reduction of the repolarization reserve by the blocking of I(Ks) with chromanol 239B augmented the effect of the selective I(Kr) blocker E-4031, but not of risperidone, although both drugs completely blocked I(Kr). In contrast to E-4031 risperidone markedly reduced the force of contraction due to the partial blocking of I(Ca,L) in the same concentration range as required for block of I(Kr). Reduction of the repolarization reserve by the blocking of I(Ks) cannot exacerbate the APD-prolonging effect of risperidone. However, even incomplete concomitant blocking of I(Ca,L) attenuates the APD-prolonging effect of the complete blocking of I(Kr). This behaviour may explain the small APD-prolonging effect of risperidone despite the drug's robust blocking of I(Kr).

Anisotropic variation of restitution properties in the in vivo swine heart

Action potential duration (APD) restitution refers to the fact that the cardiac APD depends on the previous diastolic interval (DI). Several studies have indicated the importance of a steep slope of the restitution curve in influencing the inducibility and sustainability of arrhythmias. However, these studies assume that the restitution relationship is independent of cardiac activation and recovery sequences. Yet it is known that a change in the activation and recovery sequences can alter refractory periods.

Dispersion of cardiac action potential duration and the initiation of re-entry: a computational study.

BackgroundThe initiation of re-entrant cardiac arrhythmias is associated with increased dispersion of repolarisation, but the details are difficult to investigate either experimentally or clinically. We used a computational model of cardiac tissue to study systematically the association between action potential duration (APD) dispersion and susceptibility to re-entry.MethodsWe simulated a 60 × 60 mm 2 D sheet of cardiac ventricular tissue using the Luo-Rudy phase 1 model, with maximal conductance of the K+ channel gKmax set to 0.004 mS mm-2. Within the central 40 × 40 mm region we introduced square regions with prolonged APD by reducing gKmax to between 0.001 and 0.003 mS mm-2. We varied (i) the spatial scale of these regions, (ii) the magnitude of gKmax in these regions, and (iii) cell-to-cell coupling.ResultsChanging spatial scale from 5 to 20 mm increased APD dispersion from 49 to 102 ms, and the susceptible window from 31 to 86 ms. Decreasing gKmax in regions with prolonged APD from 0.003 to 0.001 mS mm-2 increased APD dispersion from 22 to 70 ms, and the susceptible window from <1 to 56 ms. Decreasing cell-to-cell coupling by changing the diffusion coefficient from 0.2 to 0.05 mm2 ms-1 increased APD dispersion from 57 to 88 ms, and increased the susceptible window from 41 to 74 ms.ConclusionWe found a close association between increased APD dispersion and susceptibility to re-entrant arrhythmias, when APD dispersion is increased by larger spatial scale of heterogeneity, greater electrophysiological heterogeneity, and weaker cell-to-cell coupling.

Cross-talk between ?1-adrenoceptors and ETA receptors in modulation of the slow component of delayed rectifier K+ currents

Delayed rectifier K(+) currents (I(K)) play a critical role in determining cardiac action potential duration (APD). Modulation of I(K) affects cardiac excitability critically. There are three components of cardiac delayed rectifier, and the slowly activating component (I(Ks)) is influenced strongly by a variety of stimuli. Plasma levels of noradrenaline and endothelin are elevated in heart failure, and arrhythmias are promoted by such humoral abnormalities through modulation of ion channels. It has been reported that protein kinase A (PKA) and protein kinase C (PKC) modulate I(Ks) from human minK in a complex manner. In the present study, we coexpressed human minK with the human beta(1)-adrenoceptor (hbeta(1)AR) and the endothelin receptor subtype A (hET(A)R) in Xenopus oocytes and investigated the effects of receptor activation on the currents (I(Ks)) flowing through the oocytes. ET-1 modulated I(Ks) biphasically: a transient increase followed by a decrease. The PKC inhibitor chelerythrine completely inhibited the effects of ET-1. Intracellular EGTA abolished the transient increase by ET-1 and partially inhibited the subsequent decrease in the currents. When I(Ks) was increased by 10(-6) M isoproterenol (ISO), ET-1 did not increase but rather decreased the current to an even greater extent than under control conditions. In addition, the effects of ISO on I(Ks) were suppressed by ET(A)R stimulation. These data indicate that I(Ks) can be regulated by cross-talk between the ET(A)R and beta(1)AR systems in addition to direct regulation by each receptor system.