Dobutamine Treatment Research Articles

Dobutamine Enhances the Targeted Inhibitory Effect of Quizartinib on FLT3-ITD Mutant Acute Myeloid Leukemia

To observe the inhibitory effect of dobutamine on proliferation of FLT3-ITD mutated acute myeloid leukemia (AML) cells and explore the feasibility of dobutamine as a monotherapy or in combination with quizartinib for the treatment of this type of AML. FLT3-ITD mutant cell lines MOLM13 and MV4-11 were cultured in vitro and divided into control group, dobutamine treatment group, quizartinib treatment group, and dobutamine combined with quizartinib treatment group. Cell viability, ROS levels, and apoptosis rate were detected by CCK-8, Flow cytometry, respectively, as well as the expression of YAP1 protein by Western blot. Both dobutamine and quizartinib inhibited the proliferation of FLT3-ITD mutant AML cell lines. Compared with the control group, the dobutamine group exhibited a significant increase in ROS levels (P < 0.01), an increase in apoptosis rates (P < 0.05), and a decrease in YAP1 protein expression (P < 0.01), and decreased YAP1 expression (P < 0.05). Dobutamine as a monotherapy can inhibit theproliferation of FLT3-ITD mutated AML cells, inducing apoptosis. Additionally, the combination of quizartinib enhances the targeted inhibitory effect on FLT3-ITD mutated AML. The mechanism may involve the inhibition of YAP1 protein expression in AML cells of this type, leading to an increase in ROS levels and exerting its anti-tumor effects.

The effect of dobutamine treatment on salvage of digital replantation and revascularization.

One of the most common causes of a failure after replantation and revascularization surgeries is 'no reflow' from proximal artery that occurs, especially following crush and avulsion injuries. In this study, we aimed to evaluate the effect of dobutamine treatment on salvage of replanted and revascularized digits. The patients with no reflow phenomenon detected in the salvage operations of replanted/revascularized digits between the years 2017 and 2020 were included in the study. Dobutamine treatment was infused at a rate of 4µg·kg-1·min-1 intraoperatively and of 2µg·kg-1 min-1 postoperatively. Demographic data (age, sex), digit survival rate, ischemia time, and level of injury were retrospectively analysed. Pre-infusion, intraoperative and postoperative values of cardiac index (CI), mean arterial pressure (MAP), and heart rate (HR) were recorded. The phenomenon of 'no reflow' was encountered in 35 digits of 22 patients who underwent salvage surgery due to vascular compromise. The survival rate in the revascularization group was 75%, while it was 42.1% in the replanted digits. Metaphysis level of proximal phalanx was the most common localization for 'no reflow' phenomenon. The least values of CI, MAP and HR to obtain sufficient perfusion in salvaged digits were as follows: 4.2l.min-1.m-2, 76mm Hg, and 83 beat·min-1, respectively. It was demonstrated that dobutamine infusion at a rate of 4µg·kg-1·min-1 intraoperatively and at 2µg·kg-1·min-1 postoperatively has favorable effects on the vascular compromise derived from no reflow of proximal artery.

Cardio-centric hemodynamic management with and without adjuvant ethyl nitrite improves mean arterial pressure in rodents with chronic high-thoracic traumatic spinal cord injury

Objective: Traumatic spinal cord injury (SCI) causes an initial injury followed by a protracted phase of spinal cord tissue hypoxia. This tissue hypoxia contributes to secondary injury, leading to worse motor and cardio-autonomic outcomes in the chronic setting. No neuroprotective agents to mitigate secondary injury have been identified as efficacious in clinical trials. However, we have demonstrated that taking a cardio-centric approach to hemodynamic management following SCI by augmenting cardiac output and mean arterial pressure (MAP) with the b1-adrenoceptor agonist dobutamine (DOB), and further coupling DOB infusion with the inhalation of ethyl nitrite (ENO), an S-nitrosylating agent, is associated with improved spinal cord oxygenation in the acute phase post-SCI. Aim: To determine the influence of a cardio-centric approach to hemodynamic management with adjuvant ENO inhalation following SCI on long term outcomes. We hypothesized that treatment with DOB and ENO in the acute phase following SCI would mitigate secondary injury and improve cardiovascular outcomes in the chronic setting. Methods. A total of 34 male Wistar rats underwent a T3 contusion injury (300 kdyn) and were assigned into 4 treatment groups: control (n=6), ENO (n=6), DOB (n=12), and combined DOB and ENO (n=10). At 11-weeks post-SCI, a locomotor assessment was conducted using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. At 12-weeks post-SCI, rodents were anesthetized with intravenous urethane (2.44±0.50 g/kg) and instrumented with a solid-state pressure transducer in the carotid artery to measure MAP. Results. We observed a higher MAP in both DOB (113.6 ± 11.4 mmHg; p = 0.030) and ENO+DOB (116.7 ± 14.6 mmHg; p=0.013) treated groups when compared with controls (94.65 ± 11.62 mmHg). The MAP of ENO treated animals (91.6 ± 7.3 mmHg; P= 0.97) was not different from controls. No differences in BBB scores were found between DOB (15.17 ± 4.49), ENO+DOB (13.95 ± 3.86), ENO (12.5 ± 2.5) and control (11.8 ± 2.7)(P=0.29). Collectively, these data suggest that DOB treatment, alone or in combination with ENO, improves systemic hemodynamics in the chronic high-thoracic SCI setting US Department of Defense, ICORD Seed Grant, Craig H. Neilsen Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sodium nitroprusside on acute cardiogenic pulmonary edema in dogs: case reports

This study reports the efficacy of the vasodilator sodium nitroprusside (SNP), for treatment of acute cardiogenic pulmonary edema in dogs. For this study, the patients were divided into the SNP only treatment group, the SNP, furosemide and dobutamine treatment group, and non-SNP treatment group. Seven dogs, 6 dogs and 2 dogs were favorable responders in SNP only group, group with SNP, furosemide and dobutamine and non-SNP treatment group, each. The results of this study suggest that SNP can be an effective alternative therapy for dogs with acute cardiogenic pulmonary edema.

Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates.

To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the haemodynamic response to dobutamine in critically ill neonates. Alleles in the known genetic single nucleotide polymorphisms in β1- and β2-adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Twenty-six neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8-60.7) beats/min per AUC of 100 μg L-1 h, P = .0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C > T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2-42.9) mL kg-1 min-1 per AUC of 100 μg L-1 h, P = .0095 and 33.2 (12.1-54.3) mL kg-1 min-1 per AUC of 100 μg L-1 h, P = .0025, respectively. In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C > T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

Clinical Pharmacology Of Dobutamine In Infants And Children

Dobutamine resembles dopamine structurally but possess a bulky aromatic substituent on the amino group. The pharmacological effects of dobutamine are due to direct interaction with α and β receptors. Dobutamine possess a centre of asymmetry, the (-) isomer of dobutamine is a potent α1 agonist and can cause marked pressor response. In contrast, (+) dobutamine is a potent α1 receptor antagonist which can block the effect of (-) dobutamine. Both isomers are full agonist at β receptors; the (+) isomer is a more potent β agonist than the (-) isomer by about 10-fold. Dobutamine is indicated for the short-term treatment of cardiac decompensation that may occur after cardiac surgery and dobutamine is used in the treatment of hypotension especially if related to myocardial dysfunction. Dobutamine is administered by continuous intravenous infusion and the initial dose is 5 µg/kg per min in infants and children. Some authors stated that dopamine is more effective than dobutamine in increasing blood pressure whereas other authors observed that dobutamine and dopamine produce similar pressure response. Dobutamine is methylated and is also conjugated with glucuronic acid. The elimination half-life of dobutamine is 25.6 min in infants and children but it ranges in a wide interval. The treatment of infants and children with dobutamine has been extensively studied and some authors observed that dobutamine increase the blood pressure and decreases vascular resistance. The aim of this study is to review the dobutamine dosing, effects, metabolism, pharmacokinetics, and treatment.

Norepinephrine and dobutamine improve cardiac index equally by supporting opposite sides of the heart in an experimental model of chronic pulmonary hypertension

BackgroundPulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension.MethodPulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2–3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilising period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test.ResultsAt baseline, pulmonary artery-banded animals had increased right ventricular pressure (+ 39%, p = 0.04), lower cardiac index (− 23% p = 0.04), lower systolic blood pressure (− 13%, p = 0.02) and reduced left ventricular end-diastolic volume (− 33%, p = 0.02). When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p < 0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p < 0.05) in pulmonary artery-banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery-banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p < 0.05) and diastolic arterial pressure (p < 0.05).ConclusionWhile norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume.

The cerebral haemodynamic response to somatosensory stimulation in preterm newborn lambs is reduced with dopamine or dobutamine infusion

BackgroundIn the adult brain, increases in neural activity lead to increases in local blood flow. However, in the preterm neonate, studies of cerebral functional haemodynamics have yielded inconsistent results, including negative responses suggesting decreased perfusion and localised tissue hypoxia, probably due to immature neurovascular coupling. Furthermore, the impact of vasoactive medications, such as dopamine and dobutamine used as inotropic therapies in preterm neonates, on cerebrovascular responses to somatosensory input is unknown. We aimed to characterise the cerebral haemodynamic functional response after somatosensory stimulation in the preterm newborn brain, with and without dopamine or dobutamine treatment. MethodsWe studied the cerebral haemodynamic functional response in 13 anaesthetised preterm lambs, using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) following left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. The 4.8 and 7.8 s stimulations were repeated during dopamine or dobutamine infusion. ResultsStimulation always produced a somatosensory evoked response. Majority of preterm lambs demonstrated positive functional responses (i.e. increased ΔoxyHb) in the contralateral cortex following stimulus trains of all durations. Dopamine increased baseline oxyHb and total Hb, whereas dobutamine increased baseline deoxyHb. Both dopamine and dobutamine reduced the evoked ΔoxyHb responses to 4.8 and 7.8 s stimulations. ConclusionsSomatosensory stimulation increases cerebral oxygenation in the preterm brain, consistent with increased cerebral blood flow due to neurovascular coupling. Notably, our results show that dopamine/dobutamine reduces oxygen delivery relative to consumption in the preterm brain during somatosensory stimulations, suggesting there may be a risk of intermittent localised tissue hypoxia which has clear implications for clinical practice and warrants further investigation.

Застосування левосимендану порівняно з добутаміном за необхідності інотропної підтримки в пацієнтів з гострою декомпенсованою хронічною серцевою недостатністю тяжкого ступеня

The aim – to conduct clinical effectiveness, meta-analysis of 30 and 120-days mortality data, pharmacoeconomic evaluation of levosimendan treatment compared with dobutamine in patients with severe acute decompensated chronic heart failure (ADCHF) who require inotropic support.Materials and methods. The PubMed and Cochrane databases were searched for direct randomized clinical trials of levosimendan treatment compared with dobutamine in patients with ADCHF. The clinical efficacy of levosimendan and dobutamine was analyzed. Pharmacoeconomic analysis was carried out using the cost-effectiveness method with an assessment of the incremental cost-effectiveness ratio. A decision tree model of levosimendan or dobutamine treatments was constructed. The efficacy endpoints and impact on the budget were analyzed in terms of long-term effectiveness of levosimendan and dobutamine use. Discounted was conducted with rate of 3 %. Sensitivity analysis was carried out in terms of price changing of drugs, the cost of drugs in mg, the likelihood of re-hospitalization of the patient in a 3-year horizon and survival in the long term.Results and discussion. Analysis of clinical data and meta-analysis of randomized clinical trials found that mortality rates with levosimendan and dobutamine in the 30-day period were 9.6 % and 13.8 %, RR 0.71 (95 % CI 0.53–0.95) and in the 120-day period – 13.5 % and 25.2 %, RR 0.54 (95 % CI 0.32–0.92), respectively. The total cost of the course of treatment, taking into account the price of the drug, medical devices, staff services, diagnostic procedures and treatment of adverse reactions when using levosimendan, was 34 003.02 UAH per patient and 18 787.28 UAH when treated with dobutamine. The weighted average hospital stay was 6.4 days in case of levosimendan treatment and 7.5 days of dobutamine treatment. Extrapolation of the data from clinical trials to the 3-year survival rate of patients allowed us to determine an additional indicator of efficacy – the number of life years saved with levosimendan – 2.64 and 2.37 with dobutamine treatment. A cost-effectiveness analysis found that levosimendan is more efficient but more expensive technology compare to dobutamine. The incremental cost-effectiveness ratio for the additional life year saved of a patient with severe CHF is 43,473.55 UAH, which is 6 times less than the likely threshold of willingness to pay in Ukraine.Conclusions. The multivariate sensitivity analysis detected the model sustainability to the most crucial parameters of the model – drug price; the cost of drugs associated with their actual use in mg, the possibility of re-hospitalization of the patient in a 3-year horizon, and long-term survival, which is associated with the time horizon of the model. The total cost of a cohort of patients with ADCHF in Ukraine when using scenario 1 (100 % distribution of costs for dobutamine treatment) over 5 years is 268 188 351.94 UAH, when using scenario 2 (100 % distribution for treatment with levosimendan) total budget costs will be in amount of 485 393 073.09 UAH, if scenario 3 is applied (gradual 5 % transition in the treatment of patients with ADCHF with dobutamine for treatment with levosimendan within 5 years), the total budget costs will amount to 289 916 431.92 UAH.

The Long-term Effect of Dobutamine on Intrinsic Myocardial Function and Myocardial Injury in Septic Rats with Myocardial Dysfunction.

Dobutamine (DOB) is recommended as an inotrope for septic patients with low cardiac output, but its long-term impact on sepsis-induced cardiomyopathy remains unclear. This study investigated the long-term effect of DOB on septic myocardial dysfunction and injury. Rats were exposed to cecal ligation and puncture (CLP), the intrinsic myocardial function, other organ functions, hemodynamics, inflammatory response, serum myocardial injury biomarkers, myocardial apoptosis, and vascular permeability were determined. At 6 h after CLP, the left ventricular ±dP/dt were significantly depressed, cardiac tumor necrosis factor-α and vascular cell adhesion molecule-1 expression were increased, but not serum cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine, and urea nitrogen concentrations in CLP group compared with controls. At 9 h after CLP, hepatic dysfunction was present in CLP rats compared with controls. At 6 h after CLP, DOB treatment did not affect hemodynamics, the left ventricular ±dP/dt, cytokine levels in serum and myocardium, as well as cardiomyocyte apoptosis and cardiac vascular hyperpermeability at 20 h after CLP. However, DOB (10.0 μg/kg) increased serum IL-10 level and improved survival in septic rats. These results indicate that the intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in sepsis and serum cTnI, NT-proBNP, and H-FABP are not suitable as early biomarkers for sepsis-induced myocardial dysfunction. Although DOB treatment (10.0 μg/kg) in the presence of myocardial dysfunction improves survival in septic rats, it neither improves myocardial function and hemodynamics nor attenuates myocardial injury at the later stage of sepsis.

Levosimendan Plus Dobutamine in Acute Decompensated Heart Failure Refractory to Dobutamine.

Randomized studies showed that Dobutamine and Levosimendan have similar impact on outcome but their combination has never been assessed in acute decompensated heart failure (ADHF) with low cardiac output. This is a retrospective, single-center study that included 89 patients (61 ± 15 years) admitted for ADHF requiring inotropic support. The first group consisted of patients treated with dobutamine alone (n = 42). In the second group, levosimendan was administered on top of dobutamine, when the superior vena cava oxygen saturation (ScVO2) remained <60% after 3 days of dobutamine treatment (n = 47). The primary outcome was the occurrence of major cardiovascular events (MACE) at 6 months, defined as all cause death, heart transplantation or need for mechanical circulatory support. Baseline clinical characteristics were similar in both groups. At day-3, the ScVO2 target (>60%) was reached in 36% and 32% of patients in the dobutamine and dobutamine-levosimendan group, respectively. After adding levosimendan, 72% of the dobutamine-levosimendan-group reached the ScVO2 target value at dobutamine weaning. At six months, 42 (47%) patients experienced MACE (n = 29 for death). MACE was less frequent in the dobutamine-levosimendan (32%) than in the dobutamine-group (64%, p = 0.003). Independent variables associated with outcome were admission systolic blood pressure and dobutamine-levosimendan strategy (OR = 0.44 (0.23–0.84), p = 0.01). In conclusion, levosimendan added to dobutamine may improve the outcome of ADHF refractory to dobutamine alone.

Abstract 902: Leveraging Natural Cardiomyocyte Variability to Investigate Downregulation of β-1 Adrenoceptors Following Dobutamine Treatment

In heart failure, the most consistent effect on the myocardial beta-adrenergic pathway is a downregulation of β-1 adrenoceptors (β1AR). This loss of receptors impairs the ability of the heart to respond to increases in cardiac demand, and can lead to decreased myocyte function even at rest. As a model of the process that leads to downregulation of β1AR, we measured intracellular Ca 2+ transients and unloaded sarcomere shortening in electrically stimulated isolated adult rat cardiomyocytes undergoing 30 minutes of exposure to 40 nM dobutamine. These experiments were facilitated by a custom device containing micro-patterned wells that orient and immobilize the cardiomyocytes, allowing for rapid and consistent measurements over an extended time period. After functional measurements, cells are picked up individually with a computerized micro-aspirator and subjected to single-cell RT-qPCR to quantify abundance of transcripts of interest. In this way, the physiological responses of individual cells to β1AR stimulus can be correlated to gene expression levels. We found a surprising diversity in the single-cell responses to dobutamine exposure. Although average cardiomyocyte contractility increased significantly, several apparently healthy cells registered no change or even a decrease in sarcomere shortening in the presence of dobutamine. Gene expression was quantified in cardiomyocytes representing a spectrum of sensitivities to dobutamine (n = 7). The transcript for β1AR was significantly downregulated in all cells after 30 minutes, indicating consistent adaptation to chronic stimulus. However, abundance of the gene encoding PKA was negatively correlated with dobutamine-triggered augmentation of Ca 2+ release (p-value: 0.0201). In other words, PKA expression was reduced in cells that experienced potent increases in Ca 2+ release after dobutamine treatment. These data suggest the presence of gene regulatory circuits that modulate individual components of the β1AR pathway independent of overall β1AR abundance. These circuits may be critical to restoring β1AR sensitivity in the failing heart.

Effects of Dobutamine and Levosimendan on Systolic Time Intervals in Patients with Decompensated Heart Failure

Background/Objective: Levosimendan represents an alternative to other positive inotropic agents based on its different mechanisms of action and favorable electrophysiological properties. This study compared the effects of levosimendan and dobutamine on echocardiographic parameters in heart failure patients with acute decompensation necessitating positive inotropic support. Methods: Patients with acute decompensated heart failure were randomized to receive inotropic support with either levosimendan (n=25) or dobutamine (n=25). Treatment groups were compared in terms of echocardiography measurements including tissue Doppler examination findings, systolic time interval assessments and diastolic parameters. In addition, groups were compared for demographic features, clinical characteristics and laboratory findings. Results: Among tissue Doppler measurements, Sm-lateral and Sm-septal significantly increased after treatment in both groups. E/E’ lateral and E/E’ septal significantly decreased only in the levosimendan group. Among systolic time interval parameters, increasing in left ventricular ejection time and shortening in pre-ejection period are similar in both groups, however a significant decrease in QS2i was observed in the levosimendan group. Levosimendan treatment was associated with significant decreases in blood pressures along with a significant increase in ejection fraction. Dobutamine treatment on the other hand resulted in significant increases in blood pressure, heart rate and ejection fraction. Conclusions: Our findings suggest that levosimendan and dopamine treatments are associated with only marginal differences in echocardiographic parameters. This study suggests that both levosimendan and dobutamine are almost equally effective in systolic time intervals. However, levosimendan appears to have additional advantage over dobutamine in shortening QS2i, indicating a fairly strong positive inotropic effect. Keywords : decompensated heart failure, dobutamine, levosimendan, inotropic support, echocardiography, tissue doppler, systolic time intervals DOI : 10.7176/JSTR/5-3-07

Dobutamine treatment reduces inflammation in the preterm fetal sheep brain exposed to acute hypoxia.

Impaired cerebral autoregulation in preterm infants makes circulatory management important to avoid cerebral hypoxic-ischemic injury. Dobutamine is frequently used as inotropic treatment in preterm neonates, but its effects on the brain exposed to cerebral hypoxia are unknown. We hypothesized that dobutamine would protect the immature brain from cerebral hypoxic injury. In preterm (0.6 gestation) fetal sheep, dobutamine (Dob, 10 μg/kg/min) or saline (Sal) was infused intravenously for 74 h. Two hours after the beginning of the infusion, umbilical cord occlusion (UCO) was performed to produce fetal asphyxia (Sal+UCO: n = 9, Dob+UCO: n = 7), or sham occlusion (Sal+sham: n = 7, Dob+sham: n = 6) was performed. Brains were collected 72 h later for neuropathology. Dobutamine did not induce cerebral changes in the sham UCO group. UCO increased apoptosis and microglia density in white matter, hippocampus, and caudate nucleus, and astrocyte density in the caudate nucleus. Dobutamine commenced before UCO reduced microglia infiltration in the white matter, and microglial and astrocyte density in the caudate. In preterm hypoxia-induced brain injury, dobutamine decreases neuroinflammation in the white matter and caudate, and reduces astrogliosis in the caudate. Early administration of dobutamine in preterm infants for cardiovascular stabilization appears safe and may be neuroprotective against unforeseeable cerebral hypoxic injury.

Neuroprotective dobutamine treatment upregulates superoxide dismutase 3, anti-oxidant and survival genes and attenuates genes mediating inflammation

BackgroundLabor subjects the fetus to an hypoxic episode and concomitant adrenomodullary catecholamine surge that may provide protection against the hypoxic insult. The beta1-adrenergic agonist dobutamine protects against hypoxia/aglycemia induced neuronal damage. We aimed to identify the associated protective biological processes involved.ResultsHippocampal slices from 6 days old mice showed significant changes of gene expression comparing slices with or without dobutamine (50 mM) in the following two experimental paradigms: (1) control conditions versus lipopolysacharide (LPS) stimulation and (2) oxygen–glucose deprivation (OGD), versus combined LPS/OGD. Dobutamine depressed the inflammatory response by modifying the toll-like receptor-4 signalling pathways, including interferon regulatory factors and nuclear factor κ B activation in experimental paradigm 1. The anti-oxidant defense genes superoxide dismutase 3 showed an upregulation in the OGD paradigm while thioredoxin reductase was upregulated in LPS paradigm. The survival genes Bag-3, Tinf2, and TMBIM-1, were up-regulated in paradigm 1. Moreover, increased levels of SOD3 were verified on the protein level 24 h after OGD and control stimulation in cultures with or without preconditioning with LPS and dobutamine, respectively.ConclusionsNeuroprotective treatment with dobutamine depresses expression of inflammatory mediators and promotes the defense against oxidative stress and depresses apoptotic genes in a model of neonatal brain hypoxia/ischemia interpreted as pharmacological preconditioning. We conclude that beta1-adrenoceptor activation might be an efficient strategy for identifying novel pharmacological targets for protection of the neonatal brain.

Autonomic Receptor-mediated Regulation of Production and Release of Nitric Oxide in Normal and Malignant Human Urothelial Cells.

In the urinary bladder, the main source of NO seems to be the urothelium and the underlying suburothelium. In this study, we aimed to characterize how receptors in the human urothelium regulate the production and release of NO. For this, we cultured two human urothelial cell lines - the normal immortalized cell line UROtsa and the malignant cell line T24. These were treated with an array of agonists and antagonists with affinity for adrenergic, muscarinic and purinergic receptors. The production of NO and expression of nitric oxide synthase (NOS) was studied by immunocytochemistry and Western blotting. The amount of released NO was measured indirectly by detecting nitrite using amperometry and a Griess reaction kit. The results showed that NO, endothelial NOS and inducible NOS were predominantly produced and expressed in the close vicinity of the nucleus in untreated human urothelial cells. Upon treatment with a beta-adrenoceptor agonist, but not any of the other agonists or antagonists, the pattern of NO production changed, showing a more even production throughout the cytosol. The pattern of expression of endothelial NOS changed in a similar way upon dobutamine treatment. The release of nitrite, as a measurement of NO, increased after treatment with dobutamine from 0.31±0.029 to 1.97±0.18nmol and 0.80±0.12 to 3.27±0.24nmol in UROtsa and T24, respectively. In conclusion, our results show that the expression of NOS and production of NO as well as the release of NO from human urothelial cells is regulated by beta-adrenoceptor activation.

Nesiritide Therapy Is Associated With Better Clinical Outcomes Than Dobutamine Therapy in Heart Failure.

To evaluate the therapeutic effects of dobutamine and nesiritide in the treatment of heart failure (HF), a meta-analysis of published studies was conducted. Computerized bibliographic databases in Chinese and English languages were carefully searched to identify the relevant literature. A total of 6 cohort studies were enrolled in current meta-analysis for statistical analyses. The effect of dobutamine and nesiritide in patients with HF was estimated by odds ratios (ORs) and 95% confidence interval (CI). Our results revealed a significantly higher survival rate in nesiritide-treated patients, compared with those treated with dobutamine (OR = 1.97; 95% CI, 1.43-2.71; P < 0.001). In addition, a lower readmission rate was also associated with the nesiritide-treated group in comparison with the dobutamine-treated group (OR = 1.96; 95% CI, 1.39-2.78; P < 0.001). A stratified analysis revealed that the subgroup of patients with HF treated with nesiritide showed higher survival outcomes than those patients with HF treated with dobutamine when follow-up period was greater than 6 months (OR = 1.70; 95% CI, 1.21-2.38; P = 0.002) but not under 6 months (P > 0.05). This indicated that nesiritide treatment had longer term benefits as well. Interestingly, based on the reason for readmission, a subgroup analysis of the HF subgroup and the "all-cause" subgroup showed that higher readmission rates were associated with dobutamine treatment in both subgroups (HF: OR = 2.71; 95% CI, = 1.51-4.83; P = 0.001; all-cause: OR = 1.64; 95% CI, 1.06-2.53; P = 0.026; respectively). Our results suggest that nesiritide therapy is associated with a lower in-hospital mortality rates and decreased readmission rates compared with dobutamine treatment in patients with HF.

Effect of dobutamine on extravascular lung water index, ventilator function, and perfusion parameters in acute respiratory distress syndrome associated with septic shock

Background: The role of dobutamine in the relief of pulmonary edema during septic shock-induced acute respiratory distress syndrome (ARDS) remains undetermined, due to a lack of controllable and quantitative clinical studies. Our objective was to assess the potential effects of dobutamine on extravascular lung water index (ELWI) in septic shock-induced ARDS, reflecting its importance in pulmonary edema. At the same time, ventilator function and perfusion parameters were evaluated. Methods: We designed a prospective, non-randomized, non-blinded, controlled study to compare the differences in PiCCO parameters after 6 h of constant dobutamine infusion (15 μg/kg/min), in the baseline parameters in 26 septic shock-related ARDS patients with cardiac index ≥ 2.5I/min/m2 and hyperlactatemia. These patients (12 survivors/14 non-survivors) were monitored using the PiCCO catheter system within 48 h of onset of septic shock. The dynamic changes in ELWI, which is typically used for quantifying the extent of pulmonary edema, were evaluated, and the corresponding ventilator function and tissue perfusion parameters were also measured. Results: Decreasing ELWI (p = 0.0376) was accompanied by significantly decreased SVRI (p < 0.0001). Despite a significant increase in cardiac output (p < 0.0001), no differences were found in ITBI or GEDI. Moreover, the required dose of norepinephrine was decreased (p = 0.0389), and urine output was increased (p = 0.0358), accompanied by stabilized lactacidemia and MAP. Additionally, airway pressure was moderately improved. Conclusion: During the early stage of septic shock-induced ARDS, dobutamine treatment demonstrated a beneficial effect by relieving pulmonary edema in patients, without a negative elevation in preload or hemodynamics, which might account for the improvements in ventilator function and tissue hypoperfusion.

Dobutamine Therapy is Associated with Worse Clinical Outcomes Compared with Nesiritide Therapy for Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis.

Inotropes and natriuretic peptides are essential components of current therapeutic options for acute decompensated heart failure (ADHF). This systematic review examines the therapeutic effectiveness of dobutamine and brain natriuretic peptide, nesiritide, in reducing mortality and readmission rates for ADHF treatment. Published studies related to dobutamine and nesiritide therapy in ADHF were identified via an exhaustive search of scientific literature databases. The identified studies, published between 2002 and 2012, were carefully screened based on our predefined inclusion criteria. Selected studies were pooled, and odds ratios (ORs) and 95% confidence intervals (95% CI) for each outcome were calculated. Subgroup analysis was conducted to assess the influence of ethnicity on the study outcome. Seven cohort studies were selected for this meta-analysis. These seven studies included 959 ADHF patients who underwent nesiritide treatment and 1748 ADHF patients who received dobutamine therapy. Our meta-analysis revealed a significantly lower survival rate in dobutamine-treated patients compared with nesiritide-treated patients (OR 0.48, 95% CI 0.36-0.63, P < 0.001). Additionally, a markedly higher readmission rate was associated with dobutamine treatment compared with nesiritide treatment (OR 0.52, 95% CI 0.36-0.73, P < 0.001). A stratified analysis based on ethnicity revealed a significantly lower survival in dobutamine-treated ADHF patients in Caucasian and mixed populations compared with nesiritide treatment (Caucasian: OR 0.60, 95% CI 0.38-0.94, P = 0.024; Mixed: OR 0.38, 95% CI 0.26-0.56, P < 0.001). However, a similar association was not detected in Asian populations (P = 0.738). Further, dobutamine-treated ADHF patients displayed higher readmission rates than did nesiritide-treated patients in both Caucasian and mixed-race populations (all P < 0.05). Our study suggests that dobutamine therapy is associated with poorer outcomes, with higher in-hospital mortality rates and increased readmission rates compared with nesiritide therapy in ADHF patients. Thus, current treatment strategies need to be redesigned for better outcomes.

Hippo pathway elements Co-localize with Occludin: A possible sensor system in pancreatic epithelial cells

External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1). Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-ζ) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1 could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.