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At least 19 recordsLinked to original sources
PubMed1987

Interaction of dopamine, (+/-)-dobutamine and the (-)-enantiomer of dobutamine with alpha- and beta-adrenoceptors in the pulmonary circulation of the dog.

The effects of dopamine, (+/-)-dobutamine (racemic mixture) and (-)-dobutamine on alpha-adrenoceptor-mediated vasoconstriction were evaluated in the pulmonary circulation of the anesthetized dog. The drugs were studied in the absence and presence of propranolol (1 mg/kg, i.v.) in order to assess beta-adrenoceptor-mediated effects in the pulmonary circulation. Intra-arterial administration of dopamine, (+/-)-dobutamine and (-)-dobutamine elicited dose-dependent increases in pulmonary perfusion pressure, reflecting increases in pulmonary vascular resistance. In control animals, dopamine elicited the largest increases in pulmonary perfusion pressure (45% above resting pulmonary pressure) followed by (-)-dobutamine (30% increase) and (+/-)-dobutamine (15% increase). The pressor effects of dopamine in the pulmonary circulation were mediated by both postjunctional vascular alpha 1- and alpha 2-adrenoceptors, since prazosin, (100 micrograms/kg, i.v.), a selective alpha 1-adrenoceptor antagonist, and rauwolscine (100 micrograms/kg, i.v.), a selective alpha 2-adrenoceptor antagonist, both inhibited the vasopressor response elicited by dopamine to roughly equivalent degrees. Pulmonary vasoconstriction produced by (+/-)-dobutamine and (-)-dobutamine was mediated primarily by postsynaptic vascular alpha 1-adrenoceptors, although alpha 2-adrenoceptor-mediated vasoconstriction was observed. In propranolol-pretreated animals, the increase in pulmonary perfusion pressure elicited by dopamine and (-)-dobutamine was qualitatively and quantitatively similar to that observed in control animals, suggesting that these agents have little activity on vascular beta 2-adrenoceptors in the pulmonary circulation. In marked contrast, the maximum pulmonary vasopressor response obtained with (+/-)-dobutamine were greater in propranolol-pretreated animals, indicating that (+/-)-dobutamine also has the capacity to stimulate pulmonary vascular beta 2-adrenoceptors which mediate pulmonary vasodilation that, in part, mask alpha-adrenoceptor-mediated pulmonary vasoconstriction. Since the (-)-enantiomer of dobutamine has little or no beta 2-adrenoceptor agonist activity, the beta 2-adrenoceptor-mediated effect of (+/-)-dobutamine must result from the (+)-enantiomer as has been previously proposed. The results of the present study indicate that dopamine has a greater propensity for increasing pulmonary vascular resistance, and therefore pulmonary arterial blood pressure, relative to (+/-)-dobutamine. This results, at least in part, from the relatively weaker activity of dopamine in stimulating pulmonary vascular beta 2-adrenoceptors which mediate vasodilation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Effects of dopamine, (+/-)-dobutamine and the (+)- and (-)-enantiomers of dobutamine on cardiac function in pithed rats.

The effects of dopamine, (+/-)-dobutamine (racemic mixture) and the (+)- and (-)-enantiomers of dobutamine on myocardial function were evaluated in pithed rats. Dopamine and (+/-)-dobutamine produced effects on cardiac function in pithed rats that were qualitatively similar to those reported for these compounds in humans. The increase in cardiac output produced by dopamine and (+/-)-dobutamine was due mainly to an increase in stroke volume, with increases in heart rate contributing to a significant but lesser degree. For both dopamine and (+/-)-dobutamine, the increase in stroke volume appears to result from an increase in myocardial contractility as assessed by increases in left ventricular (LV) dp/dt. Dopamine produced a marked increase in mean arterial blood pressure, whereas (+/-)-dobutamine only modestly increased blood pressure. The (-)-enantiomer of dobutamine, which possesses mainly alpha-1 adrenoceptor agonist activity, produced dose-dependent increases in cardiac output, stroke volume, LVdp/dt and mean arterial blood pressure, but did not significantly increase heart rate except at high doses. Thus, the increase in cardiac output produced by (-)-dobutamine was derived almost exclusively from an augmentation in stroke volume resulting from an increase in myocardial contractility. In contrast, (+)-dobutamine, which possesses predominantly beta-1 and beta-2 adrenoceptor agonist activity, elicited only a modest increase in cardiac output which was due both to an increase in heart rate and stroke volume. Mean arterial blood pressure was not significantly affected by (+)-dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Systemic hemodynamic effects of dopamine, (+/-)-dobutamine and the (+)-and (-)-enantiomers of dobutamine in anesthetized normotensive rats.

The hemodynamic effects of dopamine, (+/-)-dobutamine (racemic mixture) and the (+)- and (-)-enantiomers of dobutamine were evaluated in anesthetized normotensive rats. Dopamine and (+/-)-dobutamine produced hemodynamic effects in anesthetized rat that were qualitatively similar to those reported for these compounds in man. The increase in cardiac output produced by dopamine and (+/-)-dobutamine was due mainly to an increase in stroke volume, with heart rate being only minimally affected. Dopamine produced a large increase in mean arterial pressure and slightly increased total peripheral vascular resistance, whereas (+/-)-dobutamine only modestly increased blood pressure and significantly reduced total peripheral resistance. The (-)-enantiomer of dobutamine, which possesses mainly alpha 1-adrenoceptor agonist activity, produced marked increases in cardiac output, stroke volume, total peripheral resistance and mean arterial pressure, but did not significantly increase heart rate. In contrast, (+)-dobutamine, which possesses predominantly beta 1-and beta 2-adrenoceptor agonist activity, elicited only a modest increase in cardiac output which was due entirely to increased heart rate since stroke volume was not increased. Total peripheral vascular resistance and mean arterial blood pressure were both reduced by (+)-dobutamine, characteristic of a beta-adrenoceptor agonist. The increase in cardiac output and blood pressure produced by (+/-)-dobutamine, but not the positive chronotropic effect, were significantly inhibited by alpha 1-adrenoceptor blockade with prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1992

[Comparison of results of echo-dobutamine and ECG-dobutamine tests in the diagnosis of coronary disease].

The aim of the study was to compare the results of 2D-Echocardiographic (ECHO) vs 12-lead Electrocardiographic (ECG) monitoring during Dobutamine (DOB) infusion performed as a stress test in patients referred for the evaluation of chest pain of suspected ischemic origin. Fourty-seven consecutive patients, 40 m and 7 f, mean age 52 +/- 9 years, were studied after interruption of any antianginal therapy. DOB was infused in 5-minute stages with incremental doses of 5 mcg/kg/min up to a maximal dose of 40 mcg/kg/min. 2D-ECHO monitoring could not be performed in 3 out of 47 patients because of a poor acoustic window. Thus, the overall feasibility was 94% for 2D-ECHO DOB test vs 100% for ECG DOB test (p = ns). The ECG and 2D-ECHO findings were compared in the remaining 44 patients. Criteria for positivity were: transient regional dyssynergy absent or of lesser degree in the baseline examination for 2D-ECHO; ST-segment shift > 0.1 mV from baseline for ECG. The test was stopped when a regional wall motion abnormality developed even in the absence of significant ECG changes. Angiographically assessed coronary artery disease (CAD) was considered significant when a > 50% reduction of the luminal diameter in at least 1 major coronary vessel occurred. There were 10/44 patients with no significant CAD and 34/44 patients with CAD; 16 had single, 18 double or triple and/or left main vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Role of the alpha agonist activity of dobutamine in mediating cardiac output: effects of prolonged isoproterenol infusion.

Hemodynamic activities of dobutamine enantiomers were studied in either control rats or those infused with isoproterenol (400 micrograms/kg/hr) for 4 days. In control animals prazosin attenuated the effects of (+/-)-dobutamine on cardiac output by approximately 50%; remaining activity was blocked by propranolol. After isoproterenol infusion (+/-)-dobutamine was less efficacious and the blocking effects of prazosin were greater than 90%. Isoproterenol infusion had no effect on (-)-dobutamine-mediated (alpha-1 adrenoceptor agonist) increases in cardiac output and these actions were blocked by prazosin. By contrast, compared to (+/-)- and (-)-dobutamine, effects of (+)-dobutamine (beta adrenoceptor agonist) on cardiac output were modest, not altered by prazosin and were blocked by propranolol; (+)-dobutamine was inactive after isoproterenol infusion. (-)-Dobutamine increased systemic vascular resistance in both control and isoproterenol infused rats, whereas (+)-dobutamine was inactive. (+/-)-Dobutamine increased systemic vascular resistance only in isoproterenol-infused rats. All increases in systemic vascular resistance were blocked by prazosin. Neither (+/-)- nor (+)-dobutamine significantly altered stroke volume. By contrast, (-)-dobutamine resulted in prazosin-sensitive increases in stroke volume in both control and isoproterenol-infused rats. In control animals, (+/-)-, (+)- and (-)-dobutamine increased heart rate in a dose-dependent manner; chronotropic effects of (-)-dobutamine were less than those of either (+/-)- or (+)-dobutamine. Chronotropic effects were not demonstrable in isoproterenol-infused animals. These data support the notion that in control rats cardiac output may be increased by either alpha or beta adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1988

Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition.

We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.

Catecholamines↗
PubMed1992

Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of dobutamine in critically ill children. DESIGN: A prospective study of pediatric patients receiving continuous infusions of dobutamine in a stepwise format from 2.5 to 10.0 micrograms/kg/min. SETTING: A pediatric critical care unit. PATIENTS: Twelve children ranging in age from 1 month to 17 yrs with primary medical conditions. MEASUREMENTS: Plasma dobutamine concentrations and hemodynamic responses were measured at each infusion rate at steady state. Dose response data were analyzed to determine the threshold or minimum plasma dobutamine concentration necessary for discernible hemodynamic effects. MAIN RESULTS: Dobutamine plasma clearance rates ranged from 40 to 130 mL/kg/min. Each patient presented a linear increase in the plasma dobutamine concentration at each infusion rate (r2 = .97, p less than .001). Plasma clearance rate vs. actual dobutamine concentration did not vary. Cardiac output, BP, and heart rate increased 30%, 17%, and 7%, respectively, at maximal dose. The dobutamine concentration thresholds for changes in cardiac output, BP, and heart rate were 13 +/- 6, 23 +/- 14, and 65 +/- 30 ng/mL, respectively. CONCLUSIONS: There was no effect of plasma dobutamine concentration or infusion rate on plasma clearance rate. For this group of patients, over the range of the intravenous doses studied, dobutamine pharmacokinetics followed a first-order kinetic model. Threshold values for dobutamine usually show increases in cardiac output before changes in heart rate. These data demonstrate that dobutamine is an effective inotropic agent in critically ill pediatric patients and has minimal chronotropic action.

Blood Pressure↗
PubMed1991

Two weeks of intermittent dobutamine therapy restores cardiac performance and inotropic responsiveness in conscious rats with heart failure.

Dobutamine is frequently used for acute therapy in heart failure. In the present study, the hemodynamic effects of long-term intermittent dobutamine therapy were investigated in conscious rats with heart failure. Rats with healed myocardial infarctions received two i.p. injections of dobutamine per day for 2 weeks. Hemodynamic measurements were performed 90-180 min after the last injection. Two weeks of intermittent dobutamine significantly restored all hemodynamic changes induced by infarction. The maximal cardiac output during volume loading was depressed due to infarction and dose-dependently restored by 2 weeks of intermittent dobutamine. An increased stroke volume accounted for this improvement since the heart rate was not altered. In order to investigate changes in adrenergic responsiveness, the effects of acute dobutamine in nontreated and 2 weeks of dobutamine-treated infarcted rats were compared to those in control rats. Whereas chronotropic responses to acute dobutamine were comparable for all experimental groups, the inotropic response was reduced in nontreated infarcted rats but dose-dependently restored after 2 weeks of intermittent dobutamine therapy. From the data, we conclude that 2 weeks of intermittent dobutamine therapy in conscious rats with healed myocardial infarcts improved cardiac performance and restored the inotropic response to acute dobutamine administration. Data indicate that dobutamine has a long-term effect on cardiac function, which differs from the acute inotropic effect.

Animals↗
PubMed1985

Role of alpha-adrenergic receptors in the intrinsic inotropic selectivity of dobutamine in anesthetized dogs.

The inotropic selectivity of dobutamine was examined in pentobarbital-anesthetized, vagotomized dogs pretreated with a ganglion blocker. The purpose was to determine if, in the presence of hexamethonium and vagotomy, the inotropic selectivity of dobutamine could be attributed to an action of dobutamine on alpha-adrenoreceptors. Dose-response curves were determined for either isoproterenol or dobutamine 30 min after treatment with hexamethonium (20mg/kg). Analysis of heart rate versus right ventricular contractile force showed that dobutamine produced less tachycardia for a given increase in contractile force than isoproterenol; this was statistically significant when contractile force was increased by either 50 or 100%. In a separate series of experiments, dobutamine (8 micrograms . kg(1-) . min(-1)) was administered 20 min after propranolol (3 mg/kg). Under these conditions there was a slight increase in contractile force which represented 12% of the dobutamine response prior to propranolol administration. This increase in contractile force in the presence of propranolol was completely prevented by the addition of phentolamine (1 mg/kg). Consequently, in another series of experiments, dose-response curves for dobutamine were performed in the presence of hexamethonium before and 30 min after phentolamine alone (1 mg/kg) or vehicle. Phentolamine did not influence the effect of dobutamine on heart rate or contractile force, but prevented the increase in diastolic blood pressure caused by dobutamine. In addition, analysis of heart rate versus contractile force indicated that there were no statistically significant effects of phentolamine on the inotropic selectivity of dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1985

Effects of beta adrenoceptor down-regulation on the cardiovascular responses to the stereoisomers of dobutamine.

Effects of prolonged in vivo infusion of either saline (control) or isoproterenol (beta adrenoceptor desensitization) on acute cardiovascular responses to (+) (beta agonist)-, (-) (alpha agonist)- and (+/-)-dobutamine were studied in pithed rats. Each form of dobutamine resulted in comparable dose-dependent increases in maximum left ventricular dP/dt (LVdP/dtmax) in control animals. Effects of (+)-dobutamine were blocked by propranolol whereas those of l-dobutamine were sensitive to prazosin; both alpha and beta antagonists were required to block the inotropic effects of the racemic mixture. Contractile responses to (+)- and (+/-)-dobutamine were accompanied by tachycardia (characteristic of beta adrenoceptor stimulation) whereas (-)-dobutamine enhanced LVdP/dtmax without altering heart rate (characteristic of alpha adrenoceptor stimulation). Isoproterenol infusion resulted in a pronounced desensitization to the inotropic effects (LVdP/dtmax) of (+/-)- and (+)-dobutamine. Ed30 values for (+/-)- and (+)-dobutamine were increased by approximately 15- and 50-fold, respectively, and maximal responses to both drugs were severely attenuated. Prazosin further blunted remaining inotropic responses to (+/-)-dobutamine and propranolol resulted in a complete block. Responses to (+)-dobutamine were only sensitive to propranolol. Attenuation of heart rate responses paralleled those observed for LVdP/dtmax. By contrast, the inotropic effects of (-)-dobutamine in either control or desensitized rats were both qualitatively and quantitatively comparable; responses were blocked by the alpha-1 antagonist, prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Inotropic selectivity of dobutamine enantiomers in the pithed rat.

The inotropic selectivities of the (-)- and (+)-enantiomers of dobutamine were assessed in pithed rat by comparing the relative ability of each enantiomer to increase left ventricular contractility (left ventricular dp/dt) and heart rate. The (-)-enantiomer of dobutamine, which is predominantly an alpha-1 adrenoceptor agonist, displayed greater inotropic selectivity than the (+)-enantiomer, which is predominantly a beta-1 and beta-2 adrenoceptor agonist. Pretreatment with the alpha-1 adrenoceptor antagonist prazosin significantly inhibited the effect of (-)-dobutamine on left ventricular dp/dt, but did not affect the chronotropic activity of this enantiomer. As such, pretreatment with prazosin decreased the inotropic selectivity of (-)-dobutamine. In contrast, the inotropic activity and selectivity of (+)-dobutamine were not affected by prazosin pretreatment. These results indicate that the inotropic effects of (-)-dobutamine are mediated, at least in part, by alpha-1 adrenoceptors. We conclude, based on the marked inotropic activity of (-)-dobutamine and the greater inotropic selectivity of (-)-dobutamine over (+)-dobutamine, that alpha-1 adrenoceptors may play a role in the inotropic activity and selectivity of racemic dobutamine used clinically. The possible involvement of both myocardial alpha-1 and beta-1 adrenoceptors in the inotropic activity of dobutamine must be considered.

Animals↗
PubMedDate not supplied

The effect of (+/-)-dobutamine on adrenergic nerve endings.

Possible effects of (+/-)-dobutamine on adrenergic nerve endings were determined in experiments with ghosts of bovine chromaffin granules, with rat phaeochromocytoma (PC-12) cells and with the rat vas deferens. Dobutamine inhibited the vesicular uptake of a mixture of 70% adrenaline + 30% 3H-noradrenaline into ghosts, with an IC50 of 1.7 mumol/l. Dobutamine inhibited uptake1 of 3H-noradrenaline in PC-12 cells (with an IC50 of 0.38 mumol/l) without being a substrate. However, dobutamine easily entered PC-12 cells by diffusion. After inhibition of MAO, COMT and vesicular uptake dobutamine (15 and 45 mumol/l) released tritium from rat vasa deferentia preloaded with 3H-noradrenaline. Equi-inhibitory concentrations of dobutamine and desipramine (against uptake1) were equi-releasing. On the other hand, when MAO and vesicular uptake were intact, dobutamine (15 mumol/l) increased the efflux of tritium from preloaded vasa deferentia much more than did an equi-inhibitory concentration of desipramine. Most of the released tritium was then 3H-DOPEG. Dobutamine is a potent inhibitor of uptake1 as well as of vesicular uptake; moreover, it easily diffuses into adrenergic nerve endings. Hence, it blocks the neuronal and the vesicular re-uptake of noradrenaline; consequently, when MAO and vesicular uptake are intact, dobutamine increases the net leakage of noradrenaline from the storage vesicles, thereby leading to an efflux of deaminated metabolites. However, dobutamine is virtually unable to release noradrenaline into the extracellular space.

Adenosine Triphosphate↗
PubMed1987

Outpatient dobutamine and dopamine infusions in the management of chronic heart failure: clinical experience in 21 patients.

Dobutamine (and dopamine) are potent positive inotropic drugs which are frequently given to treat decompensated congestive heart failure. This study reports on the use of ambulatory dobutamine (and dopamine) infusions in 21 outpatients with advanced congestive heart failure. Each patient was initially hospitalized, and hemodynamic and clinical efficacy to dobutamine (and dopamine) was assessed. These 21 patients were carefully selected from a larger population of approximately 40 patients referred for this therapy. Chronic venous access was established and a drug infusion pump was supplied. Patients and family members were trained in the use of these devices. Eleven patients were treated with intermittent dobutamine infusions for 48 consecutive hours weekly, six patients with continuous (i.e., 24 hours daily) dobutamine infusions, and four patients with continuous, daily dobutamine and dopamine infusions. Significant (p less than 0.001) increases in cardiac index (1.8 +/- 0.6 to 2.7 +/- 0.7 L/min/m2) occurred during the initial dobutamine titrations. Functional classification (3.8 +/- 0.4 to 2.8 +/- 0.7) also improved significantly (p less than 0.01) during the 1.8 to 24 (mean 7.8) months of outpatient infusion therapy with dobutamine (and dopamine). Complications during outpatient therapy included drug tolerance (two instances), infection (two with bacteremias, eight with exit site infections), drug extravasation (three instances), and pump malfunction (two instances). Twenty patients have died: eleven from heart failure, four suddenly (one of them 9 months after dobutamine was stopped), and five from noncardiac causes. Our data suggest that outpatient dobutamine (and dopamine) infusions may be an effective form of therapy for selected patients with severe congestive failure who are refractory to more conventional treatment or who are awaiting cardiac transplantation.

Adult↗
PubMed1992

Direct effect of dobutamine on action potential duration in ischemic compared with normal areas in the human ventricle.

BACKGROUND AND OBJECTIVES: The arrhythmogenic effect of beta-adrenoceptor stimulation is complex and may differ in ischemic and normal myocardium. In this study we examined the differential effect of beta-adrenergic stimulation on ventricular action potential duration and, hence, dispersion of repolarization in potentially ischemic versus nonischemic human ventricular myocardium. METHODS: Simultaneous biventricular monophasic action potentials were recorded in 14 patients (28 recording sites) during infusion of dobutamine in incremental doses (low dose 5 micrograms/kg per min, high dose 10 to 15 micrograms/kg per min) during atrial pacing. Perfusion at the action potential recording site was assessed by incorporating myocardial perfusion scintigraphy with injection of technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile during the recording at peak doses of dobutamine. Action potential duration during dobutamine infusion was compared with that during atrial pacing to identical rates in the absence of dobutamine. RESULTS: In 21 normal zone recordings, dobutamine produced a variable effect over that produced by atrial pacing to identical heart rates, either lengthening or shortening the action potential duration. The mean (+/- SEM) value for the additional effect of dobutamine was 0.9 +/- 2.5 ms with low doses and -4 +/- 2.6 ms with high doses (p = NS). In seven recordings from potentially ischemic zones, low dose dobutamine had a similar effect (mean change -3.4 +/- 6.5 ms; p = NS vs. normal zone values). However, the high dose dobutamine invariably shortened the action potential duration by a mean of -22.9 +/- 2.9 ms. (p less than 0.05 vs. low dose in ischemic areas, p less than 0.01 vs. normal zone recordings). Pacing alone or the addition of dobutamine had no significant effect on the normal dispersion of action potential duration between two nonischemic recording sites. In recordings in a normal and an abnormally perfused site, high dose dobutamine significantly altered the dispersion of action potential duration. CONCLUSIONS: These results suggest a different effect of beta adrenergic stimulation in potentially ischemic compared with nonischemic human ventricular myocardium. The abnormal dispersion of repolarization thus created may well be important in beta-receptor-mediated arrhythmogenesis during myocardial ischemia.

Action Potentials↗
PubMed1987

The pharmacology of dobutamine.

Dobutamine is a sympathomimetic amine that was designed as an inotropic agent for use in congestive heart failure. Clinically, dobutamine increases cardiac output by selectively augmenting stroke volume, and this is associated with a decrease in total peripheral vascular resistance that is mediated, in part, by reflex withdrawal of sympathetic tone to the vasculature. This hemodynamic profile of dobutamine makes the drug of value in the management of low output cardiac failure. The inotropic activity of dobutamine has previously been attributed to selective stimulation of myocardial beta 1-adrenoceptors. However, recent studies from a number of laboratories indicate that the mechanism of action of dobutamine is substantially more complex. Dobutamine has the capacity to stimulate beta 1-, beta 2-, and alpha 1-adrenoceptors in the cardiovascular system at doses that approximate those used clinically. It has recently been suggested that the inotropic activity of dobutamine results from combined beta 1- and alpha 1-adrenoceptor stimulation in the myocardium, and that this activity could explain, at least in part, the inotropic selectivity of the compound. Furthermore, in the vasculature, the beta 2-adrenoceptor-mediated vasodilatory effect of dobutamine is exactly offset by the alpha 1-adrenoceptor-mediated vasoconstrictor activity, such that net changes in blood pressure are minimal following the administration of dobutamine. It is concluded, therefore, that the hemodynamic profile of dobutamine in patients with congestive heart failure is derived from a unique and complex series of interactions with alpha- and beta-adrenoceptors in the cardiovascular system.

Dobutamine↗
PubMed1992

Hemodynamic effects of dobutamine in an intact animal model.

BACKGROUND AND METHODS: Actions of dobutamine at the beta 1, beta 2, and alpha 1 adrenoreceptors were studied in anesthetized dogs. Six animals received dobutamine (at infusion rates of 0 to 160 micrograms/kg/min) with and without beta-adrenergic receptor blockade. Five animals received phenylephrine (0 to 16 micrograms/kg/min), with and without concurrent dobutamine (20 micrograms/kg/min); this procedure was repeated in five animals after beta-blockade. RESULTS: Dobutamine (10 to 160 micrograms/kg/min) increased heart rate (HR), cardiac output, and left ventricular change in pressure over time, and decreased systemic vascular resistance. beta-blockade prevented only dobutamine-induced changes in HR. Mean arterial pressure (MAP), unaffected by dobutamine alone, decreased with concurrent beta-blockade. Phenylephrine (1 to 16 micrograms/kg/min)-induced increases in MAP were unaffected by dobutamine; with beta-blockade, phenylephrine reduced MAP. Dobutamine prevented a phenylephrine-induced increase in systemic vascular resistance, an effect eliminated by beta-adrenergic receptor blockade. CONCLUSIONS: Dobutamine appeared to be an agonist at the beta 1- and beta 2-adrenoreceptors and at the myocardial alpha-adrenoreceptor. Dobutamine appeared to be an alpha-adrenergic receptor antagonist in the peripheral vasculature.

Adrenergic beta-Antagonists↗
PubMed1986

Use of intermittent dobutamine infusion in congestive heart failure.

Dobutamine is a cardiac inotrope useful in the acute treatment of congestive heart failure. Dobutamine improves cardiac output, decreases pulmonary wedge pressure, and decreases total systemic vascular resistance with little effect on heart rate or systemic arterial pressure. Clinical benefit has been observed to continue for weeks to months following the discontinuation of dobutamine. In addition, tolerance to dobutamine has been observed when infusions last 72 hours or longer. This has led investigators to study the effectiveness of chronic intermittent infusions of dobutamine. Studies utilizing dobutamine doses ranging from 1.5 to 15 micrograms/kg/min for 4-48 h/wk have shown sustained clinical and hemodynamic improvement in patients suffering from congestive heart failure. The mechanism by which dobutamine creates this effect is not entirely known; however, studies suggest dobutamine exerts a physical conditioning effect similar to exercise. Dobutamine infusions have also been associated with morphological and metabolic changes in myocardial tissue consistent with improved myocardial structure and function. The intermittent use of dobutamine may be beneficial in the chronic treatment of congestive heart failure in patients who fail to respond to conventional therapy.

Dobutamine↗
PubMed1988

Enantiomers of dobutamine increase the force of contraction via beta adrenoceptors, but antagonize competitively the positive inotropic effect mediated by alpha-1 adrenoceptors in the rabbit ventricular myocardium.

Experiments were carried out to characterize the pharmacological properties of enantiomers and racemic mixture of dobutamine to modulate the myocardial contractility through alpha and beta adrenoceptors in the rabbit papillary muscle. Dobutamine caused the concentration-dependent positive inotropic effect: the rank order of potency was R-(+)- greater than (+/-) - greater than S-(-)-dobutamine. The positive inotropic effect of (+)-, (-)- and (+/-)-dobutamine was antagonized by a beta adrenoceptor antagonist, (+/-)-bupranolol in a competitive manner, but was not affected by an alpha-1 adrenoceptor antagonist, prazosin. The concentration-response curve for (-)-phenylephrine mediated by alpha adrenoceptors in the presence of 10(-6) M (+/-)-bupranolol was shifted by enantiomers of dobutamine to the right in a concentration-dependent manner. Thus, enantiomers of dobutamine antagonized the positive inotropic effect of (-)-phenylephrine in a competitive manner, and pA2 values [negative logarithm of the dissociation constant (KB)] for (+)- and (-)-dobutamine were 6.67 and 5.99, respectively. The specific binding of [3H]prazosin to membrane fractions of rabbit ventricular myocardium was displaced by dobutamine with a high potency: the -log Ki values for (+)- and (-)-dobutamine were 6.43 and 5.97, respectively, which correspond well with pA2 values of these compounds for functional modification. These findings indicate that enantiomers of dobutamine elicit the positive inotropic effect through activation of beta adrenoceptors, whereas both enantiomers behave as the competitive antagonist of myocardial alpha adrenoceptors mediating the positive inotropic effect in the isolated rabbit papillary muscle.

Animals↗