Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 microg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 +/- 1.40 vs 56.60 +/- 0.748 msec, mean +/- SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.     

Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol

INTRODUCTION: Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects. METHODS AND RESULTS: We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7). CONCLUSION: In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.     

Effects of quinidine on repolarization in canine epicardium, midmyocardium, and endocardium: II. In vivo study

BACKGROUND: In the companion article, we report a significant difference in quinidine effects on the action potential duration between surface (epicardial and endocardial) cells and midmyocardial cells (M cells) of canine left ventricle in vitro. This article considers two questions raised by the previous study: (1) Are the complex quinidine effects in vitro reflected in its actions on the heart in situ? (2) What are the cellular determinants of quinidine effects on QT interval in ECG? METHODS AND RESULTS: We used plunge and surface electrodes to measure activation-recovery intervals (ARIs) of bipolar electrograms obtained from epicardium, endocardium, and midmyocardium (3, 5, and 9 mm from epicardium) of canine left ventricle in conditions of AV block and right ventricular pacing. Quinidine was infused continuously; its plasma level increased from 1.6+/-0.1 microg/mL at 30 minutes to 7.6+/-0.7 microg/mL at 180 minutes. At cycle lengths (CLs) from 300 to 1500 ms, there was no ARI gradient across the ventricular wall before and during quinidine infusion. At a CL of 300 ms, therapeutic concentrations of quinidine prolonged ARIs and QT intervals. At a CL of 1500 ms, ARIs were significantly prolonged at low quinidine concentrations. With an increase of quinidine concentration, this effect subsided and disappeared. CONCLUSIONS: In situ, quinidine-induced prolongation of repolarization is uniform in all myocardial layers and follows the pattern observed in M cells in vitro. The ability of quinidine in therapeutic concentrations to prolong repolarization at rapid heart rates can contribute to its antiarrhythmic efficacy.     

Effects of hyperkalaemia on the depression of maximum rate of depolarization by class I antiarrhythmic agents in guinea-pig myocardium

1 Standard microelectrode methods were used to record intracellular action potentials from strips of guinea-pig right ventricular myocardium superfused with either standard physiological saline ([K+] = 5.6 mM) or the same solution modified to contain [K+] = 11.2 mM. 2 The effects on action potential parameters of three therapeutic concentrations of mexiletine, quinidine and disopyramide were studied under both conditions at four different drive rates (interstimulus intervals = 2400, 1200, 600 and 300 ms). 3 Hyperkalaemia in the absence of drugs produced reductions in resting potential (-86.7 +/- 2.5 mV to -71.8 +/- 3.7 mV; n = 30; P < 0.001), maximum rate of depolarization (300 +/- 46.5 V s-1 to 205.6 +/- 37.6 V s-1; P < 0.0001), and action potential duration (205 +/- 26 ms to 188 +/- 32 ms; P < 0.05). 4 All three drugs produced increased depression of maximum rate of depolarization in hyperkalaemia compared to control conditions, but at all three concentrations this enhancement of effect was greater for mexiletine than for quinidine, with disopyramide exhibiting intermediate behaviour. 5 Mexiletine behaved very similarly to therapeutic concentrations of lignocaine as described in previous reports from this laboratory. 6 Quinidine behaved very similarly to Class Ic agents. 7 It is concluded that mexiletine demonstrated significantly greater selectivity for depolarized myocardium than quinidine and that this may have implications in terms of proarrhythmic potential. 8 Disopyramide exhibited intermediate selectivity for depolarized myocardium between mexiletine and quinidine.     

The electrophysiological mechanism of the long QT syndrome

There are several functions to modulate if action potential prolongation and early and late after depolarizations are expected to appear, namely: calcium/sodium channels gating modes, potassium channels rectification, 3Na+/1Ca+2 exchange function, left/to/right balance of the sympathetic innervation of the heart. Based upon chronological correspondence of electrophysiological events and surface ecg waves, heterogeneous prolonged repolarization and after depolarizations are two possible explanations for QT interval prolongation and dispersion in both acquired and congenital long QT syndromes. Pauses commonly trigger arrhythmias in acquired LQTS, and imbalanced sympathetic drive commonly triggers arrhythmias in the congenital type of the syndrome.     

Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines

BACKGROUND: The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis. METHODS AND RESULTS: We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01). CONCLUSIONS: Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.     

Surgical relevance of diagnostic imaging of abdominal tumors--decision making in pancreatic tumor

1. An association has been reported between QT interval abnormalities and cardiovascular autonomic neuropathy in diabetic patients. The QT interval abnormalities reflect local inhomogeneities of ventricular recovery time and may be related to an imbalance in cardiac sympathetic innervation. Sympathetic innervation of the heart can be visualized and quantified by single-photon emission-computed tomography with m-[123I]iodobenzylguanidine. In this study we evaluated cardiac sympathetic integrity by m-[123I]iodobenzylguanidine imaging and the relationship between both QT interval prolongation and QT dispersion from standard 12-lead ECG variables and m-[123I]iodobenzylguanidine uptake in insulin-dependent diabetic patients. 2. Three patient groups were studied, comprising six healthy control subjects, nine diabetic patients without cardiovascular autonomic neuropathy (CAN-) and 12 diabetic patients with cardiovascular neuropathy (CAN+). Resting 12-lead ECG was recorded for measurement of maximal QT interval and QT dispersion. The QT interval was heart rate corrected using Bazett's formula (QTc) and the Karjalainen approach (QTk). Quantitative measurement (in counts/min per g) and visual defect pattern of m-[123I]iodobenzylguanidine uptake were performed using m-[123I]iodobenzylguanidine single-photo emission-computed tomography. 3. Global myocardial m-[123I]iodobenzylguanidine uptake was significantly reduced in both diabetic patient groups compared with control subjects. The visual defect score of m-[123I]iodobenzylguanidine uptake was significantly higher in CAN+ diabetic patients than in control subjects and in CAN- patients. This score was not significantly different between control subjects and CAN- patients. QTc interval and QT dispersion were significantly increased in CAN+ diabetic patients as compared with control subjects (QTc: 432 +/- 15 ms versus 404 +/- 19 ms, P < 0.05; QT dispersion: 42 +/- 10 versus 28 +/- 8 ms, P < 0.05). QT dispersion was also significantly longer in CAN- diabetic patients than in control subjects (41 +/- 9 ms versus 28 +/- 8 ms, P < 0.05). QTc interval was significantly related to global myocardial m-[123I]iodobenzylguanidine uptake and defect score in diabetic patients (r = -0.648, P < 0.01, and r = 0.527, P < 0.05, respectively). There was no correlation between QT dispersion and both m-[123I]iodobenzylguanidine uptake measures. 4. In conclusion, these findings suggest that m-[123I]iodobenzylguanidine imaging is a valuable tool for the detection of early alterations in myocardial sympathetic innervation in long-term diabetic patients without cardiovascular autonomic neuropathy. Insulin-dependent diabetic patients with cardiovascular autonomic neuropathy have a delayed cardiac repolarization and increased variability of ventricular refractoriness. The cardiac sympathetic nervous system seems to be one of the determinants of QT interval lengthening, but does not appear to be involved in dispersion of ventricular recovery time. It is assumed that QT dispersion is based on more complex electrophysiological mechanisms which remain to be elucidated.     

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.     

T cell-mediated induction of airway hyperresponsiveness and altered lung functions in mice are independent of increased vascular permeability and mononuclear cell infiltration

To evaluate extra-natriuretic effects of atrial natriuretic peptide (ANP), plasma ANP (pANP) levels were assessed in seven healthy men on low-sodium diet (80 mEq NaCl/day), in basal conditions and during stepwise infusion of human ANP (2, 4, 8 and 16 ng/min/kg). To determine the individual physiological (PHY) pANP level, we measured pANP in the same subjects after a high-salt diet (400 mEq NaCl/day), that is, in a physiological stimulation of ANP. We then compared the effects of the PHY levels of ANP to the effects of pharmacological (PHA) pANP levels. Neither PHY nor PHA pANP levels modified creatinine clearance or blood pressure. The progressive rise in pANP levels was associated with increases in urinary excretion of Na+, K+ and urea. ANP alone respectively accounted for 41%, 30% and 92% of the increase in natriuresis, kaliuresis and urea excretion that occurred after changing salt intake from 80 to 400 mEq/day. Pharmacological ANP levels raised CH2O and reduced UOsm. Interestingly, PHA levels were associated with significant decrease in serum K+ (from 4.5 +/- .1 to 4.0 +/- .1 mEq/liter) and plasma urea (from 31.9 +/- 5 to 24.2 +/- 4 mg/dl). The mean cumulative urinary potassium and urea losses corresponded to the theoretical body losses of potassium and urea; moreover, the individual cumulative urinary losses of potassium and urea significantly correlated with the corresponding decrement in their plasma levels. In conclusion, ANP has both physiological and pharmacological significance in the control of potassium and urea metabolism by decreasing plasma levels of K+ and urea through effects on the renal excretory function.     

Induction of HLA class II in HTLV-I infected neuronal cell lines

Prenatal methylazoxymethanol acetate (MAMac) injection disrupts cell migration in developing rats. We investigated the electrophysiological characteristics of hippocampal CA1 pyramidal neurons from young MAMac-treated animals (postnatal days 25-35). In vitro intracellular recordings from CA1 cells in MAMac-treated tissue revealed resting membrane potential (mean, -61.5 +/- 1.5 mV), action potential amplitude (mean, 69 +/- 3.1 mV), action potential duration (mean, 2.1 +/- 0.2 ms), input resistance (mean, 51.5 +/- 3.6 M omega) and time constant (mean, 33.2 +/- 1.2 ms) similar to those of CA1 cells from control tissue. However, MAMac-treated tissue could be distinguished as having a higher percentage of cells (62% vs. 10%) which fire a burst of action potentials in response to suprathreshold current injection. The synaptic responses of CA1 cells in MAMac-treated and control tissue were comparable. The CA1 field response to stimulation was also comparable at all stimulus intensities tested (50-1500 microA). Elevation of extracellular potassium concentration ([K+]o) from 3 mM to 6 mM resulted in epileptiform discharge activity in response to stratum radiatum stimulation in all MAMac-treated slices (10/10) but in only one-third of controls (3/9). Spontaneous epileptiform discharges were also observed in the majority (8/13) of MAMac-treated slices bathed in 6 mM KCl but in no controls. These data suggest that MAMac treatment during fetal development not only disrupts normal anatomical organization but also leads to alterations in electrophysiological features of the hippocampal CA1 pyramidal cell region. As such, the MAMac model may provide insights into early onset seizure syndromes associated with developmental abnormalities.     

K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes

The K+ channel blocking action of the class Ic antiarrhythmic agent flecainide was compared with that of propafenone and quinidine in isolated adult rat ventricular myocytes by using the whole-cell patch-clamp technique. In rat ventricular myocytes, depolarization activates both an inactivating (ITO) and a maintained (IK) outward K+ current. Flecainide, propafenone and quinidine all were potent inhibitors of ITO with IC50s of 3.7, 3.3 and 3.9 microM, respectively. Flecainide and quinidine were less potent inhibitors of IK than was propafenone with IC50s of 15 and 14 microM compared with an IC50 of 5 microM for propafenone. By contrast with their effects on outward currents, these agents produced little or no inhibition of the inward rectifier K+ current, even when present at 300 microM. All three agents produced a concentration-dependent increase in the rate of inactivation of ITO but they only produced minor hyperpolarizing shifts (approximately 3 mV) in the voltage dependence of steady-state inactivation. Although propafenone had little effect on the rate of ITO recovery from inactivation (tau CONTROL = 64 +/- 5 ms; tau PROPAFENONE = 84 +/- 9 ms), ITO recovery in the presence of flecainide and quinidine was biexponential; it exhibited an additional slow component (tau FAST = 67 +/- 5 ms and tau SLOW = 2580 +/- 1500 ms for flecainide; tau FAST = 55 +/- 5 ms and tau SLOW = 871 +/- 99 ms for quinidine). Consistent with these observations, flecainide and quinidine, but not propafenone, produced use-dependent block of ITO at a stimulation frequency of 1 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of a left bundle-branch block on ventricular repolarization dispersion

Patients with left bundle-branch block (LBBB) often present electrocardiographic abnormalities and, therefore, are excluded from studies concerning electrocardiographic evaluation of ventricular repolarization. The aim of the study was to assess whether LBBB could influence dispersion of ventricular repolarization. Surface electrocardiograms of 16 patients (9 males and 7 females, mean age 58 +/- 14 years) with episodes of intermittent LBBB were analyzed. Six patients were affected by coronary artery disease, 6 by hypertensive cardiomyopathy and 4 by dilated cardiomyopathy. Maximal QT and JT corrected intervals, QT and JT dispersion, and QT and JT dispersion corrected for heart rate, were obtained before and after LBBB. We observed a significant prolongation of maximal QT (412 +/- 29 vs 433 +/- 25 ms; p < 0.05), and of maximal corrected QT (457 +/- 37 vs 497 +/- 56 ms; p < 0.05) after LBBB. Maximal JT interval, also corrected for heart rate, did not show any significant modification after LBBB. Moreover, we did not observe any significant difference in electrocardiographic parameters of dispersion of repolarization. Our results seem to indicate that LBBB did not alter significantly dispersion of ventricular repolarization. QT dispersion is considered an important marker of risk for incidence of ventricular arrhythmias. If our results will be confirmed in larger groups of patients, analysis of QT dispersion could be extended even to patients with LBBB.     

Projections of submucous neurons to the myenteric plexus in the guinea pig small intestine

Coronary venous hypertension induced by partial coronary sinus obstruction (CSO) in the dog, prevents or delays the predictable ventricular fibrillation (VF) of the early phase of acute ischemia. Also, CSO acting presumably through enhanced myocardial hydration, normalizes the inhomogenous extracellular potassium ([K+]o) accumulation, a major factor in producing the electrophysiological disparities, characteristic of arrhythmogenic substrate. To further clarify the mechanism of early ischemic VF prevention in dogs, radioactive microspheres were used to evaluate regional perfusion changes, resulting from CSO sufficient to raise the coronary sinus pressure to 40 mmHg, before and during ischemia induced by double coronary artery occlusion (CAO) (n=5). Also, global or regional unipolar electrogram mapping was used to assess changes of epicardial ventricular activation times (AT) and sequence and activation recovery intervals (ARI) during CSO, CAO and combined CSO and CAO, induced in random order (n=8). CSO did not affect regional perfusion nor improved collateral blood flow during ischemia. With CSO, AT shortened modestly over time (0.41+/-1.1 ms/min, r=0.85, P<0. 05) and ARI transiently decreased by up to 5.5%. With CAO, AT became variably delayed and isochrone map distortions were indicative of localized conduction delays or blocks, consistent with elevated [K+]o. In contrast, when CAO was preceded by CSO, AT delays were homogenous and normal activation sequence was preserved. Also, whereas with CAO, ARI shortened unequally over the ischemic region by as much as 43% at individual sites (average of 38.3+/-6.8 ms, P<0. 001), with combined CSO and CAO, ARI shortening was less pronounced and more homogenous (26.1+/-5.6 ms, P<0.05), not exceeding 29% at any site. Thus, in accordance with previous findings of enhanced [K+]o homogeneity, coronary venous hypertension reduces the disparities of activation and refractoriness of ischemia attributable, at least in part, to disparate [K+]o accumulation. Since no collateral blood flow improvement could be identified, the salutary electrophysiological effects of CSO may reflect a more homogenous extracellular environment, due to preservation of normal microvascular pressure (Pmv) and sustained filtration and lymph flow.     

Information on type 1 diabetes mellitus and QT interval from identical twins

To determine whether QT interval is influenced by genetic factors and whether QT-interval prolongation occurs in type 1 diabetes or is related to diabetic autonomic neuropathy, QT intervals were measured, and autonomic function was assessed in 44 pairs of identical twins who were discordant for type 1 diabetes. Twins were compared with 44 normal control subjects of similar age and sex. QT intervals were corrected for heart rate (QTc). QTc in diabetic twins correlated with that in their nondiabetic co-twins (r = 0.41; p = 0.006). Diabetic twins had significantly longer QTc than did their nondiabetic co-twins and control subjects (416 +/- 18 vs 407 +/- 16 and 403 +/- 19 ms, respectively; p < 0.005). A greater number of abnormal autonomic function tests were detected in diabetic twins than in their nondiabetic co-twins and control subjects (8 vs 2 and 0%, respectively; p < 0.01). Diabetic twins with disease duration > 14 years (n = 22) had longer QTc than did their nondiabetic co-twins (420 +/- 17 vs 402 +/- 14 ms; p < 0.0005). Twins with diabetes for > 14 years had a greater frequency of abnormal autonomic function tests than did those with diabetes < 14 years (15 vs 2%; p < 0.001). QTc did not correlate with autonomic function in diabetic twins. It is concluded that QT interval is influenced by genetic factors, and in type 1 diabetes, QTc can be prolonged independently of autonomic neuropathy.     

Reduced myocardial Na+, K(+)-pump capacity in congestive heart failure following myocardial infarction in rats

We examined changes in expression and function of the cardiac Na+, K(+)-pump in a post-infarction rat model of hypertrophy and congestive heart failure (CHF). Myocardial infarction was induced by ligation of the left coronary artery in Wistar rats and hearts were obtained from animals with CHF and from sham operated rats after 6 weeks. In the CHF group the ratio of heart weight to body weight was 70% greater compared to sham (*P < 0.05) and all left-ventricular end-diastolic pressures (LVEDP) were above 15 mmHg. The expression of the alpha 1- and beta 1-subunits (mRNA and protein) of the Na+, K(+)-pump was not significantly different in CHF and sham. As compared to sham the alpha 2 isoform, mRNA and protein levels were lower in CHF hearts by 25 and 55%, respectively, whereas the alpha 3 isoform mRNA was greater by 120% in CHF. The alpha 3 protein was not detectable in sham but a prominent band was seen in CHF. Cell volume of isolated cardiomyocytes was 30% larger in CHF. Cardiomyocytes containing the Na+ sensitive fluorescent dye SBFI were loaded to an intracellular Na+ concentration ([Na+]i] of about 140 mM in a K(+)- and Mg(2+)-free medium (140 mM Na+, free Ca2+ of 10(-8) M). To avoid back leak of Na+ and to ensure no voltage effects on the Na+, K(+)-pump extracellular Na+ was subsequently removed, and 6 mM Mg2+ was added to the superfusate, The Na+, K(+)-pump was then reactivated by 10 mM Rb+. SBFI fluorescence ratio decreased mono-exponentially with a time constant (tau) of 191 +/- 15 s in sham (n = 8) and 320 +/- 38 s in CHF (n = 9) rats (P < 0.01). These changes in fluorescence indicate that the maximum rate of decline of [Na+]i from 100 to 35 mM was 39% (P < 0.005) slower in CHF compared to sham, whereas maximum pump rate per cell was not significantly altered (9.0 +/- 0.7 fmol/s in sham and 7.1 +/- 0.7 fmol/s in CHF cells). The [Na+]i which caused 50% pump activation (k0.5) was also not altered in CHF (40 mM in both groups). We conclude that the number of Na+, K(+)-pumps per cell was maintained in CHF but an isoform switch of the alpha 3-replacing the alpha 2-isoform occurred. However, maximum Na+, K(+)-pump rate in terms of rate of change of [Na+]i was significantly attenuated in CHF, most likely as a result of increased cell size.     

Histochemistry of the surface mucous gel layer of the human colon

Two characteristic features of the rapid component of the cardiac delayed rectifier current (IKr) are prominent inward rectification and an unexpected reduction in activating current with decreased [K+]o. Similar features are observed with heterologous expression of HERG, the gene thought to encode the channel carrying IKr, moreover, recent studies indicate that the mechanism underlying rectification of HERG current is the inactivation that channels rapidly undergo during depolarizing pulses. The present studies were designed to determine the mechanism of IKr rectification and [K+]o sensitivity in the mouse atrial myocyte cell line, AT-1 cells. Reducing [Mg2+]i to 0, which reverses inward rectification of some K+ channels, did not alter IKr current-voltage relationships, although it did decrease sensitivity to the IKr blockers dofetilide and quinidine 2- to 5-fold. To determine the presence and extent of fast inactivation of IKr in AT-1 cells, a brief hyperpolarizing pulse (20 ms to -120 mV) was applied during long depolarizations. Immediately after this pulse, a very large outward current that decayed rapidly to the previous activating current baseline was observed. This outward current component was blocked by the IKr-specific inhibitor dofetilide, indicating that it represented recovery from fast inactivation during the hyperpolarizing step, with fast reinactivation during the return to depolarized potential. With removal of inactivation using this approach, current-voltage relationships for IKr ([K+]o, 1 to 20 mmol/L) were linar and reversed close to the predicted Nernst potential for K+. In addition, decreased [K+]o decreased the time constants for open-->inactivated and inactivated-->open transitions. Thus, in these cardiac myocytes, as with heterologously expressed HERG, IKr undergoes fast inactivation that determines its characteristic inward rectification. These studies demonstrate that the mechanism underlying decreased activating current observed at low [K+]o is more extensive fast inactivation.     

Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease

Polycystic kidney disease (PKD) has been shown to be exacerbated by acidosis or a low potassium intake, and there is evidence that administration of alkali might have a beneficial effect. This study determined whether ingestion of potassium citrate and citric acid would ameliorate PKD. Healthy normal and heterozygous littermate Han:SPRD rats with autosomal dominant PKD were provided with either tap water or 55 mM K3citrate/67 mM citric acid solution (KCitr) to drink starting at the age of 1 mo. Renal clearance measurements and histologic assessments were performed when the rats were 3 mo old. KCitr intake did not affect body weight or urine flow, but completely prevented the decline in GFR found in untreated rats with PKD. In rats that drank tap water, left kidney GFR averaged (in microliter/min per 100 g body wt) 503 +/- 78 (n = 9) in normal animals and 242 +/- 56 (n = 6) in rats with PKD. In rats that drank KCitr, GFR averaged 562 +/- 123 (n = 7) in normal animals and 534 +/- 103 (n = 7) in rats with PKD. Kidneys of rats with PKD were approximately double normal size. KCitr treatment did not affect kidney size, but led to fewer interstitial abnormalities and smaller cysts in cystic kidneys. KCitr ingestion led to a significantly lower (P < 0.001) plasma [K+] in rats with PKD (3.3 +/- 0.2 versus 4.1 +/- 0.2 mEq/L in rats on tap water). Chronic KCitr intake in the young heterozygous Han:SPRD rat with PKD yields a modest improvement of kidney histology and a dramatic improvement in GFR. The mechanism of action of KCitr and the long-term effects of this treatment on renal structure and function in PKD deserve further study.     

Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study

The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 +/- 114 vs 443 +/- 54 ms [mean +/- SD], P < 0.01), a larger precordial QT dispersion (50 +/- 74 vs 27 +/- 26 ms, P < 0.05), and a lower T wave amplitude (0.12 +/- 0.21 vs 0.24 +/- 0.16 mV, P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 +/- 26 vs 489 +/- 74 ms, P < 0.001), a larger QT dispersion in precordial (82 +/- 7 vs 54 +/- 52 ms, P < 0.01) and extremity leads (163 +/- 0 vs 40 +/- 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.     

Effect of coronary angioplasty on precordial QT dispersion

Dispersion of the QT interval is a measure of inhomogeneity of ventricular repolarization. Because ischemia is associated with regional abnormalities of conduction and repolarization, we hypothesized that the surface electrocardiographic interval dispersion would increase in patients with symptomatic coronary artery disease in the absence of myocardial infarction and that successful revascularization would reduce QT interval dispersion. Thirty-seven consecutive patients with ischemia due to 1-vessel coronary artery disease without prior myocardial infarction who underwent percutaneous transluminal coronary angioplasty (PTCA) were evaluated. Standard 12-lead electrocardiograms were performed 24 hours before, 24 hours after, and late (>2 months) after PTCA. Precordial QT interval dispersions were determined from differences in the maximum and minimum corrected QT intervals. Mean QT interval dispersion before PTCA was 60 +/- 9 ms, immediately after PTCA 23 +/- 14 ms (p <0.001), and late after PTCA 29 +/- 18 ms (p <0.001 vs before PTCA). The shortest precordial QT interval increased immediately after PTCA (367 +/- 40 vs 391 +/- 39 ms; p <0.02) and then remained stable late after PTCA (376 +/- 36 ms, p = NS vs immediately after PTCA). Symptomatic recurrent ischemia in 8 patients with documented restenosis increased QT interval dispersion (56 +/- 15 ms [p <0.01] vs 25 +/- 14 ms immediately after PTCA), which decreased again after successful repeat PTCA (22 +/- 13 ms [p <0.01] vs before the second PTCA). QT interval dispersion decreases after successful coronary artery revascularization and increases with restenosis. Therefore, QT interval dispersion may be a marker of recurrent ischemia due to restenosis after PTCA.     

QT interval dispersion in healthy subjects and survivors of sudden cardiac death: circadian variation in a twenty-four-hour assessment

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.