Nicorandil augments regional ischemia-induced monophasic action potential shortening and potassium accumulation without serious proarrhythmia

Nicorandil is a clinically used nitrovasodilator that has a property as an opener of ATP-sensitive potassium (KATP) channels in vitro. We examined whether nicorandil at a clinically used dose augmented regional ischemia-induced monophasic action potential (MAP) shortening and increase in extracellular potassium concentration ([K+]o), and how it affected arrhythmia occurrence. Five-minute occlusion of a distal site of the left anterior descending coronary artery (LAD) was repeated at 30-min intervals in anesthetized open-chest dogs while recording MAP or measuring [K+]o with a potassium-sensitive valinomycin electrode from the epicardial center of the ischemic myocardium. Nicorandil (0.2-0.5 mg/kg) was administered intravenously (i.v.) 5 min before the third occlusion, and the data were compared with those during the second occlusion (control). During the second occlusion, MAP duration at 90% repolarization (APD90) shortened (mean rate for 5 min, 13 +/- 3%, n = 11) and [K+]o increased from 3.7 +/- 0.1 to 6.2 +/- 0.8 mM at 5 min (n = 12). These changes were reversed < or = 3 min after reperfusion. Before the third occlusion, baseline APD90 and [K+]o were not altered by nicorandil; however, the extent of occlusion-induced shortening of APD90 (25 +/- 4%) and [K+]o increase (7.8 +/- 1.6 mM) was augmented by the pretreatment. The drug effect was attenuated by a concomitant pretreatment with 5-hydroxydecanoate, a specific blocker of KATP channels (n = 2). The prevalence of ventricular fibrillation (VF) during occlusion/reperfusion sequence was reduced after nicorandil (1 of 25 vs. 5 of 25) without de novo VF. These results suggest that nicorandil at a clinical dose facilitates regional ischemia-induced activation of myocardial KATP channels without causing serious proarrhythmia. Such a property might help protect the myocardium against ischemia/reperfusion damage.     

Modulating L-type calcium current affects discontinuous cardiac action potential conduction

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.     

Differences between proximal left and right bundle branch block action potential durations and refractoriness in the dog heart

To date the electrophysiological mechanism responsible for aberrant intraventricular conduction of critically timed premature supraventricular impulses has not been documented. Microelectrode techniques were used to measure in vitro action potential and refractory period durations of the canine proximal right and left bundle branches equidistant from the distal bundle of His. Both measurements in the right bundle branch were statistically significantly longer than these parameters of the left bundle branch. Transection of the bundle branches immediately distal to the distalmost recording sites effected no change in the proximal right bundle action potential but caused marked prolongation of proximal left bundle branch action potential and refractory period durations. We conclude that functional right bundle branch aberrancy is most likely due to the longer proximal right bundle action potential duration and refractoriness. Our data also suggest that the shorter proximal left bundle branch action potential durations and refractory periods may be due to the proximity of the low ohmic resistance Purkinje fiber-muscle junctions on the left septal surface, effecting electrotonic foreshortening of these proximal left bundle branch parameters.     

Postrepolarization refractoriness as a potential anti-atrial fibrillation mechanism of pilsicainide, a pure sodium channel blocker with slow recovery kinetics

OBJECTIVE: Taking into account the high prevalence of behavioral problems in the pediatric outpatient clinic, a need for a useful and easy to administer tool for the evaluation of this problem arises. The psychometric characteristics of the Spanish version of the Eyberg Behavioral Child Inventory (EBCI), [in Spanish Inventario de Eyberg para el Comportamiento de Ni?o (IECN)], a 36-item questionnaire were established. PATIENTS AND METHODS: The ECBI inventory/questionnaire was translated into Spanish. The basis of the ECBI is the evaluation of the child's behavior through the parents' answers to the questionnaire. Healthy children between 2 and 12 years of age were included and were taken from pediatric outpatient clinics from urban and suburban areas of Barcelona and from our hospital's own ambulatory clinic. RESULTS: The final sample included 518 subjects. The mean score on the intensity scale was 96.8 and on the problem scale 3.9. Internal consistency (Cronbach's alpha) was 0.73 and the test-retest had an r of 0.89 (p < 0.001) for the intensity scale and r = 0.93 (p < 0.001) for the problem scale. Interrater reliability for the intensity scale was r = 0.58 (p < 0.001) and r = 0.32 (p < 0.001) for the problem scale. Concurrent validity between both scales was r = 0.343 (p < 0.001). CONCLUSIONS: The IECN is a useful and easy tool to apply in the pediatrician's office as a method for early detection of behavior problems.     

The energetics of shortening amphibian cardiac muscle

An isolated amphibian cardiac muscle preparation, toad ventricular strip, was used to examine the energetics of shortening. Simultaneous measurements of force and length changes and the associated heat production were made. Both the isometric heat/stress and the enthalpy (heat+work)/load relationships were similar to those previously reported in mammalian cardiac muscle. The activation metabolism was higher in this preparation and, like its mammalian counterpart, was length dependent. The heat production measured in an isometric contraction was approximately 50% higher than that observed at the same stress level in rodent mammalian cardiac muscle. This did not affect the maximum isotonic mechanical efficiency (work divided by enthalpy) of the preparation which, at an afterload of 20% of the maximum stress was 18.1 +/- 1.7% (n = 8). There was no evidence for a shortening heat component in this preparation during isotonic contractions. It appears therefore that the energetics of shortening amphibian cardiac muscle closely resemble the energetics of mammalian cardiac tissue.     

Mechanism of alpha-2 adrenergic modulation of canine cardiac Purkinje action potential

We reported recently that stimulation of postjunctional alpha-2 adrenergic receptors prolongs the action potential durations (APD) of isolated canine Purkinje fibers. With standard microelectrode techniques, we examined the ionic mechanism through which alpha-2 adrenergic stimulation prolonged Purkinje APD, by measuring the effects of inhibitors of the various plateau currents on the alpha-2-mediated prolongation of APD. The alpha-2-specific agonist UK 14,304 (0.1 microM) prolonged the Purkinje APD at 50% repolarization and the APD at 90% repolarization, and these effects were inhibited by yohimbine (0.1 microM). The Purkinje APD at 50% repolarization and the APD at 90% repolarization were prolonged significantly with the transient outward potassium current inhibitor 4-aminopyridine (1 mM), the rapid component of delayed rectifier potassium current inhibitor d-sotalol (10 microM), the slow component of delayed rectifier potassium current inhibitor indapamide (0.1 microM) and the chloride current inhibitor mefenamic acid (10 nM) and were shortened significantly with the calcium current inhibitor nifedipine (0.3 microM). Prolongation of Purkinje APD at 50% repolarization and APD at 90% repolarization by UK 14,304 remained intact in the presence of d-sotalol, indapamide, mefenamic acid and nifedipine. All of these UK 14,304 effects were significantly reversed by yohimbine. Only in the presence of 4-aminopyridine did UK 14,304 fail to prolong Purkinje APD. The phase 1 magnitudes of Purkinje action potentials were also significantly inhibited by UK 14,304. This effect was completely abolished only in the presence of 4-aminopyridine. These results suggest that inhibition of the 4-aminopyridine-sensitive transient outward potassium current is the major ionic mechanism by which alpha-2 adrenergic stimulation prolongs Purkinje APD.     

Phase angle convergence of multiple monophasic action potential recordings precedes spontaneous termination of ventricular fibrillation

Cell-surface expression of endothelial P-selectin increases adhesion and migration of leukocytes and thus may participate in the pathogenesis of reperfusion injury and atherosclerosis. Angiotensin II (Ang II) is also thought to be involved in such disease states. Nitric oxide (NO) downregulates P-selectin expression, and bradykinin (BK) is known to stimulate NO release from endothelial cells. The objective of this study was to determine the effects of 10-min stimulation of cultured human umbilical endothelial cells (HUVECs) with Ang II, BK, or both on P-selectin expression. Ang II (10(-9)-10(-5) M) stimulated P-selectin expression in a concentration-dependent manner, exhibiting a significant effect at 10(-7) M and reaching a plateau at 5 x 10(-5) M. Pretreatment of HUVECs with the AT1 antagonist losartan and the AT1/AT2 antagonist saralasin but not the AT2 antagonist PD123319 (all at 10(-5) M) markedly attenuated the effect of 10(-7) M Ang II. The effects of Ang II on P-selectin expression were not affected by the presence of the NO synthase inhibitor nitro-L-arginine (L-NA, 5 x 10(-4) M) but were abolished by pretreatment with superoxide dismutase (SOD). BK (10(-6) M) abolished the effects of 10(-7) M Ang II on P-selectin expression but did not affect P-selectin expression induced by desmopressin (0.01-10 microM). L-NA obliterated the blunting effect of BK on the Ang II-induced P-selectin membrane expression. BK alone slightly stimulated P-selectin expression, but in the presence of L-NA, BK markedly enhanced P-selectin expression. The effects of BK in the presence of NA were not altered by SOD, indicating that at difference with Ang II, it acts by a mechanism other than superoxide generation. Thus, Ang II acting on AT1 receptors stimulates superoxide generation, which, in turn, induces expression of P-selectin on the endothelial cell surface. BK inhibits the effects of Ang II, likely acting via NO. We conclude that the balance between Ang II, BK, and NO can regulate P-selectin expression on the endothelial cell membrane, an important component of the cascade leading to leukocyte adhesion to the vascular endothelium.     

Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling

BACKGROUND: Rapid atrial activation causes electrical remodeling that promotes the occurrence and the maintenance of atrial fibrillation (AF). Although remodeling has been shown to alter electrophysiological variables, the spatial uniformity of these changes is unknown. METHODS AND RESULTS: Dogs subjected to rapid atrial pacing (400 bpm) for 24 hours (n=12) were compared with sham-operated dogs (instrumented but not paced, n=12). Epicardial mapping (240 bipolar electrodes) and extrastimulation at a large number of sites (mean+/-SEM, 66+/-4 per dog) were used to evaluate atrial activation and the heterogeneity of the effective refractory period (ERP), respectively. Rapid pacing increased both the percentage of sites at which AF could be induced by single premature stimuli (from 2.6+/-0.9% to 11.8+/-2.8%, P=0.007) and AF duration (from 39+/-28 to 146+/-49 seconds, P=0.03). Atrial tachycardia decreased atrial ERP (from 120+/-4 to 103+/-2 ms, P=0.003), increased the coefficient of variation of ERP (from 14.9+/-0.9% to 20.7+/-0.9%, P<0.0001), and accelerated conduction velocity (from 91+/-2 to 108+/-3 cm/s, P=0.0004), with no change in the wavelength. The increase in ERP heterogeneity was due both to interregional differences in the extent of ERP remodeling and to increased intersite variability within regions. Stepwise multilinear regression indicated that ERP heterogeneity was an independent determinant of the inducibility (P<0.0001) and duration (P<0.0001) of AF, whereas ERP per se and wavelength were not significant determinants. Combined mapping of AF induction and atrial ERP showed that premature extrastimuli induced AF at sites with short ERP by causing local conduction slowing and/or block in adjacent zones with longer ERP values. CONCLUSIONS: Atrial tachycardia causes nonuniform remodeling of atrial refractoriness that plays an important role in increasing atrial vulnerability to AF induction and the duration of induced AF.     

Severe and early alteration of action potential during acute cardiac rejection in rats

INTRODUCTION: Alteration of cardiac action potential and its adaptation to heart rate could contribute to cardiac dysfunction and arrhythmias during acute cardiac rejection. METHODS AND RESULTS: Heterotopic heart transplantation was performed in allogeneic and syngeneic rats in which the action potentials of right and left ventricles were measured at 1, 2.5, 3.3, and 5.7 Hz successively using standard microelectrode techniques and compared with nontransplanted hearts. For each frequency, we measured action potential amplitude, action potential duration, transmembrane resting potential, and Vmax. In the right ventricle, at 1 Hz in the presence of rejection (n = 40), a significant increase was observed in action potential duration at 20%, 50%, and 70% repolarization (82.5%, 75.6%, and 70.8%, respectively) and in action potential amplitude (+17.9 mV), and the resting potential was decreased (-5.3 mV). A lack of adaptation of action potential duration to the driving frequency was observed in the rejecting heart group in contrast to controls (n = 20) and nonrejecting hearts (n = 13). Similar results were observed in the left ventricle and surprisingly in the native hearts (n = 11) of recipients with allografted rejecting hearts in the abdominal position. CONCLUSION: Action potential and its adaptation to the driving frequency is considerably altered during acute rejection. A humoral factor could contribute to cardiac dysfunction.     

Simulation of cardiac activity and the ECG using a heart model with a reaction-diffusion action potential

A computerized model of the heart for the simulation of the electrical cardiac activity is described. The cardiac cells are arranged in a three-dimensional cubic lattice and their action potential is governed by modified FitzHugh-Nagumo reaction-diffusion state equations system which exhibits properties such as oscillations, variable excitability and refractoriness. The modifications of the FitzHugh-Nagumo equations system account for asymmetric action potential regarding the fast depolarization and slow repolarization rate and for rotational anisotropic propagation. An isolated cell is tested for reproduction of the strength-duration curves and restitution. The structure basic unit cell is assigned with an individual set of control parameters that creates inhomogeneity and anisotropy to simulate the various cardiac components such as pacers, muscle cells and conduction fibers. The spatial resolution of the structure is 1 mm. The collective activity of the cells generates a realistic ECG waveform that scales the simulated temporal step unit to 0.2 msec. The effective diffusion coefficient ranges between 0.055 mm2/msec to 1 mm2/msec. The propagation velocity of the myocardial activation is calculated at normal direction to the wavefront surface and values obtained are 1.17 mm/msec at the muscle cells and 2.5 mm/msec at the main conduction fibers. An ischemia is induced to verify the capability of the model to account for abnormalities. The developed model can give an insight into the local and global complex dynamics of the heart's electrical activity in the transition from normal to abnormal myocardial activity and may help to estimate the effects of myocardial properties on the ECG rhythm.     

Improving comprehensibility by shortening sentences.

As measured by cloz tests, technical passages divided into short sentences were significantly more comprehensible than their long sentence counterparts, but the magnitude of the improvement was small--about 6%. A sentence-by-sentence comparison suggested these hypotheses for more detailed study (a) It may improve comprehensibility if "clause fragments" such as subordinate clauses are raised to full sentences (b) It may improve comprehensibly to divide sentences joined by conjunctions (but, for, because, etc.) that signal that the 1st clause is qualified by the 2nd one (c) It will not improve comprehensibility to divide a sentence joined by "and" into 2 sentences (d) Shortening clauses may be more effective than merely emphasizing their boundaries by punctuating them as separate sentences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pentameric assembly of phospholamban facilitates inhibition of cardiac function in vivo

Phospholamban has been proposed to coexist as pentamers and monomers in native sarcoplasmic reticulum membranes. To determine its functional unit in vivo, we reintroduced wild-type (pentameric) or monomeric mutant (C41F) phospholamban in the hearts of phospholamban knockout mice. Transgenic lines, expressing similar levels of mutant or wild-type phospholamban, were identified, and their cardiac phenotypes were characterized in parallel. Sarcoplasmic reticulum Ca2+ transport assays indicated similar decreases in SERCA2 Ca2+ affinity by mutant or wild-type phospholamban. However, the time constants of relaxation and Ca2+ transient decline in isolated cardiomyocytes were diminished to a greater extent by wild-type than mutant phospholamban, even without significant differences in the amplitudes of myocyte contraction and Ca2+ transients between the two groups. Langendorff perfusion also indicated that mutant phospholamban was not capable of depressing the enhanced relaxation parameters of the phospholamban knockout hearts to the same extent as wild-type phospholamban. Moreover, in vivo assessment of mouse hemodynamics revealed a greater depression of cardiac function in wild-type than mutant phospholamban hearts. Thus, the mutant or monomeric form of phospholamban was not as effective in slowing Ca2+ decline or relaxation in cardiomyocytes, hearts, or intact animals as wild-type or pentameric phospholamban. These findings suggest that pentameric assembly of phospholamban is necessary for optimal regulation of myocardial contractility in vivo.     

alpha 1-Adrenoceptor stimulation partially inhibits ATP-sensitive K+ current in guinea pig ventricular cells: attenuation of the action potential shortening induced by hypoxia and K+ channel openers

Effects of alpha 1-adrenoceptor stimulation on the action potential shortening produced by K+ channel openers (KCOs) or hypoxia and on the ATP-sensitive K+ current (IK.ATP) activated by KCOs were examined in guinea-pig ventricular cells by using conventional microelectrode and patch-clamp techniques. In papillary muscles, nicorandil (1 mM) or cromakalim (30 microM) markedly shortened the action potential duration (APD) (to 51 +/- 2% and 40 +/- 5% of each control value). Addition of 100 microM methoxamine, an alpha 1-adrenoceptor agonist, partially but significantly reversed the KCOs-induced APD shortening (to 69 +/- 3% and 50 +/- 4% of each control value). The APD-prolonging effect of methoxamine was antagonized by 1 microM prazosin (alpha 1-antagonist) and 100 nM WB4101 (alpha 1A-antagonist) but not by 10 microM chloroethylclonidine (alpha 1B-antagonist). In papillary muscles exposed to a hypoxic, glucose-free solution, APD declined gradually. In the presence of 100 microM methoxamine or 10 microM glibenclamide, the hypoxia-induced action potential shortening was significantly inhibited. In single ventricular myocytes, the KCOs increased a steady-state outward current that was abolished by glibenclamide (1 microM), thereby suggesting that these KCOs activate IK.ATP. Methoxamine (100 microM) significantly inhibited the nicorandil-induced IK.ATP by 18 +/- 5% and the cromakalim-induced IK.ATP by 16 +/- 2%. 4 beta-Phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, failed to mimic the alpha 1-adrenoceptor-mediated inhibition of the nicorandil-induced outward current. Staurosporine (30 nM), a protein kinase C inhibitor, also failed to affect the partial inhibition of IK.ATP by methoxamine. Neither intracellular loading of heparin (100 micrograms/ml), an inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release inhibitor, nor IP3 (20 microM) plus inositol 1,3,4,5-tetrakisphosphate (IP4 5 microM) could affect the inhibitory action of methoxamine. In conclusion, alpha 1A-adrenergic stimulation partially inhibits IK.ATP in cardiac cells. Neither protein kinase C activation nor IP3 formation appears to be involved in the partial inhibition of IK.ATP. The alpha 1A-adrenoceptor-mediated inhibition of IK.ATP may be deleterious for ischemic myocardium and partly offset the cardioprotective effect of KCOs because attenuation of action potential shortening may potentially increase Ca2+ influx in ischemic cells.     

Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle

Direct effects of ONO-1101 ?(-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-3-[4-[(S) -2-hydroxy-3-(2-morpholino carbonylamino)ethylamino] propoxy]phenylpropionate monohydrochloride), a novel beta-antagonist, on action potential parameters and membrane currents, and its beta adrenoceptor antagonism were examined in cardiac muscle. Action potential-parameters in papillary muscle of reserpinized animals and membrane currents recorded from single myocytes obtained from guinea pig and rabbit hearts were not affected by 1 to 100 microM ONO-1101. On the other hand, ONO-1101 markedly inhibited the potentiation of Ca current by isoproterenol in single cardiac myocytes of the guinea pig. The concentration-response relationship of Ca current for isoproterenol was shifted to the right. This effect resembled that of esmolol, which is also a beta adrenoceptor antagonist. A Schild plot analysis revealed the slope and pA2 value of each antagonist (ONO-1101, 0.94, 8.0; and esmolol, 0.98, 7.3, respectively) and demonstrated that ONO-1101 is about 5 times more potent than esmolol as a beta-antagonist. Two other effects of isoproterenol: 1) potentiation of delayed rectifier K current and 2) activation of chloride current, were also inhibited by ONO-1101. The time required for 50% removal of beta-antagonism of ONO-1101 and esmolol after the washout was estimated as 4 and 6 min, respectively, in depolarized papillary muscle. These results suggest that ONO-1101 is a potent beta-antagonist whose effects were removed quickly by washout. When applied at what is thought to be a clinical dosage, ONO-1101 had no direct effects on action potential-parameters and membrane currents in cardiac muscle. These characteristics of ONO-1101 suggest that this agent may be effective in clinical use.     

Effects of beta-blockade on atrial and atrioventricular nodal refractoriness, and atrial fibrillatory rate during atrial fibrillation in pigs

Despite their widespread use in atrial fibrillation, the effects of beta-adrenoceptor blockers on atrial and atrioventricular (AV) nodal refractoriness, and atrial fibrillatory rate during atrial fibrillation have been incompletely characterised. In particular, it is unknown whether additional sodium channel (class I) blocking effects play a role. Effects of bisoprolol (no class I effect) and metoprolol (mild class I effect) were therefore compared in 12 open-chest pigs. Atrial and AV-nodal effective refractory periods were determined at pacing cycle length 500 ms and 300 ms. Atrial fibrillation was then induced by premature stimulation and topical application of metacholine, and atrial fibrillatory intervals and ventricular intervals were recorded. After resumption of sinus rhythm, bisoprolol 0.1 mg/kg or metoprolol 0.3 mg/kg was administered, and measurements were repeated. Also, effects on plasma catecholamines and signal-averaged QRS duration were determined. Both bisoprolol and metoprolol prolonged atrial and AV-nodal effective refractory periods at both pacing cycle lengths, however, no differences were noted between the two drugs. No significant effects were observed on atrial and ventricular intervals during atrial fibrillation. Plasma catecholamines were low and unaffected by either drug, as was the QRS duration. It is concluded that the mild class I effect of metoprolol does not play a role in atrial fibrillation. Also, the results confirm the clinical notion that beta-blockers exert insignificant effects during atrial fibrillation in the setting of low sympathetic tone.     

Acceleration-induced action potential prolongation and early afterdepolarizations

INTRODUCTION: Precipitation of torsades de pointes (TdP) has been shown to be associated with acceleration of heart rate in both experimental and clinical studies. To gain insight into the cellular mechanism(s) responsible for the initiation of acceleration-induced TdP, we studied the effect of acceleration of pacing rate in canine left ventricular epicardial, M region, endocardial, and Purkinje fiber preparations pretreated with E-4031, an IKr blocker known to induce the long QT syndrome and TdP. METHODS AND RESULTS: Standard microelectrode techniques were used. E-4031 (1 to 2 microM) induced early after depolarization (EAD) activity in 31 of 36 M cell, 0 of 10 epicardial, 0 of 10 endocardial, and 9 of 12 Purkinje fiber preparations at basic cycle lengths (BCLs) > or = 800 msec. In 30 of 36 M cells, sudden acceleration from a BCL range of 900 to 4,000 msec to a range of 500 to 1,500 msec induced transient EAD activity if none existed before or increased the amplitude of EADs if already present. Acceleration-induced augmentation of EAD activity was far less impressive and less readily demonstrable in Purkinje fibers (4/12). In M cells, appearance of EAD activity during acceleration usually was accompanied by an abbreviation of action potential duration (APD). Within discrete ranges of rates in the physiologic range, acceleration caused a transient prolongation of APD in 38% of M cells, whether or not a distinct EAD was generated. Acceleration produced still more dramatic APD prolongation and EADs in M cells after the BCL was returned to the original slow rate. Epicardium and endocardium APD showed little change immediately after acceleration. A decrease of BCL as small as 10% and, in some cases, a single premature beat could promote EAD activity and APD prolongation in some M cells. Ryanodine (1 microM, 10/10), flunarizine (10 microM, 3/6), and low Na (97 vs 129 mM, 5/5) abolished the acceleration-induced EAD activity and APD prolongation as well as the EAD activity observed at slow rates in M cells pretreated with E-4031. CONCLUSION: Our results suggest that acceleration from an initially slow rate or a single premature beat can induce or facilitate transient EAD activity and APD prolongation in canine ventricular M cell preparations pretreated with an IKr blocker via a mechanism linked to intracellular calcium loading. Our data provide evidence in support of an important contribution of electrogenic Na/Ca exchange current to this process. These acceleration-induced changes can result in the development of triggered activity as well as a marked dispersion of repolarization in ventricular myocardium and, thus, may contribute to the precipitation of TdP in patients with the congenital (HERG defect) and acquired (drug-induced) long QT syndrome.     

Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination

Thirty-four adults were vaccinated with 1/50 of the usual dose of meningococcal polysaccharide vaccine (1 microg of A, C, Y, and W135 polysaccharides, given intramuscularly). This dose was selected as a probe to assess B cell memory. The probe elicited meningococcal C bactericidal antibody responses in all 18 adults who had been vaccinated 4 years earlier with an investigational meningococcal A and C oligosaccharide-protein conjugate vaccine and in the majority of the 11 subjects vaccinated for the first time. In contrast, the responses of the 5 adults given a full dose of licensed polysaccharide vaccine 4 years earlier were <1/10 of those of the other 2 groups. Thus, adults previously given a full dose of meningococcal polysaccharide vaccine show evidence of immunologic refractoriness to group C polysaccharide, whereas refractoriness is not observed after conjugate vaccination. These findings have implications for the use of meningococcal polysaccharide vaccine when the risk of disease is low.