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PubMed1999

Voltage-gated sodium and potassium channels in radial glial cells of trout optic tectum studied by patch clamp analysis and single cell RT-PCR.

Radial glial cells in the visual center of trout were analyzed immunocytochemically and with the whole cell mode of the patch-clamp technique in combination with RT-PCR. By immunostaining with anti-GFAP antibodies radially oriented cell processes spanning the entire width of the tectum were brightly labeled, while with anti-S-100 antiserum the cell bodies residing in a discrete layer close to the ventricular border became most clearly visible. Virtually all radial glial cells examined in brain slices exhibited voltage-gated sodium inward currents that were activated above -40 mV, blocked by micromolar concentrations of TTX and totally eliminated if sodium was substituted for Tris in the bath solution. In contrast with adjacent nerve cells of the same slices radial glial cells did not exhibit spontaneous electrical activity and could not be stimulated to generate action potentials by depolarizing current injections. Two types of voltage-gated potassium outward currents were elicited by depolarizing voltage steps: a sustained current with delayed rectifier properties and a superimposed transient "A"-type current, both being activated at a threshold potential of -40 mV. In cultured radial glial cells subtle differences were noticed regarding current density, inactivation kinetics, and TEA-sensitivity of the potassium currents. Inwardly rectifying potassium currents activating at hyperpolarized voltages were not observed. By single cell RT-PCR the transcripts of two shaker-related potassium channel genes (termed tsha1-a fish homologue to Kv1.2- and tsha3) were amplified, while transcripts for tsha 2 and tsha 4 were not detected.

Animals↗
PubMed1984

Asymmetric proton block of inward rectifier K channels in skeletal muscle.

Inward rectifier and delayed rectifier K currents were measured in frog skeletal muscle fibers with the vaseline gap voltage clamp technique as internal or external pH were lowered. Inward rectifier currents were only slightly reduced by low external pH but were completely and reversibly blocked when the internal pH was reduced to below 5.5 either by cutting the fiber ends in low pH solutions or by bathing the fiber exterior with permeant acetate buffers at low pH. The steepness of the pH dependence of this block suggests that more than one and perhaps three hydrogen ions are required to bind to the blocking site. The voltage dependence of inward rectifier gating was not shifted by low external pH. Either these channels are not located near the fixed negatively charged groups which apparently alter the voltage sensed by many other ionic channels or the membrane potential drop and the external [K+] are altered in a compensating manner such that the driving force on K+ (upon which inward rectification depends) remains unchanged. In contrast, delayed rectifier channels were blocked and their kinetics dramatically shifted by lowering external pH.

Acetates↗
PubMed1990

Delayed rectifying and calcium-activated K+ channels and their significance for action potential repolarization in mouse pancreatic beta-cells.

The contribution of Ca2(+)-activated and delayed rectifying K+ channels to the voltage-dependent outward current involved in spike repolarization in mouse pancreatic beta-cells (Rorsman, P., and G. Trube. 1986. J. Physiol. 374:531-550) was assessed using patch-clamp techniques. A Ca2(+)-dependent component could be identified by its rapid inactivation and sensitivity to the Ca2+ channel blocker Cd2+. This current showed the same voltage dependence as the voltage-activated (Cd2(+)-sensitive) Ca2+ current and contributed 10-20% to the total beta-cell delayed outward current. The single-channel events underlying the Ca2(+)-activated component were investigated in cell-attached patches. Increase of [Ca2+]i invariably induced a dramatic increase in the open state probability of a Ca2(+)-activated K+ channel. This channel had a single-channel conductance of 70 pS [( K+]o = 5.6 mM). The Ca2(+)-independent outward current (constituting greater than 80% of the total) reflected the activation of an 8 pS [( K+]o = 5.6 mM; [K+]i = 155 mM) K+ channel. This channel was the only type observed to be associated with action potentials in cell-attached patches. It is suggested that in mouse beta-cells spike repolarization results mainly from the opening of the 8-pS delayed rectifying K+ channel.

Action Potentials↗
PubMed1998

Altered ATP sensitivity of ATP-dependent K+ channels in diabetic rat hearts.

The effects of streptozotocin-induced diabetes (5-7 days or 7 wk) on cardiac ATP-sensitive potassium channels (KATP channels) were investigated with the use of single-channel and action potential recordings from dissociated ventricular myocytes isolated from control and diabetic rat hearts. In inside-out patches from diabetic myocytes (5-7 days), the IC50 for ATP inhibition was 82 +/- 7.2 microM (mean +/- SE, n = 8), twice that in controls (43 +/- 3.6 microM, n = 12). For 7-wk diabetic rats, the IC50 was 75 +/- 2.3 microM (n = 6). Increasing internal ADP concentration attenuated ATP-induced inhibition in both controls and diabetics. On reducing the internal pH from 7.4 to 6.8, both control and diabetic myocytes showed a 1.7-fold increase in the IC50 for ATP inhibition. No differences were observed in either intraburst kinetics or unitary conductance of single channels from control and diabetic myocytes. In diabetic myocytes, action potential duration at 90% repolarization (APD90) was longer and more variable than in controls and was significantly shortened by application of the KATP channel opener cromakalim (50 microM). Cromakalim scarcely affected APD90 in controls. Computer simulation of the longer diabetic APD90 required a lower background conductance during the plateau phase in addition to small, measured changes in the delayed rectifier current, transient outward current, and ATP-sensitive K+ current (KATP current, IKATP). The simulations reproduced the enhanced sensitivity of the diabetic APD90 to changes in IKATP. These results have important implications for cardiac function in diabetics and their treatment by sulfonylureas.

Action Potentials↗
PubMed1988

Delayed rectifier K+ current in embryonic chick heart ventricle.

Single ventricular cells from 7- to 10-day-old embryonic chicks were studied with the use of whole cell, outside-out, and cell-attached patch-clamp techniques. The macroscopic delayed rectifier current, IK, activated at membrane potentials above -25 mV. Peak IK at +40 mV was 103 +/- 20 pA (5.7 +/- 1 microA/cm2). IK was selective for K ions with reversal potentials close to the Nernst equilibrium potentials. The onset of current during a voltage step was sigmoidal and was fit by the function IK = IKoo (1-e-t/tau)2. The peak time constant of activation was greater than 6 s at -25 mV (22 degrees C). Significant inactivation was not observed. IK was blocked by intracellular cesium, extracellular 1 mM 4-aminopyridine, 20 mM tetraethylammonium chloride, and 1 mM barium chloride. Single-channel recordings revealed a K+-selective channel with a slope conductance of 15 pS (extracellular [K+] = 4 mM, intracellular [K+] = 145 mM). An ensemble average of consecutive single-channel traces reproduced the whole cell current. The single-channel density was approximately 0.04/micron 2 based on frequency of patches containing the 15-pS single conductance. Approximately 100 channels/cell would sum to account for the net IK. We have described for the first time a channel underlying the main delayed rectifier current and, as such, a main repolarization current in chick ventricle.

4-Aminopyridine↗
PubMed2005

QT PRODACT: a multi-site study of in vitro action potential assays on 21 compounds in isolated guinea-pig papillary muscles.

To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (IKr) prolonged action potential duration at 90% repolarization (APD90) in a concentration-dependent manner, those showing Ca2+ current (ICa) inhibition shortened APD30, and those showing Na+ current (INa) inhibition decreased action potential amplitude (APA) and Vmax. Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD90, probably due to their blockade of INa and/or ICa, sometimes leading to a false-negative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with IKr-blocking activity prolonged APD30-90 regardless of their INa- and/or ICa-blocking activities, suggesting that APD30-90 is a useful parameter for evaluating the IKr-blocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD90 and APD30-90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies.

Action Potentials↗
PubMed1998

Expression of Panulirus shaker potassium channel splice variants.

In Drosophila shaker voltage-dependent potassium channels, alternative splicing at the amino and carboxy termini produces currents with different electrophysiological characteristics. We have cloned alternatively spliced forms of shaker from the spiny lobster Panulirus interruptus. Alternative exons were found at three sites of the gene; eight different 5' exons, two alternative exons encoding the pore-forming P region, and an alternative 3' exon. Two of the different amino terminal splice forms were expressed with two alternatively spliced pore forms to produce channels with markedly different characteristics. One of the amino termini produced a channel with transient characteristics while the other produced a delayed rectifier-type channel. The effects of alternative exons at the amino terminus and in the P region appear to be additive. Our results provide new information on the structural requirements for rapid N-type inactivation.

Alternative Splicing↗
PubMed1992

Insensitivity of guinea pig ventricular delayed rectifier IK to intracellular trypsin: implications for channel structure and function.

OBJECTIVE: Intracellular application of proteolytic agents modifies the function of many voltage gated ion channels. The presence of a trypsin sensitive inhibitory domain in a channel protein may be important for G protein dependent activation. Guinea pig ventricular IK is modulated by a direct G protein pathway. The aim was to determine if guinea pig ventricular IK is also modified by intracellularly applied trypsin. METHODS: Whole cell and excised inside out configurations of patch clamp were used to record IK from guinea pig ventricular myocytes before and after cytosolic application of trypsin (1 mg.ml-1). We used previously reported effects of trypsin on the L type calcium current (ICa) to monitor dialysis time and enzyme activity in whole cell experiments where IK and ICa were measured concomitantly. RESULTS: Addition of trypsin to the solution bathing the cytosolic face of excised membrane patches had no effect on the amplitude or kinetics of IK. When added to the pipette solution and introduced by cell dialysis, trypsin had no effect on whole cell IK, even when significant effects on the amplitude and kinetics of ICa were evident. CONCLUSIONS: Guinea pig ventricular IK is not enhanced or otherwise altered by intracellularly applied trypsin. Therefore direct phosphorylation independent enhancement of IK by guanine nucleotides cannot depend on interactions between G protein subunits and trypsin sensitive inhibitory channel domains. The lack of trypsin modification of cardiac ventricular IK suggests that the structure of the endogenous delayed rectifier K+ channel may be different than that of other voltage gated channels.

Animals↗
PubMed1987

Elevation of a potassium current in differentiating human leukemic (HL-60) cells.

Human promyelocytic leukemia (HL-60) cells display a novel voltage-dependent outward current under voltage clamp. This current is present at low levels in the proliferative state and in granulocytes derived from HL-60 cells which were induced to differentiate with retinoic acid. It is elevated in macrophages derived from HL-60 cells after exposure to phorbol-12-myristate-13-acetate (PMA). The current is carried primarily by K+, is blocked by Cs+ and by increased intracellular concentrations of Cl-. From a holding potential of -80 mV, significant activation required depolarization to +20 mV membrane potential. Activation was not influenced by intracellular Ca2+ (1-2 X 10(-6) M). These properties appear to differ significantly from the Ca2+-activated K+ channel and the delayed rectifier. The increase of this voltage-activated current in differentiation toward the macrophage, but not the granulocyte, suggests that this current is correlated specifically with macrophage differentiation.

Calcium↗
PubMed1991

Blockade by lithium ions of potassium channels in rat anterior pituitary cells.

Extracellular Li+ has been known to facilitate the basal secretion of growth hormone from anterior pituitary cells and of catecholamine from chromaffin cells. In both cases, the intracellular accumulation of Li+ seems to be the prerequisite, and the presence of extracellular Ca2+ is indispensable. In this series of experiments, we examined whether Li+ blocked K+ currents by using primary cultured anterior pituitary cells from male rats. K+ currents were measured in the whole cell configuration of the patch-clamp technique. Extracellular Li+ (140 mM) suppressed both the delayed rectifier K+ current (IK) and the transient outward K+ current to 71 and 69% of control, respectively, in a reversible manner. IK elicited by a voltage step to +70 mV from holding potential of -70 mV was suppressed by 32.5 mM internal Li+ to 28% of control. Half-maximal suppression of K+ conductance by internal Li+ was 16 mM. Furthermore, Ca(2+)-channel blocker methoxyverapamil potently suppressed Li(+)-induced growth hormone secretion. From these results we propose that the blockade by Li+ of K+ channels could depolarize the cells and activate Ca2+ channels, thereby promoting the influx of Ca2+ and hormone secretion as a mechanism of Li(+)-induced hormone secretion.

Animals↗
PubMed1997

Suppression of mammalian K+ channel family by ebastine.

Nonsedating H1 receptor (H1-R) antagonists exert variable effects on QT interval, most likely mediated through modulation of cardiac K+ channels. We examined the effects of a novel H1-R antagonist, ebastine, on a family of K+ currents in isolated rat and guinea pig ventricular cardiomyocytes as well as on HERG-induced rapidly delayed rectifier K+ current (I(Kr)) in Xenopus laevis oocytes. The effect of ebastine was compared with that of two other H1-R antagonists, terfenadine and loratadine, with and without reported cardiotoxicity, respectively. In guinea pig ventricular myocytes, ebastine at concentrations approximating those found in plasma under certain conditions suppressed in a voltage-independent manner the I(Kr) (Kd = 0.14 microM, maximum block 74%) more effectively than the slowly delayed rectifier K+ current (I(Ks)) (Kd = 0.8 microM, maximum block 60%). Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM. The block of the rapidly activating delayed rectifier channel in rat myocytes (Iped) (Kd = 1.7 microM, maximum block 58%) had a small voltage dependence. Ebastine only minimally suppressed rat transient K+ current (Ito) (Kd = 1.1 microM, maximum block 10%). The drug was also not a very potent blocker of the inwardly rectifier K+ current (I(K1)) of rat and guinea pig (15 +/- 3% block at 3 microM). At concentrations of <100 nM, ebastine produced negligible effect on all K+ currents. We conclude that ebastine blocks various cardiac K+ channels with different potencies. The group of delayed rectifier K+ currents appeared to be most susceptible to ebastine with the order of sensitivity of I(Kr) > I(Ks) > Iped. Ebastine-induced inhibition of all K+ current types was always weaker than that observed with similar concentrations of terfenadine.

Animals↗
PubMed1999

Nicotine depresses the functions of multiple cardiac potassium channels.

Nicotine is the main constituent of tobacco smoke responsible for the elevated risk of the cardiovascular disease and sudden coronary death associated with smoking, presumably by provoking cardiac arrhythmias. The cellular mechanisms may be related to the ability of nicotine to prolong action potentials and to depolarize membrane potential. However, the underlying ionic mechanisms remained unknown. We showed here that nicotine blocked multiple types of K+ currents, including the native currents in canine ventricular myocytes and the cloned channels expressed in Xenopus oocytes: A-type K+ currents (I(to)/Kv4.3), delayed rectifier K+ currents (I(Kr)/HERG) and inward rectifier K+ currents (I(K1)/Kir2.1). Most noticeably, nicotine at a concentration as low as of 10 nM significantly suppressed I(to) and Kv4.3 by approximately 20%. The effects of nicotine were independent of nicotinic receptor simulation or catecholamine release. Our results indicate that nicotine is a non-specific blocker of K+ channels and the inhibitory effects are the consequence of direct interactions between nicotine molecules and the channel proteins. Our study provided for the first time the evidence for the direct inhibition of cardiac K+ channels by nicotine and established a novel aspect of nicotine pharmacology.

Action Potentials↗
PubMed2006

Key role of Kv1 channels in vasoregulation.

Small arteries play an essential role in the regulation of blood pressure and organ-specific blood flow by contracting in response to increased intraluminal pressure, ie, the myogenic response. The molecular basis of the myogenic response remains to be defined. To achieve incremental changes in arterial diameter, as well as blood pressure or organ-specific blood flow, the depolarizing influence of intravascular pressure on vascular smooth muscle membrane potential that elicits myogenic contraction must be precisely controlled by an opposing hyperpolarizing influence. Here we use a dominant-negative molecular strategy and pressure myography to determine the role of voltage-dependent Kv1 potassium channels in vasoregulation, specifically, whether they act as a negative-feedback control mechanism of the myogenic response. Functional Kv1 channel expression was altered by transfection of endothelium-denuded rat middle cerebral arteries with cDNAs encoding c-myc epitope-tagged, dominant-negative mutant or wild-type rabbit Kv1.5 subunits. Expression of mutant Kv1.5 dramatically enhanced, whereas wild-type subunit expression markedly suppressed, the myogenic response over a wide range of intraluminal pressures. These effects on arterial diameter were associated with enhanced and reduced myogenic depolarization by mutant and wild-type Kv1.5 subunit expression, respectively. Expression of myc-tagged mutant and wild-type Kv1.5 subunit message and protein in transfected but not control arteries was confirmed, and isolated myocytes of transfected but not control arteries exhibited anti-c-myc immunofluorescence. No changes in message encoding other known, non-Kv1 elements of the myogenic response were apparent. These findings provide the first molecular evidence that Kv1-containing delayed rectifier K+ (K(DR)) channels are of fundamental importance for control of arterial diameter and, thereby, peripheral vascular resistance, blood pressure, and organ-specific blood flow.

Animals↗
PubMed1998

Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel.

Voltage-gated potassium channels control cardiac repolarization, and mutations of K+ channel genes recently have been shown to cause arrhythmias and sudden death in families with the congenital long QT syndrome. The precise mechanism by which the mutations lead to QT prolongation and arrhythmias is uncertain, however. We have shown previously that an N-terminal fragment including the first transmembrane segment of the rat delayed rectifier K+ channel Kv1.1 (Kv1.1N206Tag) coassembles with other K+ channels of the Kv1 subfamily in vitro, inhibits the currents encoded by Kv1.5 in a dominant-negative manner when coexpressed in Xenopus oocytes, and traps Kv1.5 polypeptide in the endoplasmic reticulum of GH3 cells. Here we report that transgenic mice overexpressing Kv1.1N206Tag in the heart have a prolonged QT interval and ventricular tachycardia. Cardiac myocytes from these mice have action potential prolongation caused by a significant reduction in the density of a rapidly activating, slowly inactivating, 4-aminopyridine sensitive outward K+ current. These changes correlate with a marked decrease in the level of Kv1.5 polypeptide. Thus, overexpression of a truncated K+ channel in the heart alters native K+ channel expression and has profound effects on cardiac excitability.

4-Aminopyridine↗
PubMed2004

Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy.

Previous studies have raised the possibility that a decrease in voltage-gated K+ currents may contribute to hyperexcitability of injured dorsal root ganglion (DRG) neurons and the emergence of neuropathic pain. We examined the effects of axotomy on mRNA levels for various Kv1 family subunits and voltage-gated K+ currents in L4-L5 DRG neurons from sham-operated and sciatic nerve-transected rats. RNase protection assay revealed that Kv1.1 and Kv 1.2 mRNAs are highly abundant while Kv1.3, Kv1.4, Kv1.5 and Kv1.6 mRNAs were detected at lower levels in L4-L5 DRGs from sham and intact rats. Axotomy significantly decreased Kv1.1, Kv1.2, Kv1.3 and Kv1.4 mRNA levels by approximately 35%, approximately 60%, approximately 40% and approximately 80%, respectively, but did not significantly change Kv1.5 or Kv1.6 mRNA levels. Patch clamp recordings revealed two types of K+ currents in small-sized L4-L5 DRG neurons: sustained delayed rectifier currents elicited from a -40 mV holding potential and slowly inactivating A-type currents that was additionally activated from a -120 mV holding potential. Axotomy decreased both types of K+ currents by 50-60% in injured DRG neurons. In addition, axotomy increased the alpha-dendrotoxin sensitivity of the delayed rectifier, but not slow A-type K+ currents in injured DRG neurons. These results suggest that Kv1.1 and Kv1.2 subunits are major components of voltage-gated K+ channels in L4-L5 DRG neurons and that the decreased expression of Kv1-family subunits significantly contributes to the reduction and altered kinetics of Kv current in axotomized neurons.

Animals↗
PubMed1993

The electrophysiological characteristics of hypertrophied ventricular myocytes from the spontaneously hypertensive rat.

OBJECTIVE: Previous studies on multicellular preparations have shown that hypertrophied cardiac muscle from the spontaneously hypertensive rat (SHR) has a prolonged action potential. The first aim of the present study was to determine whether the action potential of isolated left ventricular myocytes was similarly prolonged and to study the underlying membrane currents that might be responsible. The second aim was to evaluate the L-type calcium current amplitude of SHR myocytes, as we have recently shown that they have an increased contraction and an increase in the calcium trigger entering via the L-type calcium channel might be one possible mechanism for this. METHODS: The electrophysiological characteristics of left ventricular myocytes isolated from the SHR were compared with those from normotensive control rats. Action potentials were recorded with microelectrodes. Cells were voltage-clamped and the membrane currents elicited by steps to different potentials were analysed. Blockers of potassium and calcium currents were used to reveal the contribution made by these currents to net membrane currents. RESULTS: SHR myocytes had prolonged action potentials. The action potential duration of SHR myocytes at 90% repolarization was found to be longer, although at 20% and 50% repolarization no difference was found. There was no difference in the resting membrane potential between SHR and control myocytes. Using a voltage clamp we studied the L-type calcium current and potassium currents. The major change in SHR myocytes was a decrease in the magnitude (normalized to the membrane capacitance) of the inward rectifier potassium current elicited by negative potentials. There was no detectable difference in either the transient outward or delayed rectifier potassium currents. We also found no difference in the magnitude, time course or voltage dependence of L-type calcium current in hypertrophied SHR myocytes. CONCLUSIONS: First, the action potential of SHR myocytes was prolonged compared with control myocytes. Secondly, the main change in SHR myocytes was that pulses to negative potentials elicited a lower inward rectifier potassium current. A reduction in the density of inward rectifier channels might play a role in prolonging the SHR action potential, since a lower outward repolarizing current will flow through inward rectifier potassium channels during the SHR action potential repolarization. Thirdly, there was no difference in L-type calcium current density or time course between SHR and control myocytes. Thus, a change in L-type calcium current probably plays no role in causing the prolonged SHR action potential or the increased contraction of hypertrophied SHR ventricular myocytes. Finally, the prolonged action potential in SHR myocytes may itself be one factor responsible for the increased contraction of these cells.

Action Potentials↗
PubMed1991

An ion channel locus for the protein kinase C potentiation of transmitter glutamate release from guinea pig cerebrocortical synaptosomes.

The mechanism by which protein kinase C (PKC) activates transmitter release from guinea pig cerebrocortical synaptosomes was investigated by employing parallel fluorescent assays of glutamate release, cytoplasmic free Ca2+, and plasma membrane potential. 4 beta-Phorbol dibutyrate (4 beta-PDBu) enhances the Ca(2+)-dependent, 4-aminopyridine (4AP)-evoked release of glutamate from synaptosomes, the 4AP-evoked elevation of cytoplasmic free Ca2+, and the 4AP-evoked depolarization of the plasma membrane. 4 beta-PDBu itself causes a slow depolarization, which may underlie the small effect of 4 beta-PDBu on spontaneous, KCl-evoked, and Ca(2+)-independent/4AP-evoked glutamate release. Because 4AP (but not KCl) generates spontaneous, tetrodotoxin-sensitive action potentials in synaptosomes, a major locus of presynaptic PKC action is to enhance these action potentials, perhaps by inhibiting delayed rectifier K+ channels.

4-Aminopyridine↗
PubMed1997

Block of IKs by the diuretic agent indapamide modulates cardiac electrophysiological effects of the class III antiarrhythmic drug dl-sotalol.

Indapamide is a diuretic agent with direct electrophysiological effects on ionic currents involved in cardiac repolarization. In particular, indapamide blocks the slow component of delayed rectifier potassium current. In contrast, most class III antiarrhythmic agents, such as dl-sotalol, block the rapid component of delayed rectifier potassium current. Computer simulations have suggested potentiation of drug effects on cardiac repolarization by the combined block of the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current. Therefore, the objective of our study was to evaluate the modulation of cardiac electrophysiological effects of dl-sotalol by indapamide. Two indices of cardiac repolarization, monophasic action potential duration at 90% repolarization and effective refractory period, at two basic cycle lengths (800 and 400 msec) were determined in 24 anesthetized open-chest dogs. In two treatment groups (n = 6/group), data were obtained at base line and every 2 min during steadily increasing concentrations of dl-sotalol (0-40 microg/ml) either alone or in the presence of indapamide (500 ng/ml). Data were also obtained in dogs receiving either a low-dose (500 ng/ml) or a high-dose (up to 7.5 microg/ml) infusion regimen of indapamide alone. Administration of dl-sotalol was associated with concentration-dependent increases in monophasic action potential duration at 90% repolarization and effective refractory period, whereas repolarization was only slightly altered by the administration of indapamide alone. However, concentration-response curves of dl-sotalol were shifted to the left in dogs treated with the combination of dl-sotalol and indapamide, and the EC50 values of dl-sotalol estimated for the prolongation of monophasic action potential duration at 90% repolarization and effective refractory period were decreased 3-fold during the coadministration of both drugs (P < .05 vs. dl-sotalol alone). Thus, under conditions of normal K+ levels, clinically relevant concentrations of indapamide modulate dl-sotalol effects on cardiac repolarization. Additional block of cardiac K+ currents, especially the rapid component of delayed rectifier potassium current and the slow component of delayed rectifier potassium current could explain these observations.

Action Potentials↗