Droperidol and ondansetron in vitro electrophysiological drug interaction study

Droperidol and ondansetron are potent anti‐emetic agents which are often administered together. Although both drugs prolong QT interval in man by inhibition of Human Ether‐a‐go‐go Related Gene‐coded potassium channels, only droperidol was tested using more integrated experimental models. Therefore, we studied the effects of both compounds and their combination on action potentials (AP) of rabbit Purkinje fibers using conventional intracellular glass microelectrode. Purkinje fibers, driven at 1 Hz, were exposed to increasing concentrations (from 0.001 to 10 μm ) of droperidol (n = 7) or ondansetron (n = 8) at 30 min intervals at 36.5°C. Other fibers were exposed to a constant droperidol concentration (0.1 μm ) alone (n = 7) or together with the same increasing concentrations of ondansetron (n = 6). Droperidol increased AP duration measured at 90% repolarization (APD90) in a concentration‐dependent manner from 4.4 ± 0.8% (mean ± SEM) after 1 nm to a maximum of 158 ± 72% after 1 μm . Ondansetron significantly increased APD90 by 5.3 ± 2.1% at 100 nm up to 76 ± 14% after10 μm . Early after‐depolarization occurred in 6/7 fibers exposed to droperidol and 1/8 fibers exposed to ondansetron. When given together, pure additive effects were observed. The concentrations that increased APD90 by 50% were 0.25 ± 0.25 μm droperidol, 3.8 ± 2.4 μm ondansetron and 1.5 ± 0.8 μm ondansetron when given together with droperidol. Both ondansetron and droperidol prolong AP duration in Purkinje fibers, droperidol being 10 times more potent than ondansetron. Combination of ondansetron and droperidol exhibits an additive effect on AP duration. However, within clinically relevant concentrations, ondansetron does not further increase the AP prolongation caused by droperidol alone.     

Muscarinic Effects on Action Potential Duration and its Rate Dependence in Canine Purkinje Fibers

Studies of the autonomic influence on action potential duration (APD) in the ventricles show direct effects of muscarinic stimulation on epicardial, but not endocardial, APD and conflicting results regarding direct vagal effects on the conduction system. In canine Purkinje fibers, we analyzed the action of the M₂ agonist oxotremorine (OXO, 0.1μM) on APD and on its cycle length (CL) dependence. Fibers were impaled with glass microalectrodes and superfused with Tyrode s solution. APD₉₀ was measured after 3 minutes of drive at CL between 0.3 and 5 seconds. The best fit for the APD/CL relationship at steady state was a hyperbole: APD = APD_max*CL/(CL+CL₅₀), where APD_max (APD at infinite CL) is a rate independent measure of APD, and CL₅₀ (CL at which 50% APD_max is reached) is an index of the rate dependence of APD. In five fibers, OXO reduced APD at all CL (P < 0.05), APD_max was also reduced to 377 ± 41 ms from 447 ± 34 ms (P < 0.05), while CL₅₀ was unchanged (405 ± 46 ms from 437 ± 28 ms). No effects of OXO on APD and APD_max were seen in two fibers obtained from dogs pretreated with pertussis toxin (PTX). In conclusion, stimulation of M₂ receptors in intact, and not PTX treated, Purkinje fibers affects APD but not its CL dependence. This may reflect the activation of a rate independent, background current through a GTP binding protein-linked pathway, such as, I_K.ACH These data differ from those obtained in endocardial and epicardial muscle, stressing the regional differences in vagal modulation of ventricular electrophysiological properties.     

Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers

Summary— Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by Sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1–100 μM) do not alter the action potential parameters even at a concentration as high as 100 μM. The stimulation rate is without effect on repolarization. On the contrary, Sparfloxacin (1–100 μM) lengthens concentration-dependently the duration of action potential, this effect being significant from the concentration of 10 μM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 μTM. Under low stimulation rate, the sparfloxacin-induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 μM and in four other fibers at the concentration of 100 μM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas Sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.     

Action potential remodeling in the human right atrium with chronic lone atrial fibrillation

It has been shown in animal experiments that recurrent induction of atrial fibrillation (AF) or long-lasting atrial pacing causes a shortening of the atrial effective refractory period (ERP) and action potential duration (APD) and a loss of their physiological adaptation to rate. Much remains to be clarified as to the electrical remodeling in human patients with chronic AF. We recorded monophasic action potentials (MAPs) from the right atrium at pacing cycle lengths (CLs) of 300, 333, 400, 500, 600, and 750 ms after external cardioversion in 13 patients with chronic lone AF. Their configuration was compared with those obtained from 13 control patients. APDs at 50% and 90% repolarization (APD50, APD90) at the shortest CL (300 ms) in control and AF patients were 131 +/- 14, 211 +/- 19 ms and 136 +/- 12, 210 +/- 22 ms, respectively (mean +/- SD). APDs in control patients increased linearly with increases of CL, reaching maximal values of 174 +/- 30 ms (APD50) and 277 +/- 38 ms (APD90) at a CL of 750 ms. In AF patients, the steady-state CL-APD relation was shifted downward and flattened at CLs > 500 ms; APD50 and APD90 at a CL of 750 ms were 158 +/- 19 ms, 232 +/- 28 ms, respectively. APD90s at CLs of 600 and 750 ms were significantly shorter in AF than in control patients. No statistically significant difference was obtained in APD50 between the two groups at any CL tested. MAP configuration in AF patients was characterized by an acceleration of the late repolarization. The difference between APD90 and APD50 (APD90-50) in control patients was increased with increases of CL, reaching a plateau at a CL of 600 ms. This CL dependent slowing of the late repolarization of MAPs was abolished in AF patients. The atrial ERP, measured at CLs of 400 and 600 ms, showed changes parallel to those of APD90. ERP at a CL of 600 ms in AF patients (224 +/- 13 ms) was significantly shorter than that in control patients (247 +/- 25 ms). We conclude that chronic lone AF leads to electrical remodeling in the human atrium, which causes a loss of rate response of the late repolarization of action potential, leading to a shortening of APD and ERP at slower heart rates.     

Diverse modulating effects of estradiol and progesterone on the monophasic action potential duration in Langendorff-perfused female rabbit hearts

This study aimed to comparatively investigate the acute modulating effects of oestrogen and progesterone on the repolarization and the susceptibility of female rabbits to class III anti‐arrhythmic agents. The acute influence of estradiol and progesterone on the cardiac repolarization and the drug sensitivity of the rapidly activating delayed rectifier K⁺ channel to sotalol was comparatively studied in Langendorff‐perfused rabbit hearts at pharmacological concentrations through recording of epicardial monophasic action potentials. In Langendorff‐perfused rabbit hearts, estradiol (1–30 μm ) concentration‐dependently prolonged the monophasic action potential durations (MAPD₃₀ and MAPD₉₀) (P < 0.05); while the effects of progesterone on MAPD were biphasic: it prolonged MAPD₃₀ and MAPD₉₀ at lower concentrations (1–3 μm ) but shortened MAPD₃₀ and MAPD₉₀ at higher concentrations (10–30 μm ). Sotalol‐induced prolongation of MAPD₉₀ was significantly less in the hearts pretreated with progesterone than those treated with estradiol (P < 0.05). The incidence of the pro‐arrhythmic events induced by sotalol in the hearts pretreated with progesterone was also significantly lower than those pretreated with estradiol (P < 0.05). In conclusion, estradiol and progesterone have different modulating effects on cardiac repolarization: estradiol can concentration‐dependently prolong the cardiac repolarization time and thus may reduce the repolarization reserve and increase the susceptibility of female rabbits to sotalol‐induced arrhythmias, whereas progesterone may shorten the cardiac repolarization time at concentrations above 10 μm , thus protecting the heart from drug‐induced arrhythmias.     

Effect of antiarrhythmic drugs on the premature action potential duration in canine cardiac Purkinje fibers

We studied the effect of six class I antiarrhythmic drugs, i.e., quinidine (5 micrograms/ml), disopyramide (10 micrograms/ml), procainamide (30 micrograms/ml), flecainide (4 micrograms/ml), lidocaine (4 micrograms/ml) and mexiletine (4 micrograms/ml), on the durations of the basic action potential (APDb) at a cycle length of 500 ms and on the premature APD (APDt) elicited at progressively increasing diastolic intervals (DI) in canine Purkinje fibers. The difference between APDt elicited at diastolic intervals of 100 msec and the earliest APDt elicited at the onset of effective refractory period was defined as the range of APDt. In control this range was 98 +/- 1.8 ms (n = 59). Disopyramide and procainamide did not change the range significantly but the other four drugs decreased it significantly (P less than .01) as follows: quinidine by 50.2%, lidocaine by 60.2%, mexiletine by 61.6% and flecainide by 61.4%. The following four factors contributed to this decrease in range of APDt: shorter duration of APDb, increased effective refractory period/APD ratio, slower kinetics of APD restitution, and shift of normalized restitution curve toward longer APDt values. The magnitude of the contribution made by each of the above factors varied with different drugs. The greatest contributing factor for quinidine was an increased effective refractory period/APD ratio, for lidocaine a slower restitution and for flecainide and mexiletine the shift of the restitution curve. We concluded that antiarrhythmic drugs belonging to the same class have different effects on the range of premature APD and that these effects cannot be predicted from the effect of the drug on APDb alone.     

盐酸雷诺秦对豚鼠乳头肌动作电位及收缩力的影响

目的通过盐酸雷诺秦对离体豚鼠心室乳头肌动作电位及收缩力的影响,探讨其抗心律失常及心肌缺血的机制。方法健康成年豚鼠18只,随机分为H2O2(200 mmol.L-1)组、雷诺嗪(10 mmol.L-1)+H2O2组和TTX(2 mmol.L-1)+H2O2组,每组6只,采用给药前后自身对照的方法观察雷诺秦对豚鼠乳头肌的作用。结果H2O2可使对照组动作电位APD50、APD90明显增加(P0.001),心肌收缩力降低(P0.05),雷诺嗪可抑制H2O2引起的动作电位时程APD50、APD90的延长(P0.05和P0.01),但作用弱于TTX(P0.05和P0.001),雷诺嗪、TTX可改善H2O2引起的心肌收缩力降低。结论盐酸雷诺嗪可降低H2O2引起的豚鼠乳头肌动作电位动时程的增加和增强心肌收缩力,作用和TTX结果相似。     

Cerebellar Purkinje cell neurodegeneration after cardiac arrest: Effect of therapeutic hypothermia

Aims

The cerebellum is among the brain regions most vulnerable to damage caused by cardiac arrest, and cerebellar Purkinje cell loss may contribute to neurologic dysfunction, including post-hypoxic myoclonus. However, it remains unknown whether cerebellar Purkinje cells are protected by post-cardiac arrest therapeutic hypothermia (TH). Therefore, we examined the effect of post-cardiac arrest TH onset and duration on cerebellar Purkinje cell loss.

Methods

Samples from a previously published study of post-cardiac arrest TH were utilized for the present analysis. Adult male rats subjected to asphyxial cardiac arrest and cardiopulmonary resuscitation were block randomized to normothermia (37.0 °C) or TH (33.0 °C) initiated 0, 1, 4, or 8 h after return of spontaneous circulation (ROSC) and maintained for 24 or 48 h. Cerebella from rats surviving 7 days after ROSC were processed for histology and immunohistochemistry. Purkinje cell density was quantified in Nissl-stained sections of the primary fissure of the cerebellar vermis.

Results

With post-cardiac arrest normothermia, Purkinje cell density in the primary fissure was severely reduced compared to sham-injured controls (3.8 ± 1.8 cells mm⁻¹ vs. 35.9 ± 2.4 cells mm⁻¹, p < 0.001). TH moderately improved Purkinje cell survival in all groups combined (14.0 ± 5.6 cells mm⁻¹, p < 0.001 compared to normothermia). There was no statistical difference in Purkinje cell protection based on TH onset time or duration.

Conclusion

These results indicate that post-cardiac arrest TH protects selectively vulnerable cerebellar Purkinje cells within a broad therapeutic window. The potential clinical implications for improving Purkinje cell survival require further investigation.     

Atrial refractoriness and action potential duration after sudden reversal of atrioventricular sequence

To address the potential of atrioventricular (AV) asynchrony to provoke cardiac arrhythmias, atrial electrophysiology was examined during normal and reversed AV interval in anesthetized pigs. A new automatic stimulation technique was adapted to monitor rapid changes in the effective refractory period (ERP), using continuous AV sequential pacing, incremental extrastimulus interval scanning, and automatic detection of capture. Right atrial ERP using 2-8 ms stimulus interval increments and right atrial and ventricular monophasic action potential (MAP) duration were determined simultaneously when the AV interval was changed from normal (+80 ms) to reversed (-40 ms) and back. During reversed AV interval the peak right atrial pressure increased from 8 +/- 3 to 14 +/- 4 mmHg (P < 0.001) and mean arterial pressure decreased from 86 +/- 18 to 65 +/- 21 mmHg (P < 0.001). At new steady state, atrial ERP and MAP duration at 90% level of repolarization were lengthened by 22 +/- 16 and 42 +/- 12 ms respectively (P < 0.001). Ventricular MAP duration did not change. A statistically significant lengthening in atrial ERP could be demonstrated in 5-10 seconds. After reversion of the AV sequence, the ratio of atrial ERP to MAP duration decreased from 1.27 to 0.94 (P < 0.001) on average for 15 seconds, the change being thought to favor reentry. Thus atrial wall stress from contraction during ventricular systole even for a short period of time modifies atrial electrophysiology. Deficient AV synchrony may immediately contribute to the development of atrial arrhythmias.     

Idiopathic Left Ventricular Tachycardia with Block Between Purkinje Potential and Ventricular Myocardium

We performed radiofrequency current catheter ablation in a patient with idiopathic LV. While mapping the inferoapical LV septum during tachycardia, spontaneous termination of tachycardia was observed with block between Purkinje (P) potential and ventricular electrogram (P-V block). The cycle length of the tachycardia was associated with prolongation of P-P interval and P-V interval. P potential recording at this site was earliest and at very low amplitude during tachycardia. The radiofrequency current at this site was successful. These findings indicated that Purkinje fiber was a critical part of the tachycardia circuit. Ablation was successful at a site where both an earliest and low amplitude P potential was recorded during tachycardia, and where P-V block that was induced by catheter manipulation was observed during tachycardia.     

Global repolarization sequence of the right atrium: monphasic action potential mapping in health pigs

The aim of the study was to explore the global sequence of atrial repolarization and its correlation to that of activation. Endocardial monophasic action potentials (MAPs) were sequentially recorded from 51 +/- 14 sites in the right atrium of ten healthy pigs using the CARTO electroanatomic mapping system. Local activation time (AT), MAP duration, and 90% repolarization time (RT) were obtained, and from these data, color coded three-dimensional maps of AT and RT sequences and spatial distribution of MAP duration were reconstructed. The results of the study were: (1) An activation sequence was recognizable in all maps, starting from the posterosuperior wall and ending in the posteroinferior wall near the tricuspid annulus. (2) The repolarization sequence was also recognizable in all maps, and mainly followed the sequence of activation. (3) A significant positive correlation between the RT and AT was observed in all maps with an average r value being 0.571 +/- 0.159 (P < 0.01 - 0.0001), suggesting that progressively later AT associates with progressively longer RT. (4) No consistent correlation between the MAP duration and AT was found. In conclusion, repolarization gradients exist over the atrial endocardium in healthy pigs. The repolarization sequence follows the same sequence as the activation, suggesting that the spatiotemporal pattern of activation is an important determinant of the characteristics of the repolarization sequence.     

Modulation of the Electrical Restitution of Canine Purkinje Fibers by Local Anesthetic Drugs: A Study with Flecainide and Propafenone

Some antiarrhythmic drugs that depress conduction also influence action potential duration (APD). This could modify the time course of changes in the APD of premature stimuli (electrical restitution) and affect dispersion of repolarization and homogeneity of refractoriness. The effects of two potent local anesthetic drugs, i.e., flecainide and propafenone, on electrical restitution were studied in canine Purkinje fibers, superfused with Tyrode's solution and impaled with glass microelectrodes. APD was measured at 90% repolarization (APD₉₀): fibers were stimulated for 3 minutes at cycle lengths (CLs) between 350 msec and 1.5 seconds, and kept quiescent for 5 minutes in between. For each run we calculated the percent ratio of the second APD (APD test = APD_t) to the first APD after quiescence (APD_o) (APD_t/APD₀× 100). The ratio was correlated with the CL of the run (i.e., the coupling interval between APD₀ and APD_t= CI) by the monoexponential function APD_t/APD_o× 100 = 100 - exp(-τ/CI), whose time constant τ indicates the speed of electrical restitution. At 1 μM, flecainide decreased τ by 26%± 4% (to 310 ± 41 msec from 245 ± 30 msec, n = 6, P < 0.05), while propafenone did not change it. Thus, unlike propafenone, flecainide slows the process of electrical restitution in Purkinje fibers. This may derive from the drug's action on currents other than Na current (i.e., I_k), relevant to the duration of action potential. In a reentrant circuit, despite similar effects on conduction, APD and refractoriness of the first beat would be differently modulated by flecainide and propafenone.     

Recovery from use-dependent block of Vmax and restitution of action potential duration in canine cardiac Purkinje fibers

The recovery kinetics during diastole of various plateau currents are thought to control the restitution of action potential duration (APD). Based on the assumption that the recovery of the residual plateau Na current parallels that of Vmax, the hypothesis that Na current recovery kinetics influence the restitution of APD was tested. Drugs that reduced Vmax in a use-dependent manner (tetrodotoxin 3 microM, lidocaine 15 microM, mexiletine 20 microM) were compared with interventions that reduced Vmax in a simply tonic fashion [( Na]o 75 mM, [K]o 6.5 mM, disopyramide 30 microM). Microelectrode techniques and programmed stimulation were used to determine in vitro the kinetics of restitution of APD and of time-dependent recovery of Vmax during rest. Tetrodotoxin, lidocaine and mexiletine induced a blockade of Vmax that showed partial or full time-dependent unblocking in accordance with the known use dependence of their blocking action. Dissipation of the time-dependent component of the block in each case followed a single exponential time course, time constants being 163 +/- 12, 115 +/- 12 and 121 +/- 20 ms, respectively. Analysis of the kinetics of the APD restitution curves showed that the time constant of the fast decaying exponential component of restitution (T1) was prolonged by these drugs from 129 +/- 5 in control fibers to 295 +/- 17, 235 +/- 11 and 242 +/- 26 ms for tetrodotoxin, lidocaine and mexiletine, respectively (P less than .05). Low [Na]o and disopyramide reduced Vmax in a simply tonic fashion and did not significantly prolong the T1 component of APD restitution.(ABSTRACT TRUNCATED AT 250 WORDS)     

冲击波对兔复合肌肉动作电位及肌组织形态学的影响

目的:评估单侧小腿后方放散式体外冲击波(radial extracorporeal shock wave treatment,rESWT)处理后兔的双侧腓肠肌复合肌肉动作电位和肌组织形态学。方法:体重2±0.2kg雄性新西兰兔63只,其中3只兔进行预实验确定rESWT强度,对剩余60只兔左小腿三头肌肌腹最粗大的位置稍偏外侧行强度1.5bar,频率10Hz的2000次冲击。分为6组,在放散式体外冲击波处理当天和处理后第1、2、4、6、8周在麻醉情况下用日本光电MEB-9100K肌电图仪记录双侧腓肠肌外侧头复合肌肉动作电位,比较两侧波幅、潜伏期,每组抽取一个样本对其双侧腓肠肌外侧头行重复电刺激,记录不同频率刺激后波幅衰减情况。肌电图检查完成立即取下双侧腓肠肌外侧头肌组织,冰冻切片后进行HE染色,观察肌肉组织形态学变化。结果:前三组实验兔(处理当天和处理后第1、2周)实验侧动作电位波幅降低,与对照侧比较差异显著(P0.05),后三组实验兔实验侧动作电位波幅与对照侧无明显差异。所有实验兔双侧动作电位潜伏期差异不明显,HE染色未见肌组织形态学明显异常。结论:运用rESWT对兔小腿三头肌肌腹最肥大处行强度1.5bar,频率10Hz的2000次冲击可降低其复合肌肉动作电位的波幅但作用持续时间较短且对肌组织形态学不会产生较大影响。     

Inhomogeneity of Cellular Refractoriness in Human Atrium: Factor of Arrhythmia?

Spatial inhomogeneity of refractory periods, as measured during clinical electrophysiological studies, is a known predisposing factor of arrhythmia. We studied elective refractory periods (ERP) and action potential duration (ADP₉₀) on isolated human atrium. Twelve samples of right atrium obtained during cardiac surgery from patients with (n = 6) and without (n = 6) atrial fibrillation (AF) were studied by microelectrode technique. For each preparation, ERP were measured at basic cycle lengths (BCL) of 1,600, 1,200, 800, and 400 msec in five different cells located around (0.8 mm) the stimulating electrode. Dispersion of ERP was significantly greater in the AF group (96.7 ± 9 versus 70.9 ± 9 msec, p = 0.01). In the non-AF group, we observed a positive linear correlation between (1) ERP and BCL (f = 0.86) (2) ADP₉₀ and BCL (= 0.93). On the contrary, in the AF group this correlation was absent between ERP and BCL (= 0.28), poor between ADP₉₀ and BCL (= 0.62). These results suggest that nonhomogeneous recovery of excitability (dispersion and poor adaptation) may be an important factor of arrhythmia. This inhomogeneity is present at the cellular level as well as in the entire heart.     

Evidence for electrical remodelling of the atrial myocardium in patients with atrial fibrillation. A study using the monophasic action potential recording technique

Experimental studies have shown that remodelling of the atrial myocardium is linked to the occurrence and perpetuation of atrial fibrillation (AF). Clinical evidence, however, is insufficient. We recorded monophasic action potentials (MAP) during AF from one to three sites in the right atrium in seven patients with chronic AF (CAF) and in 11 patients with paroxysmal AF (PAF). The fibrillatory (FF) interval between two consecutive upstrokes of the MAP was measured using a computer-assisted manual method. The mean, median, 15th, 10th, 5th percentile and shortest FF intervals were calculated in each patient and used as estimates of the local atrial effective refractory period (AERP) during AF. In three patients burst pacing at 400 and 500 beats min(-1) was delivered during the MAP recording. In nine patients, the AERP was also tested using the extra stimulus technique during sinus rhythm. RESULTS: Thirty-eight recordings were obtained. The shortest FF interval was significantly shorter in patients with CAF as compared with that in patients with PAF (50+/-13 vs. 72+/-31 ms, P<005). Similar differences were seen in the mean, median, 15th, 10th, and 5th percentile FF interval. The AERP during sinusrhythm was significantly longer than the estimated AERPs (P<0 05 to P<0.01) in the nine patients. There was no significant difference in FF interval before and after the burst pacing in the three patients. CONCLUSION: The AERP was significantly shortened during AF, as compared with that during sinus rhythm, and the AERP shortening was more marked in patients with CAF than in patients with PAF. These clinical findings support the connection between the electrical remodelling and the occurrence and/ or perpetuation of the AF.     

Clarithromycin reduces Isus and Ito currents in human atrial myocytes with minor repercussions on action potential duration

The macrolide antibacterial agent clarithromycin has been shown to cause QT interval prolongation on the electrocardiogram. In rabbit heart preparations clarithromycin (concentration dependently) lengthened the action potential duration and blocked the delayed rectifier current. The aim of the present study was to investigate the clarithromycin effects: (i) on the Ca2+ L-type and the main K+ repolarizing currents on human atrial myocytes, using whole-cell patch clamp recordings and (ii) on action potentials recorded from human atrial and ventricular myocardium using conventional microelectrodes. It has been found that (i) 10-30 microM clarithromycin reduced the sustained current Isus significantly and that a 100 microM concentration was needed to cause a significant reduction in the transient outward current Ito, whereas clarithomycin did not affect the calcium current and (ii) clarithromycin (10-100 microM) prolonged the action potential duration in atrial preparations but did not alter the different parameters of the ventricular action potential. It is concluded that clarithromycin exerts direct cardiac electrophysiological effects that may contribute to pro-arrythmic potential.     

Monophasic Action Potential Duration During Programmed Electrical Stimulation

To examine changes in monophasic action potential duration (APD) with a pacing protocol similar to that used during electrophysiological testing, action potentials were recorded in vivo from the left ventricular apical endocardium of 12 normal mongrel dogs. The atrioventricular node was ablated and the dogs paced from the anterior right ventricle at a baseline cycle length of 1000 ms between interventions. Mean steady-state APD (APDss) was 266 +/- 7 ms at a pacing cycle length (PCL) of 1000 ms. Two pacing protocols were used. The first consisted of a sudden acceleration in pacing from a cycle length of 1000 ms to one between 300 and 600 ms. The second consisted of an 8-beat train at a cycle length of 400 ms followed by a premature beat at a coupling interval of 280 ms followed by a pause. The inter-train pause varied between 1 second and 32 seconds. With a sudden acceleration in pacing rate, steady-state values for APD at the faster PCLs were significantly smaller than APDss at 1000 ms with a change to cycle lengths of 600 ms (247 +/- 29 ms), 500 ms (229 +/- 21 ms), 400 ms (220 +/- 17 ms), and 300 ms (203 +/- 31 ms; P less than 0.01 for all comparisons). The time constant of the change in APD was shorter at a PCL of 300 ms (14.9 +/- 0.8 s) than 600 ms (20.3 +/- 4.7 s; P less than 0.05). With drive train pacing and incorporating an inter-train pause, the percent drop in steady-state APD compared to APD for the first train ranged from 10.1% with a 1-second inter-train pause to 2.1% with a 32-second pause. The difference in APD between the first drive train and drive trains after at least 3 minutes of pacing when APD had stabilized was not significant for an inter-train pause exceeding 8 seconds. In conclusion: (1) with a sudden acceleration in pacing rate, endocardial APD in vivo decreases exponentially. The faster the new rate, the shorter the new steady-state APD and the shorter the time constant. (2) When pacing using an 8-beat drive train and an inter-train pause, there is a decremental shortening in APD for pause lengths shorter than 16 seconds. Thus, while performing programmed stimulation using a pause, a conditioning period of at least 2 minutes should be used prior to diastole scanning to allow APD to achieve a steady state.     

An Automatic Microcomputer System for Analysis of Monophasic Action Potentials

A computer system for rapid measurement and analysis of monophasic action potentials (MAPs) recorded in vivo was developed. MAPs recorded from the epicardium of mongrel dogs using a contact electrode were digitized by analog-to-digital conversion at a sampling rate of 1 kHz per channel for computer data acquisition. Activation time was detected using a sliding 10-point window at the location where the average positive dV/dT exceeds an adjustable threshold value in order to eliminate spurious detection due to baseline variability or motion artifact. Action potential duration (APD) was determined at 50% and 90% (APD50, APD90) repolarization levels at the first sample point below these detection levels. In addition, a tangent algorithm (APDtan) that detects peak negative dV/dT during repolarization was developed. APDtan was determined from the location of onset of activation to the intersection of tangent and baseline. APDtan allowed estimation of APD in the presence of subsequent premature beats when APD90 was not measurable. To validate activation time measurements, 4,600 action potentials were analyzed during fixed rate pacing. Over a range of paced coupling intervals from 200 to 1000 msec, an R2 value of 0.99968 and a slope of 0.9959 were obtained by linear regression between paced and calculated intervals. To validate APD measurements, 5035 action potentials were analyzed in five animals during fixed rate pacing (longer than 3 minutes) when action potential duration should be constant. Average coefficient of variation of 1.25%, 1.65%, and 1.14% were obtained for APD50, APD90, and APDtan, respectively. This algorithm provides a rapid and accurate method to analyze MAP activation and duration for basic physiological studies such as the determination of initiation of arrhythmias.