Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers

AIMS: To study whether desensitization occurs after long-term administration of the 1-adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. METHODS: In a double-blind, randomized design 10 young, healthy males received ketotifen (2 x 1 mg day(-1) p.o.) or placebo for 3 weeks with xamoterol (2 x 200 mg day(-1) p.o.) administered concomitantly during the last 2 weeks. 'l1-adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline-induced tachycardia was measured as a mixed beta1-/beta2-adrenoceptor-mediated effect. RESULTS: The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise- and isoprenaline-induced tachycardia (mean dose ratios+/-s.e.mean: 1.20+/-0.05 and 2.46+/-0.23) and the isoprenaline-evoked shortening of QS2c (dose ratio 3.59+/-0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (-0.03; 0.04); isoprenaline tachycardia 0.03 (-0.15; 0.21); isoprenaline induced shortening of QS2c 0.13 (-0.22; 0.48)). CONCLUSIONS: In humans xamoterol is a partial beta1-adrenoceptor agonist with positive chrono- and inotropic effects at rest and antagonistic properties under conditions of beta-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of beta1-adrenoceptor desensitization. Ketotifen does not change the beta-adrenoceptor mediated responses of xamoterol after chronic dosing.     

The cardiovascular effects of xamoterol, a beta 1-adrenoceptor partial agonist, in healthy volunteers at rest.

The cardiovascular effects of three single intravenous doses of a beta 1-adrenoceptor partial agonist, xamoterol (0.025, 0.05 and 0.1 mg kg-1) and placebo were studied in six healthy volunteers at rest using a single-blind design. In addition to heart rate and blood pressure measurements, cardiac contractility was measured by means of M-mode echocardiography and systolic time intervals. Ambulatory 24 h Holter-monitoring of the electrocardiogram was performed. Plasma concentrations of xamoterol were measured. Compared to baseline, xamoterol (0.025 mg kg-1) increased heart rate (61 +/- 3-68 +/- 3 beats min-1, means and SEM) and systolic blood pressure (119 +/- 3-138 +/- 5 mm Hg) but decreased pre-ejection period (100 +/- 4-76 +/- 5 msec). Stroke volume (88 +/- 6-104 +/- 10 ml), cardiac output (4.8 +/- 0.4-6.6 +/- 0.61 min-1), velocity of circumferential fibre shortening (1.15 +/- 0.06-1.50 +/- 0.06 circ s-1) were increased by xamoterol. No significant changes were produced by placebo. No dose-dependent effects were seen and maximum effects were produced by 0.025 mg kg-1 xamoterol. Significant effects were observed for 2 h. The areas under the plasma concentration curves (AUC0-12) showed a linear dose response. No adverse effects attributable to xamoterol were seen in haematological, biochemical, urinalysis or electrocardiographic tests. Four volunteers were aware of a more forceful heart beat after xamoterol, but this was mild and transient. It is concluded that xamoterol has a positive inotropic action.     

The effects and dose-response relationship of xamoterol in patients with ischaemic heart disease.

1. In a double-blind placebo controlled four-way crossover study the effects and dose response relationships of xamoterol were studied in nine patients with angina and dyspnoea secondary to chronic left ventricular dysfunction. The duration of exercise on a treadmill and heart rate were measured at the end of each phase of the study at 2 h and 24 h after dosing. 2. Xamoterol at 200 mg and 400 mg orally once daily had no effect on the mean resting heart rate but there was a small (5.7 beats min-1) but significant reduction in resting heart rate on 600 mg at 2-2.5 h after dosing. All three doses of xamoterol significantly reduced the maximum exercise heart rate at 2-2.5 h after dosing. 3. Xamoterol at all three doses significantly increased exercise duration at 2-2.5 h after dosing but not at 24 h. 4. Mean plasma xamoterol concentration at both 2-2.5 h and 24 h after dosing were dose related. The EC50 for xamoterol is 33.5 ng ml-1, where EC50 is the effective plasma concentration required to produce 50% of the maximum effect on exercise heart rate.     

Haemodynamic and metabolic effects of xamoterol in exercising dogs

The effects of xamoterol on the haemodynamic adaptation to graded treadmill exercise were evaluated during five subsequent cycles in chronically instrumented dogs. At rest xamoterol, 0.2 mg/kg i.v., preferentially showed a positive inotropic effect, whereas 1 mg/kg i.v. also exhibited a marked chronotropic effect. The cardiac output and left ventricular power increased dose dependently. The mean left atrial pressure and total peripheral resistance decreased concomitantly. Xamoterol did not produce a noteworthy decrease in heart rate or positive dp/dtmax during exercise, even at a dosage of 1 mg/kg. A beta-adrenoceptor blocking effect could only be seen from the diminution of the exercise-induced changes in heart rate, dp/dtmax, cardiac output, left ventricular power and total peripheral resistance. Determination of the blood glucose, lactate and pyruvate levels before the start of each exercise cycle revealed that the drug induced a decrease in blood glucose and an increase in blood pyruvate. Thus, xamoterol exerted a dose-dependent sympathomimetic effect in dogs at rest. However, there was little evidence for a beta-adrenoceptor blocking action even at higher work loads, although preliminary experiments in conscious dogs showed that xamoterol shifted the isoprenaline dose-response curve to the right by a factor of 1.31 (0.2 mg/kg) and 3.05 (1 mg/kg).     

Relationship between positive inotropic responses and plasma concentrations of xamoterol in middle-aged and elderly patients.

1. We examined the relationship between the contractile state of the left ventricle and the plasma concentration of xamoterol in patients with ischaemic heart failure. 2. Identical studies were conducted in 14 middle-aged (all male; mean age 51.3 years, range 42-61) and 10 elderly patients (six male, four female; mean age 67.7 years, range 64-72). 3. Patients received seven cumulative doses (0.0005-0.2 mg kg-1) of xamoterol. After each dose the rate of change of pressure in the left ventricle at a developed pressure of 40 mm Hg and normalised for this pressure, (dP/dt)/DP40, and plasma concentrations of xamoterol were measured. 4. There were dose-related increases in (dP/dt)/DP40. Curves relating changes in (dP/dt)/DP40, expressed as a percent of the maximum observed response, to changes in xamoterol plasma concentrations were constructed for the middle-aged and elderly patients. From these curves the mean effective concentration (EC) value to produce a particular response could be calculated. In the sample sizes studied, the difference between the EC values over a range of responses for the middle-aged and elderly patients did not reach statistical significance, indicating that cardiac responsiveness to xamoterol was similar in the two groups of patients. 5. Plasma concentrations of xamoterol over the range of 39 to 150 ng ml-1 produced positive inotropic responses which varied between 70% and 90% of the maximum observed effect of xamoterol.     

A comparative study on the ventilatory and haemodynamic effects of xamoterol and atenolol in asthmatic patients.

The effects of single oral doses of atenolol 50 mg and xamoterol 200 mg (a recently developed partial beta 1-adrenoceptor agonist) on lung function, heart rate and blood pressure were investigated in 11 patients with asthma. Xamoterol caused a significant increase in heart rate and systolic blood pressure, which changes are consistent with the partial beta 1-adrenoceptor agonist activity of this drug. Atenolol induced a significant decrease in FEV1 and the forced vital capacity (FVC); there was a non-significant change in FEV1 and FVC after xamoterol. There was no significant difference between the effects of atenolol and xamoterol of FEV1 and FVC. Bronchospasm induced by atenolol 50 mg and xamoterol 200 mg was completely reversed by inhalation of the beta 2-adrenoceptor agonist terbutaline to a cumulative dose of 4.0 mg.     

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers

Summary The pharmacokinetics of xamoterol, a -adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design.After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min^–1 and the volume of distribution at steady-state (V_ss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose.Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.     

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.     

Effects of xamoterol (ICI 118,587) in asthmatic patients

To study the cardioselectivity of xamoterol, eight asthmatic patients took part in a randomised, double-blind, cross-over study, in which xamoterol or saline were infused, followed by four increasing doses of terbutaline i.v. Circulatory studies showed a significant increase of systolic blood pressure after xamoterol 0.1 mg/kg compared to saline (P less than 0.05), and heart rate tended to increase. Diastolic blood pressure did not show any significant changes after the different treatments. Skeletal muscle tremor measurements with terbutaline stimulation did not show any differences after pre-treatment with either xamoterol or saline. Mean values of FEV1 did not reveal any significant difference before or after terbutaline stimulation between xamoterol and saline pre-treatments. However, in one patient, FEV decreased 60% after xamoterol, an effect which was reversed by terbutaline. Xamoterol did not have any effect on beta-adrenoceptor mediated skeletal muscle tremor and no significant effect on beta-adrenoceptor mediated bronchodilation in doses which gave a significant increase of systolic blood pressure. Thus, xamoterol was shown to be a selective beta 1-adrenoceptor agonist in man.     

Xamoterol improves right ventricular systolic and diastolic function in pulmonary heart disease

Objective: Abnormal right ventricular function in patients with pulmonary heart disease (PHD) may contribute to their reduced exercise capacity. We have evaluated the effect of subacute dosing with xamoterol, a beta-1 adrenoreceptor partial agonist with inotropic properties, on right ventricular function in patients with PHD. Patients: Twelve patients with advanced chronic obstructive pulmonary disease and clinical evidence of PHD received xamoterol 200 mg twice daily or placebo for 7 days in a randomised double-blind crossover study. Right heart krypton-81m radionuclide ventriculography was used to derive right ventricular ejection fraction (RVEF) both at rest and during submaximal exercise, and indices of right ventricular systolic and diastolic function at rest. Results: During treatment with placebo, mean RVEF was 0.53 at rest and was unchanged during exercise. After xamoterol, mean RVEF was 0.55 at rest and increased to 0.59 during exercise. Xamoterol increased right ventricular peak ejection rate from 3.04 to 3.45 EDV⋅s^–1 and mean early diastolic filling rate from 1.00 to 1.20 EDV⋅s^–1. Conclusion: Subacute treatment with xamoterol in patients with PHD improves right ventricular systolic and diastolic function at rest and results in a favourable augmentation in right ventricular function during submaximal exercise. Received: 7 July 1995/Accepted in revised form: 9 October 1995     

Pharmacokinetics of xamoterol after intravenous and oral administration to patients with chronic heart failure

Summary The pharmacokinetics of xamoterol, a -adrenergic partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 8 cardiac failure patients (NYHA Class II) of mean age 62 years.After i.v. dosing, the elimination half-life was 7.4±0.4 h, the total body clearance was 228±30 ml·min^–1 and the volume of distribution at steady-state was 56±91. 72.5±4.3% of the dose was recovered unchanged in urine. After the oral dose, the absolute bioavailability of xamoterol was shown to be 5.9%. Peak plasma concentrations occurred 1 to 2.5 h after the oral dose. The apparent elimination half-life was significantly longer after oral doses (16±2 h) compared to that observed after an intravenous dose. Renal clearance of xamoterol exceeded glomerular filtration rate as measured by creatinine clearance.The pharmacokinetics of xamoterol in cardiac failure patients with good renal function (creatinine clearance >90 ml·min^–1) were similar to published data in young healthy male volunteers.     

Effects of xamoterol a new beta-adrenoceptor partial agonist,in patients with angina pectoris

Summary The effects of xamoterol on exercise capacity have been evaluated in 10 patients with angina pectoris and well-preserved left ventricular function. Compared to placebo a single 200 mg dose of xamoterol produced a slight but insignificant increase in exercise capacity. At maximum work load, ST-T segment depression was reduced (3 mm and 2.19 mm after placebo and xamoterol, respectively;p<0.05). The changes paralleled an insignificant reduction in maximal heart rate and pressure-rate product. At rest, xamoterol increased the heart rate from 80 to 86 beats/min. Thus, at rest, when sympathetic tone is low, xamoterol acts as a beta-receptor agonist but during exercise, when sympathetic tone is high, xamoterol acts as an antagonist and reduces myocardial ischaemia.     

Cardiac effects of beta-adrenoceptor antagonists with intrinsic sympathomimetic activity in humans: beta1- and/or beta2-adrenoceptor mediated?

The aim of this study was to find out whether cardiac responses to the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) xamoterol and celiprolol are mediated by cardiac beta1- or beta2-adrenoceptors or both. For this purpose we assessed, in six healthy male volunteers, the effects of xamoterol (100 and 200 mg, p.o.) and celiprolol (200, 600, and 1,200 mg, p.o.) on blood pressure, heart rate, and heart rate-corrected duration of the electromechanical systole (QS2c, as a measure of inotropism). Xamoterol, in both doses, increased systolic blood pressure and heart rate, transiently decreased diastolic blood pressure, and shortened QS2c; all these effects were attenuated after pretreatment of the volunteers with the beta1-adrenoceptor antagonist bisoprolol. Celiprolol, in all three doses, increased heart rate, decreased diastolic blood pressure, and shortened QS2c but only marginally increased systolic blood pressure. Bisoprolol did not attenuate these celiprolol effects but rather enhanced celiprolol effects on systolic blood pressure and heart rate. In a further set of experiments, we studied cardiovascular effects of celiprolol in six healthy volunteers whose beta2-adrenoceptors had been desensitized by a 2-week treatment with 3x5 mg/day terbutaline. Under these conditions, celiprolol failed to increase heart rate or to shorten QS2c. We conclude that, under resting conditions, in healthy volunteers, beta-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either cardiac beta1-adrenoceptor (xamoterol) or cardiac beta2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of beta-adrenoceptor antagonists can be a beta1- or beta2-adrenoceptor agonistic component.     

The electrophysiological effects of intravenous xamoterol in man

Summary The electrophysiological effects of xamoterol were studied in ten patients with suspected coronary artery disease by intracardiac electrography. Sino-atrial and atrioventricular conduction times were both slightly shortened by 0.1 mg/kg of xamoterol. The atrioventricular nodal refractory periods were shortened without consistent change in atrial refractoriness. This dose raised mean blood pressure by only 3 mmHg and resting heart rate by only 4 beats/min. The effects suggest a beta₁ agonist activity closer to that of prenalterol than that of pindolol under conditions of rest.     

The pharmacokinetics of xamoterol in liver disease.

The pharmacokinetics of xamoterol, a beta 1-adrenoceptor partial agonist, have been studied in patients with liver disease and a group of age- and sex-matched normal controls. No significant differences were observed after the oral administration of xamoterol 200 mg. The low bioavailability of xamoterol was confirmed (6.1% in patients, 6.9% in controls). After i.v. xamoterol 0.2 mg kg-1, no significant differences between the groups were observed. A small increase in the terminal plasma elimination half-life (t1/2) was observed in patients when compared with controls (15.3 +/- 6.4 vs 8.4 +/- 2.8 h, mean +/- s.d., P = 0.08). Renal clearance accounted for about 50% of total clearance in patients and about 30% in controls. It is suggested that in patients with heart failure, hepatic dysfunction would probably not influence xamoterol disposition.     

Influence of xamoterol,a partial beta1-selective agonist,on physical performance capacity and cardiocirculatory,metabolic and hormonal parameters

Summary In a double-blind, random, cross-over study, 14 healthy male volunteers received xamoterol 200 mg (Corwin; C) twice daily or placebo (P) for two seven-day medication periods to investigate effects on physical performance, cardiocirulatory parameters, metabolism and hormone levels during exercise. An oral glucose tolerance test (OGTT) was also done.C showed a positive inotropic effect up to an exercise intensity of 100 W, corresponding to a heart rate of about 100 beats · min^–1. Chronotropic regulation of the heart remained unchanged, but the increase in systolic blood pressure was more pronounced and the catecholamines behaved as after P. From 150 W onwards, C exhibited beta-blocking properties; heart rate was reduced by up to 8 beats · min^–1; systolic blood pressure remained unchanged; and the catecholamines showed a more pronounced increase than after P. Diastolic blood pressure behaved almost identically under all test conditions.With the exception of a slightly increased level of free fatty acids at rest, the parameters of physical performance, lipid and carbohydrate metabolism and the hormone levels under all conditions after C showed similar behaviour to that after as P.The findings indicate that physical performance capacity, cardiocirculatory system, metabolism and hormones were not negatively influenced by C.     

Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of digoxin is dose-dependent.     

Is xamoterol safe in chronic airflow obstruction?

Summary We have demonstrated in a group of 10 patients with CAO that treatment with xamoterol (200 mg b.i.d. for 7 days) did not alter lung function or respiratory symptoms.These results suggest that xamoterol can be used to treat mild heart failure in patients with CAO.     

Single and combined myocardial pharmacodynamics of xamoterol, isoprenaline and g-strophanthin in the isolated rabbit heart

The myocardial effects of g-strophanthin and the partial beta 1-adrenoceptor agonist xamoterol were compared to the effects of isoprenaline in the isolated spontaneously beating rabbit heart. Xamoterol and g-strophanthin both produced a distinct maximum increase in contractility as shown by the increase in isotonic contraction rate from 100 to 142% (pD2 7.51) and 151% (pD2 6.54), respectively, which was however less pronounced than the increase to 200% (pD2 7.81) caused by isoprenaline. The maximum chronotropic effect of xamoterol was moderate with a frequency increase from 100 to 128% (pD2 7.40) as was the increase in oxygen consumption to 130% (pD2 7.16), and no arrhythmias were seen. The positive inotropic range of g-strophanthin was very narrow (about 60-600 nM) and cardiac toxicity just overlapped and rapidly increased over this range. Xamoterol at a fixed concentration of 28 nM caused a rightwards shift of the isoprenaline concentration-response curves demonstrating the competitive beta 1-adrenoceptor blocking effect of the drug. G-strophanthin at a concentration of 268 nM acted additively with xamoterol with regard to maximum contractility and without causing any further increase in myocardial oxygen consumption except at the highest concentrations but there was a slightly increased nodal rhythm at xamoterol concentrations higher than about 20 nM.     

The dopamine congener, ibopamine, in congestive heart failure

The hemodynamic effects of the dopamine congener, ibopamine, were investigated in nine patients with chronic congestive heart failure. A placebo-controlled design was utilized. Placebo and ibopamine in doses of 100, 200, and 300 mg were given orally as a single dose to each patient on 4 successive days. Dopamine at 1, 2, 4, and 6 micrograms/kg/min intravenously, was used as an internal standard. Ibopamine did not significantly change heart rate, systemic and pulmonary arterial pressures, pulmonary capillary wedge pressure, or mean right atrial pressure. Significant decreases of systemic arterial resistance (19%) and total pulmonary arterial resistance (21%), and significant increases of cardiac index (20%) and stroke volume index (16%) were elicited by ibopamine at doses of 200 and 300 mg. Peak effects occurred at 1 to 2 h with a duration of action of less than 4 h. The 2 changes were comparable with those obtained by dopamine 2-4 micrograms/kg/min. Except for mild changes at 30 min postdosing, the inotropic indices of the systolic time intervals were not altered significantly by ibopamine. Ibopamine elicits significant hemodynamic effects in patients with chronic congestive heart failure; in large part, these effects appear to be mediated through vasodilatory properties rather than direct positive inotropy.