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BACKGROUND: Arginine vasopressin may contribute to abnormalities in hemodynamics and fluid balance in heart failure through its actions on V(1A) (vascular and myocardial effects) and V(2) receptors (renal effects). Inhibiting the action of vasopressin may be beneficial in patients with heart failure. METHODS AND RESULTS: A total of 142 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind, short-term treatment with conivaptan, a dual V(1a)/V(2) vasopressin receptor antagonist, at a single intravenous dose (10, 20, or 40 mg) or placebo. Compared with placebo, conivaptan at 20 and 40 mg significantly reduced pulmonary capillary wedge pressure (-2.6+/-0.7, -5.4+/-0.7, and -4.6+/-0.7 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) and right atrial pressure (-2.0+/-0.4, -3.7+/-0.4, and -3.5+/-0.4 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) during the 3- to 6-hour interval after intravenous administration. Conivaptan significantly increased urine output in a dose-dependent manner (-11+/-17, 68+/-17, 152+/-19, and 176+/-18 mL/hour for placebo and 10, 20, and 40 mg groups, respectively; P<0.001) during the first 4 hours after the dose. Changes in cardiac index, systemic and pulmonary vascular resistance, blood pressure, and heart rate did not significantly differ from placebo. CONCLUSIONS: In patients with advanced heart failure, vasopressin receptor antagonism with conivaptan resulted in favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate. These data suggest that vasopressin is functionally significant in advanced heart failure and that further investigations are warranted to examine the effects of conivaptan on symptom relief and natural history in such patients.

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OBJECTIVE: To determine the cost of heart failure-related hospital admissions and to compare the cost of admissions for sodium retention with the cost of admissions for other decompensating factors. DESIGN: Retrospective, non-experimental, cost analysis. SETTING: Midwestern university-affiliated, tertiary care, medical center. SAMPLE: Two hundred seven heart failure-related admissions, 117 (57%) of which were for sodium retention leading to volume overload. OUTCOME MEASURES: Cost of hospitalization. PROCEDURE: Data obtained from the patient and financial records of patients hospitalized for heart failure in 1992 were analyzed using the ratio of cost-to-charge accounting procedure. RESULTS: The total cost was $2,442,720 for the 207 heart failure-related admissions; the average cost was $12,400 per admission. Approximately half of the cost of the hospitalizations was expended in the 4 cost centers comprising routine and critical care services, which incorporate room charges and nursing care. Another one third of the cost was for supplies, medications, and laboratory tests. Admissions as a result of sodium retention had lower costs than admissions as a result of other factors. CONCLUSION: The cost of hospitalization for heart failure is high. Routine services, supplies, medications, and laboratory tests used by these patients contribute to the high cost of care. Improved outpatient management strategies are necessary to reduce hospital admissions as a result of sodium retention.

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Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

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BACKGROUND: The model for management of patients with heart failure may be a key determinant of morbidity and quality of life. Development of a better management strategy for these patients requires determination of the reasons for decompensation that leads to hospitalization. OBJECTIVES: To ascertain and rank the principal reasons for hospitalization of patients who have heart failure. METHODS: Retrospective audit of all 1992 admissions (N = 1031; 691 patients) coded for heart failure at a Veterans Affairs medical center and a tertiary care university medical center. RESULTS: The diagnosis of heart failure was verified by preset criteria in 72% of the patients. Of the 496 patients with documented heart failure, worsening heart failure was a main reason for admission in 390 (79%). Despite different socioeconomic backgrounds, excessive sodium retention was the leading factor (55%) associated with decompensation in patients at both institutions. Other factors precipitated admission much less often. CONCLUSIONS: Many hospitalizations for heart failure might be avoided by case management directed at lessening sodium overload. Increased use of medications known to be effective in persons with heart failure (angiotensin-converting enzyme inhibitors, digoxin, and adequate diuretic therapy) might reduce the likelihood of decompensation. Implementation of behavioral interventions to assist patients with self-monitoring signs of sodium retention and to improve compliance with medications and dietary sodium restrictions are strategies for further reducing the risk of decompensation.

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The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

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BACKGROUND: We assessed the effects of radiofrequency catheter ablation (RFCA) of the atrial epicardium on pacing-induced sustained atrial fibrillation (AF) and the expression and distribution of the intercellular gap junction protein connexin 43 (Cx43) in dogs. METHODS AND RESULTS: In 12 mongrel dogs, after creation of complete AV block and implantation of a ventricular inhibited pacemaker, a high-rate pulse generator (20 to 30 Hz to induce AF) was implanted in the neck, connected to a right atrial endocardial pacing lead, and used to pace the atrium for 10 to 14 weeks. In group 1 (n=9 dogs), corrected sinus node recovery time (CSNRT), P-wave duration, 24-hour Holter ECG, maximal heart rate (MHR) in response to isoproterenol, and intrinsic heart rate (IHR) after atropine (0.04 mg/kg) and propranolol were measured before and after atrial pacing and RFCA. Group 2 dogs were used to assess the effect of chronic AF alone on Cx43 expression and distribution. All group 1 dogs developed sustained (>24 hours) AF. Right-sided RFCA of the atria eliminated the sustained AF in 5 dogs, but both right and left atrial RFCA was required to abolish sustained AF in the other 4 dogs. After RFCA restored sinus rhythm, CSNRT and P-wave duration were prolonged and MHR and IHR were decreased. Chronic rapid atrial pacing (group 2) increased the expression of Cx43, which was absent in ablated areas and markedly depressed in viable atrial myocytes near the ablation zones (group 1). CONCLUSIONS: Rapid atrial pacing for long time periods induced sustained AF that can be eliminated by linear right and left atrial lesions created with RFCA, with preservation of sinus rhythm and atrial contractile function. Chronic AF increased the expression and distribution of gap junction protein Cx43, which became reduced in ablated and nearby nonablated areas.

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OBJECTIVES: We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF). BACKGROUND: The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown. METHODS: In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment. RESULTS: The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (+/- SD) plasma levels of TNF-alpha were 5.69 +/- 0.32 pg/ml, and those of IL-6 were 9.23 +/- 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event-CHF or death-occurred more commonly in patients with higher IL-6 levels. CONCLUSIONS: Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6.

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Persons with chronic heart failure (HF) must cope not only with the physical impairment of their disease but with the associated emotional distress. The primary purpose of this prospective study was to examine whether the psychosocial variables of symptom impact measured at baseline--health perception, social support and coping--differed between a group of adults with chronic HF who were hospitalized and a group who were not hospitalized during the following six months of the study. A secondary purpose was to examine indices of left ventricular dysfunction that might influence hospitalization. Within the six-month period following baseline data collection, 23 of 62 (37%) patients who completed the study were hospitalized at least once for problems pertaining to HF. Patients in the hospitalized group reported significantly more baseline symptom impact, particularly in the areas of emotional symptoms and deficits of attention and memory. Social support and coping did not differ significantly between hospitalized and nonhospitalized patients. Extent of myocardial dysfunction, age and demographic variables were not significantly different between the two groups. Heart failure decompensation requiring inpatient management was presaged by increased anxiety and disorders of mentation, suggesting that health care providers need to be sensitive to these reported symptoms and their impact, because they might be clues to impending hospitalization.

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In the present study, we have investigated the changes in the expression and distribution of the principal gap-junction channel protein in ventricular muscle, connexin 43 (Cx43), during the first 2 weeks of culturing adult guinea pig cardiomyocytes at low density to prevent formation of cellular contacts. In freshly isolated cardiomyocytes, immunoreactive Cx43 occupied 6.5 +/- 0.4% of the pixel area of the cell, with 85% being localized to dense particles at the step-like end projections of the myocytes (intercalated disk regions) and 15% being within the sarcoplasm or along the lateral surface of the myocytes ("nondisk" distribution). During the myocytes' first 48 h in culture, immunoreactive Cx43 decreased by 27.5% from control values, to 4.7 +/- 0.5% of the cells' pixel area (P < 0.01). Cx43 particles also redistributed: after 48 h in culture approximately 90% of the immunoreactive Cx43 was localized in the sarcoplasm and nondisk regions of the myocyte. After 7 days, immunoreactive Cx43 only occupied 50% of the cells' control pixel area (P < 0.01) and was nearly uniform in its punctate pattern throughout the sarcoplasm. This distribution remained the same during the 2nd week in culture. Changes in myosin light chain staining during 8 days in culture largely paralleled those in Cx43 staining. Laser confocal microscopic analysis of double-immunolabeled myocytes that had been in culture for 24-48 h showed colocalization of Cx43 with clathrin in approximately 30% of the sarcoplasmic Cx43 particles. Thus it is demonstrated that the expression of Cx43 decreases significantly during the first 48 h in culture after myocyte isolation and that Cx43 also undergoes substantial redistribution but for the next 2 weeks remains more or less unchanged and at relatively high levels (approximately 50%). These data indicate that cardiomyocytes in isolation maintain their ability to reconnect with each other for up to at least 2 weeks. This is the first time that this property has been investigated in cultured adult ventricular cardiomyocytes.

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BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

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INTRODUCTION: Terodiline hydrochloride, widely prescribed for urinary incontinence, has been reported to cause bradycardia and torsades de pointes. METHODS AND RESULTS: In this study, we characterized the electrophysiologic effects of terodiline in dog cardiac tissues in vivo and in isolated canine cardiac Purkinje fibers. Terodiline (1 to 10 microM) resulted in dose-dependent reduction of action potential amplitude and maximal upstroke velocity (Vmax). The threshold for these effects was approximately 2 microM (0.6 mg/L), and the changes were cycle-length dependent. Terodiline (> or = 2 microM) also depressed the action potential plateau but did not significantly alter action potential duration at concentrations < or = 10 microM. In vivo studies demonstrated that high doses of terodiline (3 mg/kg) lengthened AH and HV intervals, slowed spontaneous sinus rate, prolonged ventricular refractoriness, and inhibited vagally induced slowing of the sinus node. Sympathetic effects on spontaneous sinus rate were unchanged. In both isolated canine Purkinje fibers and anesthetized dogs, terodiline did not evoke afterdepolarizations, repetitive firing, or ventricular tachyarrhythmias under normal or hypokalemic conditions. CONCLUSION: Our findings suggest that terodiline (> or = 1 to 2 microM) leads to blockade of sodium and calcium channels as well as muscarinic receptors in canine cardiac tissues.

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BACKGROUND: Erythromycin is known to prolong ventricular repolarization and has been associated with the occurrence of torsades de pointes. In this study, we have investigated potential mechanisms in vivo and in vitro for induction of an acquired long QT syndrome by erythromycin. METHODS AND RESULTS: Ventricular electrograms and endocardial monophasic action potentials were recorded in anesthetized open-chest dogs before and after administration of 40 to 120 mg/kg of erythromycin lactobionate. Conventional microelectrode techniques were used to record transmembrane action potentials in isolated dog Purkinje fibers and papillary muscles. Erythromycin at concentrations > 20 mg/L prolonged action potential duration. At higher concentrations (100 to 200 mg/L), erythromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro. The effects of erythromycin on repolarization were more marked in Purkinje fibers than in papillary muscle. Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker. Pretreatment with prazosin or tetrodotoxin had no effect on erythromycin-induced changes in action potential duration. CONCLUSIONS: These pharmacological studies suggest that erythromycin prolongs repolarization to a large extent by block of IK. In turn, prolongation of action potential duration resulting from erythromycin's actions on IK may promote the development of EADs. The induction of ventricular arrhythmias observed clinically after exposure to erythromycin may be related to the development of EADs. The rarity of occurrence of ventricular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.

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Gap junctional proteins (connexins) form aqueous channels that enable direct cell-cell transfer of ions and small molecules. The distribution and conductance of gap junction channels in cardiac muscle determine the pattern and synchrony of cellular activation. However, the capacity for smooth muscle to restrict contractile events temporally and spatially suggests that cell-cell coupling or its regulation may be decidedly different in this tissue. We isolated a cDNA from vascular smooth muscle which encodes a connexin (Mr 43,187) structurally homologous to cardiac connexin43. Vascular smooth muscle connexin43 mRNA was expressed prominently in smooth muscle tissues, cultured vascular myocytes, and arterial endothelial cells. A model for functional expression of connexins was developed in two-cell B6D2 mouse embryos. Microinjection of in vitro transcribed vascular smooth muscle connexin43 mRNA was shown to be sufficient to induce intercellular coupling in previously uncoupled blastomeres. Through the construction of two deletion mutants of connexin43, we also show that the formation of cell-to-cell connections does not depend upon a predicted cytoplasmic region within 98 residues of the carboxyl terminus. Finally, the identification of connexin43 in smooth muscle and endothelial cells provides supporting evidence for the existence of heterocellular coupling between cells of the vascular intima.

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Intracellular pH (pHi) is a significant modifier of cell-to-cell communication in some tissues but its role is uncertain in heart tissue. The present studies examined the effect of cytosolic protons on electrotonic spread and conduction velocity in cardiac Purkinje fibers. Cable analysis provided values for internal longitudinal resistance (ri) and pH-selective microelectrodes monitored pHi during CO2 and HCO3- alterations. Resting fibers developed changes in ri that were proportional to intracellular free proton concentration ([H+]i) during CO2 changes at constant [HCO3-]. However, the effects on ri were small between pHi 6.9-7.8 and predicted only a 2.2% increase in ri per 10 nM increase in [H+]i. Other findings suggested that titration of cytosolic protons may not directly produce the changes in ri: (a) For an equal change in [H+]i, the effects on ri were roughly three times greater (6.8% increase per 10 nM rise in [H+]i) if bicarbonate was lost during CO2 changes. (b) pH-associated changes in ri were preceded by a time delay (1-5 min) producing hysteresis in the [H+]i-ri relation during successive perturbations. (c) The same CO2 variations modified the direction and magnitude of ri differently during pacing than at rest. The cumulative results suggest that the action of protons on ri in the heart may be subordinate to another regulator or mediated by another pH-dependent substance or reaction.

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Regulation of intracellular pH (pHi) and the relationship between H+ and Ca2+ may vary during activity. Ion-selective microelectrodes were used to record pHi during action potentials of sheep Purkinje fibres prolonged by low temperature (21 degrees C) and elevated CO2 content. Intracellular pH also was measured during changes in extracellular calcium concentration, [Ca2+]o. Cytosolic alkalinization (peak pHi change, 0.03-0.05) was observed during the long action-potential plateau and transient acidification (0.01-0.02 units) upon repolarization. Potassium-induced depolarization to plateau potentials (i.e. to -15 +/- 2 mV) simulated the peak magnitude of the alkalinization. However, compensation for the alkalinization occurred at a faster rate during the action potential (8.9 +/- 4.3 nM/min) than during K+ depolarization (1.2 +/- 0.5 nM/min). In comparison, the cytoplasm acidified in resting fibres (0.06-0.07 log units) during changes of [Ca2+]o thought to increase intracellular calcium concentration. Alterations of pHi were translated into changes of proton concentration ([H+]i). Ten- to twenty-fold elevation of [Ca2+]o evoked a comparable change in [H+]i (mean increase, 5.7 nM) but oppositely directed from that during the plateau (mean decrease, 8.8 nM). The findings in resting fibres seem consistent with displacement of bound protons by Ca2+. In contrast, the initial change in pHi during the plateau is proposed to be consequent to Ca2+-release from sarcoplasmic reticulum and/or phosphocreatine hydrolysis coupled to ATP regeneration.

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Internal longitudinal resistance (ri), a determinant of cardiac conduction, is affected by changes in intracellular calcium and protons. However, the role and mechanism by which H+ and Ca2+ may modulate ri is uncertain. Cable analysis was performed in cardiac Purkinje fibers to measure ri during various interventions. In some experiments, intracellular pH (pHi) was recorded simultaneously to study the pHi-ri relation. Both intracellular Ca2+ and H+ independently modified ri. However, internal resistance of cardiac fibers was insensitive to pHi changes compared to other tissues. A latent period preceded the pHi-related changes in ri and the amount of change depended upon methodology. The results suggest that direct action of protons or ri may be subordinate to other regulatory processes. Ionic regulation of internal longitudinal resistance may occur by more than one mechanism: i) direct cationic binding to sites on junctional membrane proteins; and ii) H+- or Ca2+-dependent phosphorylation of junctional proteins.

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Cable properties of sheep cardiac Purkinje fibres were studied under resting and paced conditions. Standard micro-electrode techniques were used to apply intracellular current pulses and record the resultant voltage changes at various distances from the current input. In a parallel set of experiments, fibre dimensions were measured after freezing and serial sectioning. Fibres selected on the basis of a cylindrical appearance had approximately uniform cross-sectional diameters which varied +/- 12% along their length. Electrotonic potentials recorded at rest and in diastole (under conditions that minimized diastolic depolarization) adhered quite closely to the behaviour expected for a unidimensional cable provided voltages were recorded greater than or equal to one fibre diameter from the current source. The unidimensional space constant, input resistance, and membrane time constant were significantly larger during quiescence than in diastole. These differences were accounted for by a 90% increase in membrane resistance at rest. There was no significant change in internal longitudinal resistance nor membrane capacitance associated with activity. The voltage distribution close to the current input (i.e. within one fibre diameter) strongly deviated from the theoretical three-dimensional voltage decay expected for a homogeneous cylinder. This finding suggests that the transverse resistance to current flow is much greater than the longitudinal resistance. The anisotropic behaviour within the cardiac Purkinje fibre may explain several previous observations: (i) the lack of a relationship between conduction velocity and fibre diameter; and (ii) the much shorter liminal length for excitation in Purkinje fibres than for point-stimulated squid axons.

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The effects of alteration of extracellular calcium ion concentration ([Ca++]o) were studied in isolated false tendons using microelectrode techniques. Several determinants of cellular excitability and conduction velocity were affected by extracellular calcium. Increasing [Ca++]o from 2 to 8 mM resulted in: (1) a progressive decrease in interelectrode conduction velocity (2) a 7-mV shift of the maximum upstroke velocity-membrane potential relation toward less negative potential, (3) an increase in rheobasic current, (4) a 14-mV shift of the voltage threshold for all-or-none depolarization to less negative potentials, (5) a 52% increase in internal longitudinal resistance per unit length, and (6) a 27% decrease in the capacitance filled by the foot of the action potential from 4.90 to 3.56 microF/cm2. Blockade of the slow inward current by Mn++ or verapamil did not alter the [Ca++]o-induced effects on the maximum upstroke velocity-membrane potential relation. Cable properties were determined during alteration of [Ca++]o in the presence of verapamil (3 X 10(-6) and 1 X 10(-5) M) or in the presence of La+++ (0.2 mM). Verapamil increased membrane resistance X unit length but did not affect internal longitudinal resistance per unit length. La+++ had no effects on either membrane resistance X unit length or internal longitudinal resistance per unit length. Verapamil did not block the increase in ri induced by elevation of [Ca++]o. However, no change in ri occurred during an increase of [Ca++]o when La+++ was present. The results suggest that [Ca++]o-induced changes in internal longitudinal resistance may occur by the influx of calcium ions through the Na+/Ca++ exchange mechanism.

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