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PubMed2001

Alosetron and the rapid component of delayed rectifying potassium current in cardiac cells.

Some drugs acting on 5-hydroxytryptamine receptors inhibit the rapid component of delayed rectifying potassium currents (I(Kr)) in cardiac muscle cells. This is associated with lengthening of the QT interval in the cardiac cycle and can lead to fatal arrhythmias. We investigated whether alosetron, a novel 5HT3 antagonist proposed for treatment of irritable bowel syndrome (IBS), blocks I(Kr) in guinea pig cardiac myocytes. I(Kr) was isolated under whole-cell voltage clamp, and was identified by its sensitivity to the selective I(Kr) antagonist E4031. Cisapride (10(-6) M) inhibited the E4031-sensitive current while alosetron (10(-10)-10(-6) M) had no effect on I(Kr). We also found that alosetron did not inhibit I(Ks). Therefore, use of alosetron for treatment of IBS should not be confounded by long QT syndrome.

Animals↗
PubMed2002

Inhibitory effects of volatile anesthetics on currents produced on heterologous expression of KvLQT1 and minK in Xenopus oocytes.

The slowly activating component of delayed rectifier K+ current (IKs) in the heart modulates the repolarization of cardiac action potential. We investigated the effects of the volatile anesthetics isoflurane and sevoflurane on cloned IKs coexpressed by KvLQT1 and minK. Currents were induced following injection into oocytes of KvLQT1 mRNA (10 ng) with or without minK mRNA (1 ng), which were transcribed in vitro from cDNAs of normal rats hearts. A two-electrode voltage-clamp recording technique was used to investigate the effects of isoflurane (0-1.5 minimum alveolar concentration, MAC) and sevoflurane (0-1.5 MAC) on IKs (KvLQT1 with minK) and KvLQT1 alone currents. Currents were activated by step depolarizations to a series of potentials from a holding potential of -80 mV and measured as the deactivating tail current on repolarization to -60 mV. Following a 2-s depolarization to 40 mV, isoflurane and sevoflurane caused potency-dependent reductions in IKs and KvLQT1 currents. Both of the volatile anesthetics tested accelerated the deactivation of IKs and KvLQT1 currents. We conclude that the significant inhibitory effect of volatile anesthetics on the cloned IKs may partly contribute to the clinical observations of the prolongation of the ventricular repolarization (Q-T interval) by the anesthetics.

Anesthetics, Inhalation↗
PubMed1995

4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: a novel class III antiarrhythmic agents.

A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1-phenyl- 1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (IKr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial IKr blockers.

Animals↗
PubMed2002

Effects of benzyltetrahydropalmatine on two components of the delayed rectifier K+ current in Guinea pig ventricular myocytes.

The effects of benzyltetrahydropalmatine (BTHP), a new class III antiarrhythmic agent, on the action potential in guinea pig papillary muscle and the rapidly activating component (I(Kr)) and the slowly activating component (I(Ks)) of the delayed rectifier potassium current (I(K)) in isolated guinea pig ventricular myocytes were investigated. The action potentials of papillary muscles were studied using a standard microelectrode technique, while the K(+) currents were recorded using the whole-cell patch clamp technique. The results showed that BTHP prolonged the action potential duration (APD) without altering other variables of the action potential in guinea pig papillary muscles. The 2 components of I(K) were blocked by BTHP (1 approximately 100 micromol x L(-1)) in time-, concentration-, voltage-, and specifically frequency-dependent fashion. The IC(50) value for blockade of I(Kr) was 13.5 micromol x L(-1), while the IC(50) value for blockade of I(Ks) was 9.3 micromol x L(-1). BTHP 30.0 micromol x L(-1) reduced I(Kr) and I(Kr,tail) by 31 +/- 4.3% and 36 +/- 4.7% (n = 6, p < 0.01) and decreased I(Ks) and I(Ks,tail) by 40 +/- 6.3% and 39 +/- 4.6% (n = 7, p < 0.01) respectively. BTHP accelerated their deactivation course by reducing the time constants of deactivation of I(Kr) and I(Ks). The activation kinetics of I(Kr) or I(Ks) were not affected by BTHP. It is concluded that BTHP prolonged the action potential duration with respect to its non-selective action on I(Kr) and I(Ks) in single guinea pig ventricular cell in a frequency-dependent fashion.

Action Potentials↗
PubMedDate not supplied

Computational study of enhanced excitability in Hermissenda: membrane conductances modulated by 5-HT.

Serotonin (5-HT) applied to the exposed but otherwise intact nervous system results in enhanced excitability of Hermissenda type-B photoreceptors. Several ion currents in the type-B photoreceptors are modulated by 5-HT, including the A-type K+ current (I(K,A)), sustained Ca2+ current (I(Ca,S)), Ca-dependent K+ current (I(K,Ca)), and a hyperpolarization-activated inward rectifier current (I(h)). In this study, we developed a computational model that reproduces physiological characteristics of type B photoreceptors, e.g. resting membrane potential, dark-adapted spike activity, spike width, and the amplitude difference between somatic and axonal spikes. We then used the model to investigate the contribution of different ion currents modulated by 5-HT to the magnitudes of enhanced excitability produced by 5-HT. Ion currents were systematically varied within limits observed experimentally, both individually and in combinations. A reduction of I(K,A) or I(K,Ca), or an increase in I(h) enhanced excitability by 20-50%. Decreasing I(Ca,S) produced a dramatic decrease in excitability. Reductions of I(K,V) produced only minimal increases in excitability, suggesting that I(K,V) probably plays a minor role in 5-HT induced enhanced excitability. Combinations of changes in I(K,A), I(K,Ca), I(h) and I(Ca,S) produced increases in excitability comparable to experimental observations. After 5-HT application, the cell's depolarization force is shifted from the I(h)-I(Ca,S) combination to predominantly I(h).

Animals↗
PubMed1998

Influence of chronic hypoxia on the contributions of non-inactivating and delayed rectifier K currents to the resting potential and tone of rat pulmonary artery smooth muscle.

Exposing rats to chronic hypoxia increased the 4-aminopyridine (4-AP) sensitivity of pulmonary arteries. 1 mM 4-AP caused smooth muscle cell depolarization and contraction in arteries from hypoxic rats, but had little effect in age-matched controls. Chronic hypoxia downregulated delayed rectifier K+ current (IK(V)), which was nearly 50% blocked by 1 mM 4-AP, and non-inactivating K+ current (IK(N)), which was little affected by 1 mM 4-AP. The results suggest that IK(N) determines resting potential in control rats and that its downregulation following hypoxia leads to depolarization, which activates IK(V) and increases its contribution to resting potential. The hypoxia-induced increase in 4-AP sensitivity thus reflects a switch in the major K+ current determining resting potential, from IK(N) to IK(V). This has important implications for the actions and specificity of pulmonary vasodilator drugs.

4-Aminopyridine↗
PubMed1999

Histamine H1-receptor-mediated modulation of the delayed rectifier K+ current in guinea-pig atrial cells: opposite effects on IKs and IKr.

1. Histamine receptor-mediated modulation of the rapid and slow components of the delayed rectifier K+ current (IK) was investigated in enzymatically-dissociated atrial cells of guinea-pigs using the whole cell configuration of the patch clamp technique. 2. Histamine at a concentration of 10 microM enhanced IK recorded during strong depolarization to potentials ranging from +20 to +40 mV and inhibited IK recorded during mild depolarization to potentials ranging from -20 to -10 mV. The increase of IK was more prominent with longer depolarizing pulses, whereas the inhibition of IK was more marked with shorter depolarizing pulses, suggesting that histamine enhances IKs (the slow component of IK) and inhibits IKr (the rapid component of IK). 3. The histamine-induced enhancement of IKs and inhibition of IKr were abolished by 3 microM chlorpheniramine but not by 10 microM cimetidine, suggesting that these opposite effects of histamine on IKr and IKs are mediated by H1-receptors. 4. In the presence of 5 microM E-4031, an IKr blocker, histamine hardly affected IK during mild depolarization although it enhanced IK during strong depolarization in a concentration-dependent manner. Histamine increased IKs with EC50 value of 0.7 microM. In the presence of 300 microM indapamide, an IKs blocker, histamine hardly affected IKs but inhibited IKr in a concentration-dependent manner. Histamine decreased IKr with IC50 value of 0.3 microM. 5. Pretreatment with 100 nM calphostin C or 30 nM staurosporine, protein kinase C inhibitors, abolished the histamine-induced enhancement of IKs, but failed to affect the histamine-induced inhibition of IKr. 6. We conclude that in guinea-pig atrial cells H1-receptor stimulation enhances IKs and inhibits IKr through different intracellular mechanisms.

Animals↗
PubMed2002

Potentiation of slow component of delayed rectifier K(+) current by cGMP via two distinct mechanisms: inhibition of phosphodiesterase 3 and activation of protein kinase G.

1. Regulation of the slowly activating component of delayed rectifier K(+) current (I(Ks)) by intracellular guanosine 3'5' cyclic monophosphate (cGMP) was investigated in guinea-pig sino-atrial (SA) node cells using the whole-cell patch-clamp method. 2. When a cell was dialyzed with pipette solution containing 100 micro M cGMP, I(Ks) started to gradually increase and reached a maximum increase of a factor of 2.37 +/- 0.39 (n = 4) about 10-15 min after rupture of patch membrane. Atrial natriuretic peptide (ANP, 100 nM) also potentiated I(Ks), consistent with intracellular cGMP-induced enhancement of I(Ks). 3. Bath application of a selective blocker of the cGMP-inhibited phosphodiesterase (PDE3) milrinone (100 microM) enhanced I(Ks) by a factor of 1.50 +/- 0.09 (n = 4) but failed to further enhance I(Ks) after a maximum stimulation by intracellular cGMP (100 microM), suggesting that blockade of PDE3 activity is involved in the enhancement of I(Ks). A potent but nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX, 100 microM) further increased I(Ks) stimulated by 100 microM milrinone, indicating that PDE subtypes other than PDE3 are also involved in the regulation of basal I(Ks) in guinea-pig SA node cells. 4. Bath application of 100 microM 8-bromoguanosine 3'5' cyclic monophosphate (8-Br-cGMP) increased I(Ks) by a factor of 1.48 +/- 0.11 (n = 5) and this stimulatory effect was totally abolished by cGMP-dependent protein kinase (PKG) inhibitor KT-5823 (500 nM), suggesting that the activation of PKG also mediates cGMP-induced potentiation of I(Ks). 5. These results strongly suggest that intracellular cGMP potentiates I(Ks) not only by blocking PDE3 but also by activating PKG in guinea-pig SA node cells.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Blocking action of chromanol 293B on the slow component of delayed rectifier K(+) current in guinea-pig sino-atrial node cells.

1. In guinea-pig sino-atrial (SA) node cells the delayed rectifier K(+) current (I(K)) is composed of rapidly and slowly activating components of I(K) (I(Kr) and I(Ks), respectively). The present study was undertaken to characterize the blocking action of the chromanol derivative 293B on I(Ks) in guinea-pig SA node cells using whole-cell patch-clamp technique. 2. Bath application of 293B blocked I(Ks), elicited by 4-s depolarizing voltage pulses from a holding potential of -50 mV, under conditions in which the L-type Ca(2+) current (I(Ca,L)) and I(Kr) were inhibited; the effect was concentration-dependent with an IC(50) of 5.3 microM, when evaluated by the decrease in the amplitude of I(Ks) tail current following 4-s depolarizing voltage steps to +50 mV. 3. The 293B block of I(Ks) progressed with time during depolarizing voltage steps with a more rapid block at higher concentrations. 4. The block of I(Ks) by 293B was fully reversed within a few minutes after washing off the drug, even when a maximal effect (a nearly full block) was achieved at high drug concentration (50 microM). 5. Bath application of 293B at 50 microM greatly and reversibly reduced the amplitude of I(Ks) which is maximally stimulated by beta-adrenergic agonist isoprenaline (1 microM), while the degree of 293B block of the isoprenaline-stimulated I(Ks) was slightly but significantly smaller than that of non-stimulated I(Ks) (94.0+/-0.98% block, n=6 vs 99.4+/-0.45% block, n=6; P<0.01). 6. We conclude that, in guinea-pig SA node cells (i) 293B is a potent and fully reversible blocker of I(Ks) in control and during beta-adrenergic stimulation and (ii) block with 293B occurs in a time-dependent manner during depolarizing voltage steps.

Animals↗
PubMed2005

Reduction of repolarization reserve by halothane anaesthesia sensitizes the guinea-pig heart for drug-induced QT interval prolongation.

The utility of halothane-anaesthetized guinea-pigs as an in vivo model for predicting the clinical potential of a drug to induce QT interval prolongation was assessed using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of D-sotalol (0.3 mg kg(-1)) and terfenadine (0.3 mg kg(-1)), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 32+/-7 and 23+/-6 ms, respectively, whereas chromanol 293B (1 mg kg(-1)), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 33+/-8 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. The MAP duration at the control was shortened by decreasing the pacing cycle length from 400 to 200 ms, but the MAP duration at each cycle length was prolonged by D-sotalol. The formulas of Van de Water, Matsunaga, Fridericia and Bazett showed good correlation of the repolarization period when compared with the MAP duration at a pacing cycle length of 400 ms. The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect drug-induced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.

Action Potentials↗
PubMed2006

Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles.

1. The rate-dependent contributions of the rapid and slow components of the cardiac delayed rectifier K+ current (IKr and IKs, respectively) to repolarization are not fully understood. It is unclear whether the addition of IKs block will attenuate reverse rate-dependence seen after IKr block. 2. The individual and combined electrophysiological effects of selective IKr and IKs blockers, dofetilide and HMR 1556, respectively, were evaluated using Langendorff-perfused rabbit hearts. Monophasic action potential duration at 90% repolarization (MAPD90) and ventricular effective refractory period (VERP) were determined at cycle lengths (CLs) of 200-500 ms (at 50 ms intervals). 3. Dofetilide (1-100 nM) prolonged MAPD90 in a concentration-dependent manner (P < 0.001, n = 6) with reverse rate-dependence (P < 0.0001). In contrast, HMR 1556 (10-240 nM) alone did not prolong MAPD90. However, in the presence of 7.5 nM dofetilide, HMR 1556 (100 nM) increased the extent of reverse rate-dependence by further prolonging MAPD90 at CLs of 400, 450 and 500 ms (P < 0.05, n = 9) and, to a lesser extent, at shorter CLs (e.g. by 17 +/- 4 ms at CL 500 vs 2 +/- 3 ms at CL 200 ms). 4. Effects of dofetilide and HMR 1556 on VERP were similar to those on MAPD90. The slope of the VERP vs CL relation was steeper after the combination (0.081 +/- 0.013) than after dofetilide alone (0.028 +/- 0.018, P < 0.01, n = 9). 5. Blockade of rabbit IKs increased reverse rate-dependence of IKr block.

Action Potentials↗
PubMed1999

Morphological, immunophenotypical and electrophysiological properties of resting microglia in vitro.

Morphological, immunophenotypical and electrophysiological properties were investigated in isolated cultured murine microglia before and after exposure to astrocyte-conditioned medium (ACM). Following application of ACM, microglial cells underwent a dramatic shape transformation from an amoeboid appearance to a ramified morphology. In parallel to morphological changes, a downregulation of macrophage surface antigens was observed in microglia exposed to ACM. Staining intensities for major histocompatibility complex (MHC) class II molecules and for the adhesion molecules leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) were significantly decreased in ramified microglia 5 days after exposure to ACM. In microglial cells treated daily with ACM over a period of 5 days, the smallest staining intensities for all surface antigens as well as the smallest ramification index as a measure for the highest degree of ramification were determined. In addition, upregulation of delayed rectifier K + currents was observed in microglia exposed to ACM for 1 day or treated daily with ACM for 5 days. In contrast, untreated amoeboid microglia or ramified microglia analysed 5 days after exposure to ACM did not express delayed rectifier K + currents. Analyses of the resting membrane potential and expression levels and properties of inward rectifier K + currents did not reveal any differences between untreated and ACM-treated microglia. It is suggested that electrophysiological properties of microglia do not strongly correlate with the morphology or the immunophenotype of microglial cells.

Animals↗
PubMed2002

Mathematical model of the rapidly activating delayed rectifier potassium current I(Kr) in rabbit sinoatrial node.

INTRODUCTION: A rapidly activating delayed rectifier potassium current (I(Kr)) is known to have an important role in determining the properties of spontaneous pacing in enzymatically isolated rabbit sinoatrial node (SAN) cells. The functional characteristics of I(Kr) are conferred by its dependence on time, voltage, and external potassium. The aim of this study was to develop a rigorous mathematical representation for I(Kr) based on experimental findings and to investigate the role of I(Kr) in the automaticity and intercellular communication of SAN cells. METHODS AND RESULTS: A Markov model was developed using available experimental data for I(Kr) in rabbit SAN. The dependence of I(Kr) on external potassium, [K+]o, was incorporated using data from both in vitro preparations and results from heterologous expression experiments for this ether-a-go-go related gene product. Our simulation results show the following. (1) I(Kr) is the dominant repolarizing current in rabbit SAN cells. (2) Deactivation of I(Kr) contributes to the net current change during the early diastolic depolarization phase. (3) Inward rectification of I(Kr) results in a decrease in membrane resistance during repolarization relative to plateau. (4) The complex [K+]o dependence of I(Kr) confers [K+]o insensitivity on isolated cells, which may account for the sensitivity of pacing rate to elevated [K+]o at the tissue level. CONCLUSION: Model results show that I(Kr) mediates diastolic depolarization by the kinetics of its decay and by lowering resistance during late repolarization. In elevated [K+]o, increased chord conductance is balanced by the changes in kinetics and voltage dependence of I(Kr) so that the pacing rate of single cells may be more [K+]o insensitive than expected. In addition, elevated [K+]o increases I(Kr) magnitude during repolarization but lowers resistance, so current flow through gap junctions is less able to hyperpolarize pacing cells.

Action Potentials↗
PubMed1996

Atrioventricular junctional rhythm induced by sympathetic stimulation in E-4031-treated dog hearts.

To investigate the role of delayed rectifier potassium current (IK) on the sympathetic control of the heart, we studied the effects of E-4031, a blocker of the rapidly activating type of IK (IKr), on the chronotropic, dromotropic, and inotropic responses to sympathetic nerve stimulation in the autonomically decentralized hearts of open-chest anesthetized dogs, E-4031 (0.01-3 mumol/kg intravenously, i.v.) decreased the heart rate (HR) dose dependently without affecting other cardiac functions. After E-4031 treatment, cardiac sympathetic nerve stimulation changed the sinus rhythm to the atrioventricular (AV) junctional rhythm in 6 of 11 anesthetized dogs (55%). In three of six junctional rhythm hearts, sinus rhythm supervened during sympathetic stimulation for 2 min. The number of pacemaker shifts to junctional rhythm increased as the dose of E-4031 was increased. However, E-4031 attenuated neither the positive chronotropic, dromotropic, nor right atrial and ventricular inotropic responses to sympathetic nerve stimulation. These results suggest that IKr inhibition may induce the AV junctional rhythm due to the combination of the different participation of IKr, the different resting potentials, and the different sensitivity to sympathetic activation among cardiac pacemaker cells.

Animals↗
PubMed1998

Azimilide causes reverse rate-dependent block while reducing both components of delayed-rectifier current in canine ventricular myocytes.

Most class III antiarrhythmic drugs reduce the rapidly activating component of delayed-rectifier current (IKr) without affecting the slowly activating component (IKs). Recently the novel antiarrhythmic agent azimilide (NE-10064) was reported to enhance IKs at low (nanomolar) concentrations and to block both IKr and IKs at higher (micromolar) concentrations. Further to understand the electrophysiologic effects of azimilide, we compared its effects on IKr and IKs (by using whole cell clamp techniques) and action potentials (microelectrode and perforated-patch techniques) on canine ventricular myocytes. A lower azimilide concentration (50 nM) did not enhance IKs. In contrast, a therapeutic azimilide concentration (2 microM) was equieffective in reducing IKr (300-ms isochrones) and IKs (3-s isochrones) by approximately 40% during depolarizing test pulses, as well as reducing IKr (38% decrease) and IKs (33% decrease) tail currents on repolarization. Block of IKs was independent of voltage at positive test potentials. In action-potential studies, 50 nM azimilide had no effect on the action-potential duration (APD), whereas 2 microM azimilide delayed repolarization and caused reverse rate-dependent effects on the APD. Whereas the extent of APD prolongation by azimilide was not correlated with the drug-free APD, azimilide preferentially exaggerated the APD-rate relationship of myocytes displaying the steepest APD-rate relationship under drug-free conditions. In conclusion, therapeutic concentrations of azimilide that cause comparable reduction of canine ventricular IKr and IKs exert reverse rate-dependent effects, which are dependent on the steepness of the APD-rate relationship.

Action Potentials↗
PubMed1999

The class III effect of azimilide is not associated with reverse use-dependence in open-chest dogs.

Certain class III antiarrhythmic agents manifest loss of effect at short cycle lengths (CLs). This effect may limit their efficacy in the presence of tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a new class III agent, on the right ventricular monophasic action potential (APD90) in 12 open-chest dogs. The monophasic action-potential duration at different pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL (VFCL) from left epicardial electrograms were recorded before and after increasing doses of intravenous azimilide. At pacing CL of 400 ms, APD90 was significantly prolonged after 7, 17, and 30 mg/kg of azimilide by 5.4, 7.7, and 10.7%, respectively. The extent of APD90 prolongation was independent of rate. Azimilide increased the APD90 by similar amounts at CL of 400 ms and at the fastest possible stimulation rate maintaining 1:1 capture (mean, 171 +/- 23 ms): by 2.6 +/- 8.6% and 5.6 +/- 5.9% at 2 mg/kg, 5.4 +/- 4.8% and 4.8 +/- 4.7% at 7 mg/kg, 7.7 +/- 5.6% and 9.9 +/-4.5% at 17 mg/kg, and 10.7 +/- 2.6% and 19.3 +/- 11.9% at 30 mg/kg, respectively. Azimilide caused no changes in arterial blood pressure or heart rate. Azimilide prolongs APD90 even at very short CLs. The absence of reverse use-dependence of effect on APD90 may have clinical importance.

Action Potentials↗
PubMed2000

Nonselective I(Kr)-blockers do not induce torsades de pointes in the anesthetized rabbit during alpha1-adrenoceptor stimulation.

Selective I(Kr)- (the rapid component of the delayed rectifier potassium current) blockers are known to induce torsades de pointes (TdPs) in anesthetized rabbits during alpha1-adrenoreceptor stimulation. However, effects of nonselective I(Kr)-blockers, which produce TdPs in other animal models and in humans, are not known in this model. We examined two nonselective I(Kr)-blockers (quinidine, 1.25 mg/kg/min i.v [n = 7]; and terfenadine, 0.31 mg/kg/min i.v. [n = 7]) for their effects on electrocardiographic parameters and on incidence of cardiac arrhythmias in anesthetized rabbits during alpha1-adrenoceptor stimulation with methoxamine. We compared the drugs with two highly selective I(Kr)-blockers (dofetilide, 0.04 mg/kg/min i.v. [n = 7]; and clofilium, 0.08 mg/kg/min i.v. [n = 6]). Polymorphic ventricular tachycardia or TdPs were induced by dofetilide and clofilium at mean doses > or =0.33 mg/kg and 0.4 mg/kg i.v., in all animals tested (vs. none in solvent; p < 0.05). TdPs usually developed into ventricular fibrillation and developed after prolongation of QT/JT interval and of QT dispersion. Terfenadine and quinidine significantly increased PQ, QT, and QTc interval and largely increased QRS duration and QT dispersion. These compounds elicited intraventricular conduction defects and cardiac arrest, due to asystole, in all animals tested (vs. 0% in solvent; p < 0.05). Interestingly, these two nonselective I(Kr)-blockers did not produce TdPs or ventricular fibrillation in any animals tested. Our results thus indicate that selective I(Kr)-blockers elicit TdPs, whereas nonselective I(Kr)-blockers do not induce this type of arrhythmia in this rabbit model. Consequently, it should be noted that this rabbit model is not always useful to evaluate nonselective I(Kr)-blocker-induced TdPs and QT interval and QT dispersion, rather than TdPs, are also important indicators for drug-induced cardiac arrhythmias.

Adrenergic alpha-1 Receptor Agonists↗