Patients with cardiogenic shock were assigned to receive milrinone or dobutamine for inotropic support. There was no significant difference between the two groups in the composite primary outcome of ...in-hospital death from any cause or cardiovascular or renal events.
β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ...ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.
Cardiogenic shock (CS) is associated with significant morbidity and mortality; however, there are limited randomized data evaluating the association between sex and clinical outcomes in patients with ...CS. Patients with CS enrolled in the DObutamine compaREd with MIlrinone (DOREMI) trial were evaluated in this post-hoc analysis.
The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary outcome. We analyzed the primary and secondary outcomes using unadjusted relative risks and performed adjusted analysis for the primary outcome and all-cause mortality using the covariates mean arterial pressure <70 mmHg at inotrope initiation, age, and acute myocardial infarction CS.
Among 192 participants in the DOREMI study, 70 patients (36 %) were female. The primary outcome occurred in 38 female patients (54 %) compared to 61 male patients (50 %) adjusted relative risk (aRR) 1.23; 95 % CI 0.78–1.95, p = 0.97. When stratified by inotrope, there was no difference in the primary outcome comparing females to males receiving dobutamine (RR 1.14; 95 % CI 0.79–1.65, p = 0.50) nor milrinone (RR 1.03; 95 % CI 0.68–1.57, p = 0.87). There was no difference in all-cause mortality comparing females to males (aRR 1.51; 95 % CI 0.78–2.94, p = 0.88). Additionally, there were no differences in any secondary outcomes between males and females (p > 0.05 for all endpoints).
In patients presenting with CS treated with milrinone or dobutamine, no differences in clinical outcomes were observed between males and females.
No sex-based difference in cardiogenic shock: a post-hoc analysis of the DOREMI trial. Display omitted
•Adverse clinical outcomes in cardiogenic shock (CS) are not associated with sex.•Sex does not influence outcomes in CS when treated with milrinone nor dobutamine.•Women with CS have lower mean arterial pressure, heart rate, and creatinine.
G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β
-adrenergic GPCR can activate G
-linked cyclic AMP (G
...-cAMP) signaling from endosomes. We show here that the homologous human β
-adrenergic receptor initiates an internal G
-cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that β-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose 'location bias' as a new principle for achieving functional selectivity of GPCR-directed drug action.
Background
Despite years of clinical experience with the two most commonly used inotropes i.e dobutamine and milrinone, in the cardiogenic shock setting, there is a lack of head-to-head comparison ...between inotropes in cardiogenic shock. We conducted a systematic review and meta-analysis on the comparison of hemodynamic and clinical effects of dobutamine and milrinone in cardiogenic shock.
Methods
A comprehensive literature search using PubMed and Scopus was performed. Among 40 studies retrieved from the database, 3 studies were included for hemodynamic comparison outcome and 2 studies for clinical outcomes.
Results
Three studies with 101 patients were included for hemodynamic analysis and two studies with 146 patients for clinical analysis. We observed no significant difference between cardiac index, pulmonary capillary wedge pressure, and mean arterial pressure at 1 hour after milrinone and dobutamine administration. However, there is significantly lower mPAP after milrinone infusion compared to dobutamine (mean difference -8,7 (-9,97 to -7,43) mmHg, p<0,01). We also observed no significant difference in in-hospital mortality but significantly shorter ICU length of stay in the milrinone group (mean difference -1 (-1,92 to -0,08) days).
Conclusion
Administration of milrinone resulted in lower PA pressure and shorter ICU LOS compared to dobutamine in patients with cardiogenic shock.
It was suggested that impaired β-adrenergic relaxation in spontaneously hypertensive rats (SHR) might contribute to their high blood pressure (BP). Our study was focused on isoprenaline-induced ...dilatation of conduit femoral or resistance mesenteric arteries and on isoprenaline-induced BP reduction in SHR and Wistar-Kyoto rats (WKY). We confirmed decreased β-adrenergic relaxation of SHR femoral arteries due to the absence of its endothelium-independent component, whereas endothelium-dependent component of β-adrenergic smooth muscle relaxation was similar in both strains. Conversely, isoprenaline-induced relaxation of resistance mesenteric arteries was similar in both strains and this was true for endothelium-dependent and endothelium-independent components. We observed moderately reduced sensitivity of SHR mesenteric arteries to salmeterol (β2-adrenergic agonist) and this strain difference disappeared after endothelium removal. However, there was no difference in mesenteric arteries relaxation by dobutamine (β1-adrenergic agonist) which was independent of endothelium. The increasing isoprenaline doses elicited similar BP decrease in both rat strains, although BP sensitivity to isoprenaline was slightly decreased in SHR. The blockade of cyclooxygenase (indomethacin) and NO synthase (L-NAME) further reduced BP sensitivity to isoprenaline in SHR. On the other hand, salmeterol elicited similar BP decrease in both strains and the blockade of cyclooxygenase and NO synthase increased BP sensitivity to salmeterol in SHR as compared to WKY. In conclusion, attenuated β-adrenergic vasodilatation of conduit arteries of SHR but similar β-adrenergic relaxation of resistance mesenteric arteries from WKY and SHR and their similar BP response to β-adrenergic agonists do not support major role of altered β-adrenergic vasodilatation for high BP in genetic hypertension.
Purpose
The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a ...beneficial effect on tissue perfusion. Our objective was to determine the potential benefits of dobutamine on hemodynamic, metabolic, peripheral, hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation.
Methods
We designed a randomized, controlled, double-blind, crossover study comparing the effects of 2.5-h infusion of dobutamine (5 mcg/kg/min fixed-dose) or placebo in 20 septic shock patients with cardiac index ≥2.5 l/min/m
2
and hyperlactatemia. Primary outcome was sublingual perfused microvascular density.
Results
Despite an increasing cardiac index, heart rate and left ventricular ejection fraction, dobutamine had no effect on sublingual perfused vessel density 9.0 (7.9–10.1) vs. 9.1 n/mm (7.9–9.9);
p
= 0.24 or microvascular flow index 2.1 (1.8–2.5) vs. 2.1 (1.9–2.5);
p
= 0.73 compared to placebo. No differences between dobutamine and placebo were found for the lactate levels, mixed venous-arterial pCO
2
gradient, thenar muscle oxygen saturation, capillary refill time or gastric-to-arterial pCO
2
gradient. The indocyanine green plasma disappearance rate 14.4 (9.5–25.6) vs. 18.8 %/min (11.7–24.6);
p
= 0.03 and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test 2.1 (1.1–3.1) vs. 2.5 %/s (1.2–3.4);
p
= 0.01 were worse with dobutamine compared to placebo.
Conclusions
Dobutamine failed to improve sublingual microcirculatory, metabolic, hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion.
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