Effects of isoflurane anesthesia on aortic compliance and systemic hemodynamics in compliant and noncompliant aortas.

OBJECTIVES: To investigate the effect of general anesthesia on aortic compliance and other cardiovascular hemodynamics in chronically instrumented pigs with compliant and noncompliant (stiff) aortas. DESIGN: Experimental study. SETTING: University animal laboratory. PARTICIPANTS: Twelve adult Yucatan miniature pigs. INTERVENTIONS: Chronic instrumentation of a compliant (control; n = 7) and noncompliant (n = 5) group to measure pressure and flow in the ascending aorta. A Teflon prosthesis was wrapped around the aorta (noncompliant group) to limit wall compliance. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were recorded on the 15th postoperative day, both awake and after general anesthesia. Banding the aorta caused a significant decrease in arterial compliance (-49%, p<0.001) and increases in systolic blood pressure (SBP: +38%, p = 0.001) and pulse pressure (+107%, p< 0.01). Induction of anesthesia in the control group produced a 15% increase in arterial compliance (p<0.05), resulting in a subtle decrease in SBP (-12%), diastolic blood pressure (DBP; -13%) and mean blood pressure (MBP; -12%). Induction of anesthesia in the noncompliant group also caused a significant increase in arterial compliance (17%, p<0.001), but caused significant decreases in SBP (21%, p<0.01), DBP (23%, p<0.01) and MBP (22%, p<0.01) as compared with controls. CONCLUSIONS: Induction of general anesthesia caused a similar increase in total arterial compliance and was associated with a decrease in SBP that was more pronounced in animals with noncompliant aortas. These results indicated that anesthesia caused a greater hemodynamic effect on noncompliant (stiff) aortas and may explain the extensive hemodynamic fluctuation and instability often observed in atherosclerotic, elderly patients with stiff aortas.

Preload-adjusted left ventricular dP/dtmax: a sensitive, continuous, load-independent contractility index.

The classical indicators of left ventricular (LV) performances have been derived from pressure-volume (PV) and stroke work-volume plots obtained during various loading or pharmacological interventions. More recently, the preload-adjusted maximal change in pressure over time (PAdP/dtmax), derived from single beat PV analysis, has been shown to reflect the LV systolic performance accurately in varying conditions of inotropy and afterload. The objective of this study was to address whether PAdP/dtmax is a valid indicator of LV function in the setting of large preload variations, compared with the classical dP/dtmax-end-diastolic volume (EDV) and stroke work-EDV (preload recruitable stroke work) relationships. Nine anaesthetized and mechanically ventilated rats were instrumented with a ventricular conductance catheter. Stepwise preload reduction was achieved by repeated blood withdrawals (up to a total of 5 ml). Steady-state and dynamic PV loops were recorded during brief occlusion of the inferior vena cava, and LV function parameters were derived from these recordings. Our results demonstrate that PAdP/dtmax behaved in a similar manner to preload recruitable stroke work, reflecting well-maintained LV contractility during controlled haemorrhage until mean arterial pressure decreased below 40 mmHg. In contrast, dP/dtmax-EDV increased significantly and exhibited a curvilinear response that was associated with a large inter- and intra-animal variability. In a model of acute preload reduction, PAdP/dtmax was found to be the best indicator of systolic LV function. Given its simplicity, this real-time index derived from single beat analysis should be tested further in clinical settings.

Time-course proteomic analysis of taurocholate-induced necrotizing acute pancreatitis.

Acute pancreatitis is an inflammatory disease of the pancreas, which varies greatly in course and severity. Severe forms are associated with serious local and/or systemic complications, and eventually death. The pathobiology of acute pancreatitis is complex. Animal models have been developed to investigate pathobiological processes and identify factors determining disease course. We performed a time-course proteomic analysis using a rat model of severe necrotizing acute pancreatitis induced by taurocholate perfusion in the pancreatic ducts. Results showed that levels of proteins associated to a given biological process changed in a coordinated fashion after disease onset. It was possible to follow the response of a particular pathobiological process to pancreatitis induction and to compare the course of protein pathways. Proteins involved in acinar cell secretion were found to follow a different kinetics than other cellular processes. After an initial decrease, secretory pathway-associated proteins raised again at 18 h post-induction. This phenomenon coincided with a burst in the expression of pancreatitis-associated protein (REG3A), an acute phase protein produced by the exocrine pancreas, and with the decrease of classical markers of pancreatic injury, suggesting that the expression of proteins associated to the secretory pathway may be a modulating factor of pancreas injury. BIOLOGICAL SIGNIFICANCE: Acute pancreatitis (AP) is a complex inflammatory disease, the pathobiology of which is not yet fully understood. Various animal models, relying on different mechanisms of disease induction, have been developed in order to investigate pathobiological processes of AP. In this study, we performed a time-course proteomic analysis to investigate changes of the pancreas proteome occurring in an experimental model of AP induced by perfusion of taurocholate, a bile acid, into the pancreatic duct. This experimental model is characterized by a severe disease with pancreatic necrosis and systemic inflammation. The objectives of this study were to determine the kinetics of functionally related proteins in the early steps of the experimental disease in order to identify protein pathways playing key roles in AP pathobiology and to correlate these data with parameters classically used to assess disease severity. The present work provides for the first time an overview of protein expression in the pancreas during the course of taurocholate-induced necrotizing AP. We believe that correlation of these results with data obtained using proteomic or biochemical approaches in various experimental models of AP will help in highlighting new features, generating hypotheses and constitute therefore a strong and reliable basis for further targeted investigations.

Cardiac output, O2 delivery and VO2 kinetics during step exercise in acute normobaric hypoxia.

We hypothesised that phase II time constant (τ2) of alveolar O2 uptake ( [Formula: see text] ) is longer in hypoxia than in normoxia as a consequence of a parallel deceleration of the kinetics of O2 delivery ( [Formula: see text] ). To test this hypothesis, breath-by-breath [Formula: see text] and beat-by-beat [Formula: see text] were measured in eight male subjects (25.4±3.4yy, 1.81±0.05m, 78.8±5.7kg) at the onset of cycling exercise (100W) in normoxia and acute hypoxia ( [Formula: see text] ). Blood lactate ([La]b) accumulation during the exercise transient was also measured. The τ2 for [Formula: see text] was shorter than that for [Formula: see text] in normoxia (8.3±6.8s versus 17.8±3.1s), but not in hypoxia (31.5±21.7s versus 28.4 5.4±5.4s). [La]b was increased in the exercise transient in hypoxia (3.0±0.5mM at exercise versus 1.7±0.2mM at rest), but not in normoxia. We conclude that the slowing down of the [Formula: see text] kinetics generated the longer τ2 for [Formula: see text] in hypoxia, with consequent contribution of anaerobic lactic metabolism to the energy balance in exercise transient, witnessed by the increase in [La]b.

Magnetic resonance-guided shielding of prefocal acoustic obstacles in focused ultrasound therapy: application to intercostal ablation in liver.

OBJECTIVES: The treatment of liver cancer is a major public health issue because the liver is a frequent site for both primary and secondary tumors. Rib heating represents a major obstacle for the application of extracorporeal focused ultrasound to liver ablation. Magnetic resonance (MR)-guided external shielding of acoustic obstacles (eg, the ribs) was investigated here to avoid unwanted prefocal energy deposition in the pathway of the focused ultrasound beam. MATERIALS AND METHODS: Ex vivo and in vivo (7 female sheep) experiments were performed in this study. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) was performed using a randomized 256-element phased-array transducer (f∼1 MHz) and a 3-T whole-body clinical MR scanner. A physical mask was inserted in the prefocal beam pathway, external to the body, to block the energy normally targeted on the ribs. The effectiveness of the reflecting material was investigated by characterizing the efficacy of high-intensity focused ultrasound beam reflection and scattering on its surface using Schlieren interferometry. Before high-intensity focused ultrasound sonication, the alignment of the protectors with the conical projections of the ribs was required and achieved in multiple steps using the embedded graphical tools of the MR scanner. Multiplanar near real-time MR thermometry (proton resonance frequency shift method) enabled the simultaneous visualization of the local temperature increase at the focal point and around the exposed ribs. The beam defocusing due to the shielding was evaluated from the MR acoustic radiation force impulse imaging data. RESULTS: Both MR thermometry (performed with hard absorber positioned behind a full-aperture blocking shield) and Schlieren interferometry indicated a very good energy barrier of the shielding material. The specific temperature contrast between rib surface (spatial average) and focus, calculated at the end point of the MRgHIFU sonication, with protectors vs no protectors, indicated an important reduction of the temperature elevation at the ribs' surface, typically by 3.3 ± 0.4 in vivo. This was translated into an exponential reduction in thermal dose by several orders of magnitude. The external shielding covering the full conical shadow of the ribs was more effective when the protectors could be placed close to the ribs' surface and had a tendency to lose its efficiency when placed further from the ribs. Hepatic parenchyma was safely ablated in vivo using this rib-sparing strategy and single-focus independent sonications. CONCLUSIONS: A readily available, MR-compatible, effective, and cost-competitive method for rib protection in transcostal MRgHIFU was validated in this study, using specific reflective strips. The current approach permitted safe intercostal ablation of small volumes (0.7 mL) of liver parenchyma.

Respiratory change in ECG-wave amplitude is a reliable parameter to estimate intravascular volume status.

Electrocardiogram (ECG) is a standard type of monitoring in intensive care medicine. Several studies suggest that changes in ECG morphology may reflect changes in volume status. The "Brody effect", a theoretical analysis of left ventricular (LV) chamber size influence on QRS-wave amplitude, is the key element of this phenomenon. It is characterised by an increase in QRS-wave amplitude that is induced by an increase in ventricular preload. This study investigated the influence of changes in intravascular volume status on respiratory variations of QRS-wave amplitudes (ΔECG) compared with respiratory pulse pressure variations (ΔPP), considered as a reference standard. In 17 pigs, ECG and arterial pressure were recorded. QRS-wave amplitude was measured from the Biopac recording to ensure that in all animals ECG electrodes were always at the same location. Maximal QRS amplitude (ECGmax) and minimal QRS amplitude (ECGmin) were determined over one respiratory cycle. ΔECG was calculated as 100 × [(ECGmax - ECGmin)/(ECGmax + ECGmin)/2]. ΔECG and ΔPP were simultaneously recorded. Measurements were performed at different time points: during normovolemic conditions, after haemorrhage (25 mL/kg), and following re-transfusion (25 mL/kg) with constant tidal volume (10 mL/kg) and respiration rate (15 breath/min). At baseline, ΔPP and ΔECG were both <12 %. ΔPP were significantly correlated with ΔECG (r(2) = 0.89, p < 0.001). Volume loss induced by haemorrhage increased significantly ΔPP and ΔECG. Moreover, during this state, ΔPP were significantly correlated with ΔECG (r(2) = 0.86, p < 0.001). Re-transfusion significantly decreased ΔPP and ΔECG, and ΔPP were significantly correlated with ΔECG (r(2) = 0.90, p < 0.001). The observed correlations between ΔPP and ΔECG at each time point of the study suggest that ΔECG is a reliable parameter to estimate the changes in intravascular volume status and provide experimental confirmation of the "Brody effect."

Superiority of desflurane over sevoflurane and isoflurane in the presence of pressure-overload right ventricle hypertrophy in rats.

BACKGROUND: Pulmonary hypertension and associated pressure-overload right ventricular (RV) hypertrophy represent a tremendous challenge for the anesthesiologist, as optimal perioperative management is mandatory. However, the ideal anesthetic agent remains unknown because scientific evidence is lacking. METHODS: Twenty-eight rats were randomly assigned to a control or a monocrotaline group (60 mg kg). Four weeks later, animals were anesthetized, instrumented with a RV conductance catheter, and underwent well-controlled dose-responses to isoflurane, desflurane, and sevoflurane inhalation (minimum alveolar concentrations 0.5, 1.0, 1.5). RESULTS: Compared with controls, rats injected with monocrotaline presented with RV hypertrophy, increased afterload, and contractility, without change in cardiac output. The ratio of pressures in the right over the left circulation increased. The halogenated volatiles differently altered hemodynamics. Sevoflurane reduced RV contractility (more than 50%) and the right over left pressures ratio increased (from 0.41 ± 0.08 [SD] to 0.82 ± 0.14; P < 0.0001) secondary to profound concomitant systemic vasodilation, demonstrating a critical pressure gradient between right and left circulations. Despite significantly higher RV systolic pressures and afterload, desflurane decreased RV contractility much less (<10%; P < 0.0001 vs. sevoflurane) and maintained the right over left pressures ratio at more favorable values (0.47 ± 0.07; P < 0.0001 vs. sevoflurane). Isoflurane presented intermediate effects. CONCLUSION: In the presence of pressure-overload RV hypertrophy, hemodynamics are better preserved under desflurane inhalation, whereas sevoflurane-and to a lesser extent isoflurane-cause large discrepancies on the left and right circulations, raising the right over left pressures ratio to critical levels despite a conserved cardiac output.

ARFI-prepared MRgHIFU in liver: simultaneous mapping of ARFI-displacement and temperature elevation, using a fast GRE-EPI sequence.

MR acoustic radiation force imaging (ARFI) is an elegant adjunct to MR-guided high intensity focused ultrasound for treatment planning and optimization, permitting in situ assessment of the focusing and targeting quality. The thermal effect of high intensity focused ultrasound pulses associated with ARFI measurements is recommended to be monitored on line, in particular when the beam crosses highly absorbent structures or interfaces (e.g., bones or air-filled cavities). A dedicated MR sequence is proposed here, derived from a segmented gradient echo-echo planar imaging kernel by adding a bipolar motion encoding gradient with interleaved alternating polarities. Temporal resolution was reduced to 2.1 s, with in-plane spatial resolution of 1 mm. MR-ARFI measurements were executed during controlled animal breathing, with trans-costal successively steered foci, to investigate the spatial modulation of the focus intensity and the targeting offset. ARFI-induced tissue displacement measurements enabled the accurate localization, in vivo, of the high intensity focused ultrasound focal point in sheep liver, with simultaneous monitoring of the temperature elevation. ARFI-based precalibration of the focal point position was immediately followed by trans-costal MR-guided high intensity focused ultrasound ablation, monitored with a conventional proton resonance frequency shift MR thermometry sequence. The latter MR thermometry sequence had spatial resolution and geometrical distortion identical with the ARFI maps, hence no coregistration was required.

Reference-free PRFS MR-thermometry using near-harmonic 2-D reconstruction of the background phase.

Proton resonance frequency shift (PRFS) MR thermometry (MRT) is the generally preferred method for monitoring thermal ablation, typically implemented with gradient-echo (GRE) sequences. Standard PRFS MRT is based on the subtraction of a temporal reference phase map and is, therefore, intrinsically sensitive to tissue motion (including deformation) and to external perturbation of the magnetic field. Reference-free (or reference-less) PRFS MRT has been previously described by Rieke and was based on a 2-D polynomial fit performed on phase data from outside the heated region, to estimate the background phase inside the region of interest. While their approach was undeniably a fundamental progress in terms of robustness against tissue motion and magnetic perturbations, the underlying mathematical formalism requires a thick unheated border and may be subject to numerical instabilities with high order polynomials. A novel method of reference-free PRFS MRT is described here, using a physically consistent formalism, which exploits mathematical properties of the magnetic field in a homogeneous or near-homogeneous medium. The present implementation requires as input the MR GRE phase values along a thin, nearly-closed and unheated border. This is a 2-D restriction of a classic Dirichlet problem, working on a slice per slice basis. The method has been validated experimentally by comparison with the "ground truth" data, considered to be the standard PRFS method for static ex vivo tissue. "Zero measurement" of the gradient-echo phase baseline was performed in healthy volunteer liver with rapid acquisition (300 ms/image). In vivo data acquired in sheep liver during MR-guided high intensity focused ultrasound (MRgHIFU) sonication were post-processed as proof of applicability in a therapeutic scenario. Bland and Altman mean absolute difference between the novel method and the "ground truth" thermometry in ex vivo static tissue ranged between 0.069 °C and 0.968 °C, compared to the inherent "white" noise SD of 0.23 °C. The accuracy and precision of the novel method in volunteer liver were found to be on average 0.13 °C and respectively 0.65 °C while the inherent "white" noise SD was on average 0.51 °C. The method was successfully applied to large ROIs, up to 6.2 cm inner diameter, and the computing time per slice was systematically less than 100 ms using C++. The current limitations of reference-free PRFS thermometry originate mainly from the need to provide a nearly-closed border, where the MR phase is artifact-free and the tissue is unheated, plus the potential need to reposition that border during breathing to track the motion of the anatomic zone being monitored.A reference-free PRFS thermometry method based on the theoretical framework of harmonic functions is described and evaluated here. The computing time is compatible with online monitoring during local thermotherapy. The current reference-free MRT approach expands the workflow flexibility, eliminates the need for respiratory triggers, enables higher temporal resolution, and is insensitive to unique-event motion of tissue.

Relevance of the volume-axis intercept, V0, compared with the slope of end-systolic pressure-volume relationship in response to large variations in inotropy and afterload in rats.

The end-systolic pressure-volume relationship (ESPVR) is proposed and used as a reliable index of left ventricular (LV) contractility despite the fact that its afterload independence has been challenged. Furthermore, the physiological relevance of its volume-axis intercept, V(0), remains unclear. Systemic haemodynamics and pressure-volume loops obtained by inferior vena cava occlusion were recorded in 21 rats anaesthetized by isoflurane inhalation and instrumented with a conductance pressure-volume catheter in response to incremental I.V. doses of adrenaline, dobutamine, phenylephrine, metoprolol, papaverine and isoflurane inhalation. In conditions with large variations (± 100%) of both inotropy and afterload, infusion of negative inotropic drugs was associated with a dose-dependent rightward shift of ESPVR accompanied by a decrease in its slope (end-systolic elastance, E(es)), whereas positive inotropic agents produced an isolated decrease in V(0). With the predominant vasoactive drugs, there was a dose-dependent change in E(es) without major horizontal shifts, demonstrating that this slope mainly represents LV afterload rather than inotropy. When contractility was altered, V(0) was negatively correlated to the preload-adjusted contractility index, PAdP/dt(max), demonstrating that a reduced V(0) provides a good reflection of increased LV contractility. From these results, we computed a logarithmically adjusted E(es)/V(0) ratio, which resulted in reasonably strong concordance with PAdP/dt(max), including all the investigated drugs and dosages [n = 288; bias, 0.8 ± 16.2% (SD)]. Concordance with E(es) (bias, 7.2 ± 58.7%) or V(0) (bias, -0.6 ± 33.4%), used alone or with other commonly used contractility indices, was far less significant. In contrast to E(es), V(0) provides a relatively good LV contractility index because it is much less sensitive to afterload.

Pre-ejection period to estimate cardiac preload dependency in mechanically ventilated pigs submitted to severe hemorrhagic shock.

BACKGROUND: Respiratory change in pre-ejection period (ΔPEP) has been described as a potential parameter for monitoring cardiac preload dependency in critically ill patients. This study was designed to describe the relationship between ΔPEP and pulse pressure variation (PPV) in pigs submitted to severe hemorrhagic shock. METHODS: In 17 paralyzed, anesthetized mechanically ventilated pigs, electrocardiography, arterial pressure, and cardiac output derived from pulmonary artery catheter were recorded. Hemorrhagic shock was induced by removal of blood volume followed by restoration. PEP was defined as the time interval between the beginning of the Q wave on the electrocardiogram and the upstroke of the invasive radial arterial pressure curve. RESULTS: At baseline, ΔPEP and PPVs were both <12% with PPV significantly correlated with ΔPEP (r = 0.96, p < 0.001). Volume loss induced by hemorrhage significantly increased PPV and ΔPEP values (p < 0.05). During severe hemorrhage, PPV correlated well with ΔPEP (r = 0.88, p < 0.001) with PPV values significantly higher than ΔPEP (p < 0.05). However, the reproducibility of ΔPEP measurements was significantly better than PPV during this step (p < 0.05). Retransfusion significantly decreased PPV and ΔPEP (p < 0.05) with PPV significantly correlated to ΔPEP (r = 0.94, p < 0.001). CONCLUSION: Available correlations between PPV and ΔPEP at each time of the study were observed, meaning that ΔPEP is a reliable parameter to estimate and track the changes in cardiac preload dependency. Moreover, during the severe hemorrhagic shock period, ΔPEP measurements were more reproducible than PPV values.

Influence of tidal volume on pulse pressure variations in hypovolemic ventilated pigs with acute respiratory distress-like syndrome.

BACKGROUND: Sensitivity and specificity of respiratory change in pulse pressure (DeltaPP) to predict preload dependency has been questioned at small tidal volumes (VT) in critically ill patients suffering from acute respiratory distress syndrome (ARDS). We studied DeltaPP in pigs with ARDS-like syndrome during reversible hemorrhagic shock. METHODS: Prospective, observational animal study in a Laboratory Investigation Unit. Sixteen deeply sedated mechanically ventilated pigs were successively ventilated with VT of 10 ml/kg at a respiratory rate of 15 breaths/min (RR15) and VT of 6 ml/kg at RR15 and RR25. ARDS-like syndrome was produced by lung lavage in eight pigs (ARDS group). Severe hemorrhagic shock was induced by removal of 40% of total blood volume followed by restoration. RESULTS: After bleeding, in the control group ventilated with a VT of 10 ml/kg, DeltaPP increased from 8.5 (95% confidence interval [CI], 7.1 to 9.9%) to 18.5% (CI, 15.3 to 21.7%; P<0.05). In the ARDS group, this index increased similarly, from 7.1% (95% CI, 5.3 to 9.0%) to 20.1% (CI, 15.3 to 24.9%; P<0.05). In control lungs, reduction in VT from 10 to 6 ml/kg reduced the DeltaPP reaction by 40%, although it remained a statistically valid indicator of hypovolemia regardless of the RR value. In contrast, in the ARDS group, DeltaPP was an unreliable hypovolemia marker at low VT ventilation, regardless of the RR value (p=not statistically significant). CONCLUSIONS: The present study suggests that DeltaPP is a reliable indicator of severe hypovolemia in pigs with healthy lungs regardless of VT or RR. In contrast, in pigs with ARDS-like syndrome ventilated with small VT, DeltaPP is not a good indicator of severe hemorrhage. However, in this setting, indexing DeltaPP to respiratory changes in transpulmonary pressure allows this marker to significantly indicate the occurrence of hypovolemia.

Delayed production of IL-18 in lungs and pancreas of rats with acute pancreatitis.

BACKGROUND/AIMS: During acute pancreatitis, tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 play a pivotal role in promoting injury in the pancreas and remote organs. IL- 18 is a more recently discovered proinflammatory cytokine whose expression is also increased in serum. However, the profile of IL-18 expression in the pancreas and lung is unknown, and the aim of our study was to investigate such expression in rats with pancreatitis. METHODS: Acute pancreatitis was induced by taurocholic acid and endotoxin. Pulmonary and pancreatic injury was measured by biological and histological parameters. Lung injury was also evaluated in ex vivo lung preparations. RESULTS: Pancreatic and pulmonary injury appeared within 2 h after pancreatitis induction and persisted until the end of the protocol (18 h). TNF-α, IL-1 and IL-6 expression increased early in the lungs and pancreas, with a partial recovery by the end of the study. In contrast, IL-18 increased mostly by the end of the protocol (18 h after pancreatitis induction). CONCLUSION: IL-18 may serve as an additional marker to monitor the severity of inflammation during pancreatitis since its tissue production is delayed and appears after that of more commonly investigated cytokines. and IAP.

In vivo labelling of resting monocytes in the reticuloendothelial system with fluorescent iron oxide nanoparticles prior to injury reveals that they are mobilized to infarcted myocardium.

AIMS: To evaluate the feasibility of loading resting monocytes/macrophages by intravenous (i.v.) injection of fluorescent iron oxide nanoparticles prior to injury and tracking of these cells in the very same animal to myocardial infarction (MI) by magnetic resonance imaging (MRI) and optical imaging. METHODS AND RESULTS: Rats were injected with fluorescent iron oxide nanoparticles (10 mg/kg) (n = 15) prior to injury. After disappearance of the nanoparticles from the blood, MI was induced. Monocytes/macrophages were then tracked in the very same animal by MRI and optical imaging. Control groups were (i) non-injected animals (n = 15), (ii) injected animals associated with a sham operation (n = 8), and (iii) animals treated with an anti-inflammatory agent (n = 6). The presence of iron-loaded cells can be detected by MRI in vivo in the infarcted myocardium. Here, we showed that the detection of inflammatory cells in vivo correlated well with ex vivo imaging (MRI and reflectance fluorescence) and histology. We also showed that the method is robust enough to depict changes in the inflammatory response. CONCLUSION: This study demonstrates that resting monocytes/macrophages can be loaded in vivo by a simple i.v. injection of fluorescent superparamagnetic iron oxide nanoparticles prior to injury and then tracked, in the same animal, in a model of ischaemia-reperfusion leading to myocardial infarct. Although previous studies of macrophages infiltration following MI have labelled the macrophages after injury, this study, for the first time, has pre-load the resting monocytes with fluorescent iron oxide nanoparticles.

Left ventricular hypertrophy induced by reduced aortic compliance.

AIM: It was the aim of this study to investigate the long- term effects of reduced aortic compliance on cardiovascular hemodynamics and cardiac remodeling. METHOD: Sixteen swine, divided into 2 groups, a control and a banding group, were instrumented for pressure and flow measurement in the ascending aorta. Teflon prosthesis was wrapped around the aortic arch in order to limit wall compliance in the banding group. Hemodynamic parameters were recorded throughout a 60-day period. After sacrifice, the mean cell surface of the left ventricle was documented. RESULTS: Banding decreased aortic compliance by 49 +/- 9, 44 +/- 16 and 42 +/- 7% on the 2nd, 30th and 60th postoperative day, respectively (p < 0.05), while systolic pressure increased by 41 +/- 11, 30 +/- 11 and 35 +/- 12% (p < 0.05), and pulse pressure by 86 +/- 27, 76 +/- 21 and 88 +/- 23%, respectively (p < 0.01). Aortic characteristic impedance increased significantly in the banding group. Diastolic pressure, cardiac output and peripheral resistance remained unaltered. The mean left ventricular cell surface area increased significantly in the banding group. CONCLUSIONS: Acute reduction in aortic compliance results in a significant increase in characteristic and input impedance, a significant decrease in systemic arterial compliance and a subsequent increase in systolic and pulse pressures leading to left ventricular hypertrophy.

Lung mechanical and vascular changes during positive- and negative-pressure lung inflations: importance of reference pressures in the pulmonary vasculature.

The continuous changes in lung mechanics were related to those in pulmonary vascular resistance (Rv) during lung inflations to clarify the mechanical changes in the bronchoalveolar system and the pulmonary vasculature. Rv and low-frequency lung impedance data (Zl) were measured continuously in isolated, perfused rat lungs during 2-min inflation-deflation maneuvers between transpulmonary pressures of 2.5 and 22 cmH(2)O, both by applying positive pressure at the trachea and by generating negative pressure around the lungs in a closed box. ZL was averaged and evaluated for 2-s time windows; airway resistance (Raw), parenchymal damping and elastance (H) were determined in each window. Lung inflation with positive and negative pressures led to very similar changes in lung mechanics, with maximum decreases in Raw [-68 +/- 4 (SE) vs. -64 +/- 18%] and maximum increases in H (379 +/- 36 vs. 348 +/- 37%). Rv, however, increased with positive inflation pressure (15 +/- 1%), whereas it exhibited mild decreases during negative-pressure expansions (-3 +/- 0.3%). These results demonstrate that pulmonary mechanical changes are not affected by the opposing modes of lung inflations and confirm the importance of relating the pulmonary vascular pressures in interpreting changes in Rv.

Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung.

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

Phase I dynamics of cardiac output, systemic O2 delivery, and lung O2 uptake at exercise onset in men in acute normobaric hypoxia.

We tested the hypothesis that vagal withdrawal plays a role in the rapid (phase I) cardiopulmonary response to exercise. To this aim, in five men (24.6+/-3.4 yr, 82.1+/-13.7 kg, maximal aerobic power 330+/-67 W), we determined beat-by-beat cardiac output (Q), oxygen delivery (QaO2), and breath-by-breath lung oxygen uptake (VO2) at light exercise (50 and 100 W) in normoxia and acute hypoxia (fraction of inspired O2=0.11), because the latter reduces resting vagal activity. We computed Q from stroke volume (Qst, by model flow) and heart rate (fH, electrocardiography), and QaO2 from Q and arterial O2 concentration. Double exponentials were fitted to the data. In hypoxia compared with normoxia, steady-state fH and Q were higher, and Qst and VO2 were unchanged. QaO2 was unchanged at rest and lower at exercise. During transients, amplitude of phase I (A1) for VO2 was unchanged. For fH, Q and QaO2, A1 was lower. Phase I time constant (tau1) for QaO2 and VO2 was unchanged. The same was the case for Q at 100 W and for fH at 50 W. Qst kinetics were unaffected. In conclusion, the results do not fully support the hypothesis that vagal withdrawal determines phase I, because it was not completely suppressed. Although we can attribute the decrease in A1 of fH to a diminished degree of vagal withdrawal in hypoxia, this is not so for Qst. Thus the dual origin of the phase I of Q and QaO2, neural (vagal) and mechanical (venous return increase by muscle pump action), would rather be confirmed.

Adverse effects of methylene blue on the central nervous system.

BACKGROUND: An increasing number of clinical observations suggest adverse neurologic outcome after methylene blue (MB) infusion in the setting of parathyroid surgery. Hence, the aim of the current study was to investigate the potentially neurotoxic effects of MB using a combination of in vivo and in vitro experimental approaches. METHODS: Isoflurane-anesthetized adult rats were used to evaluate the impact of a single bolus intravascular administration of MB on systemic hemodynamic responses and on the minimum alveolar concentration (MAC) of isoflurane using the tail clamp test. In vivo, MB-induced cell death was evaluated 24 h after MB administration using Fluoro-Jade B staining and activated caspase-3 immunohistochemistry. In vitro, neurotoxic effects of MB were examined in hippocampal slice cultures by measuring excitatory field potentials as well as propidium iodide incorporation after MB exposure. The impact of MB on dendritic arbor was evaluated in differentiated single cell neuronal cultures. RESULTS: Bolus injections of MB significantly reduced isoflurane MAC and initiated widespread neuronal apoptosis. Electrophysiologic recordings in hippocampal slices revealed a rapid suppression of evoked excitatory field potentials by MB, and this was associated with a dose-dependent effect of this drug on cell death. Dose-response experiments in single cell neuronal cultures revealed that a 2-h-long exposure to MB at non-cell-death-inducing concentrations could still induce significant retraction of dendritic arbor. CONCLUSIONS: These results suggest that MB exerts neurotoxic effects on the central nervous system and raise questions regarding the safety of using this drug at high doses during parathyroid gland surgery.

Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome.

The hepatopulmonary syndrome is a complication of cirrhosis that associates an overproduction of nitric oxide (NO) in lungs and a NO defect in the liver. Because endothelial NO synthase (eNOS) is regulated by caveolin that decreases and heat shock protein 90 (HSP90) that increases NO production, we hypothesized that an opposite regulation of eNOS by caveolin and HSP90 might explain the opposite NO production in both organs. Cirrhosis was induced by a chronic bile duct ligation (CBDL) performed 15, 30, and 60 days before sample collection and pharmacological tests. eNOS, caveolin, and HSP90 expression were measured in hepatic and lung tissues. Pharmacological tests to assess NO released by shear stress and by acetylcholine were performed in livers (n = 28) and lungs (n = 28) isolated from normal and CBDL rats. In lungs from CBDL rats, indirect evidence of high NO production induced by shear stress was associated with a high binding of HSP90 and a low binding of caveolin to eNOS. Opposite results were observed in livers from CBDL rats. Our study shows an opposite posttranslational regulation of eNOS by HSP90 and caveolin in lungs and liver from rats with CBDL. Such opposite posttranslational regulation of eNOS by regulatory proteins may explain in part the pulmonary overproduction of NO and the hepatic NO defect in rats with hepatopulmonary syndrome.