Deliberate induction of prophylactic hypercapnic acidosis protects against lung injury after in vivo ischemia-reperfusion and ventilation-induced lung injury. However, the efficacy of hypercapnic acidosis in sepsis, the commonest cause of clinical acute respiratory distress syndrome, is not known. We investigated whether hypercapnic acidosis--induced by adding CO2 to inspired gas--would be protective against endotoxin-induced lung injury in an in vivo rat model. Prophylactic institution of hypercapnic acidosis (i.e., induction before endotoxin instillation) attenuated the decrement in arterial oxygenation, improved lung compliance, and attenuated alveolar neutrophil infiltration compared with control conditions. Therapeutic institution of hypercapnic acidosis, that is, induction after endotoxin instillation, attenuated the decrement in oxygenation, improved lung compliance, and reduced alveolar neutrophil infiltration and histologic indices of lung injury. Therapeutic hypercapnic acidosis attenuated the endotoxin-induced increase in the higher oxides of nitrogen and nitrosothiols in the lung tissue and epithelial lining fluid. Lung epithelial lining fluid nitrotyrosine concentrations were increased with hypercapnic acidosis. We conclude that hypercapnic acidosis attenuates acute endotoxin-induced lung injury, and is efficacious both prophylactically and therapeutically. The beneficial actions of hypercapnic acidosis were not mediated by inhibition of peroxynitrite-induced nitration within proteins.

The effect of endothelin (ET)-1 on both cytosolic Ca2+ concentration ([Ca2+]i) and membrane current in freshly isolated myocytes, as well as on the contraction of arterial rings, was investigated in rat main pulmonary artery (RMPA) and intrapulmonary arteries (RIPA). ET-1 (5–100 nM, 30 s) induced a first [Ca2+]ipeak followed by 3–5 oscillations of decreasing amplitude. In RMPA, the ET-1-induced [Ca2+]iresponse was fully abolished by BQ-123 (0.1 μM). In RIPA, the response was inhibited by BQ-123 in only 21% of the cells, whereas it was abolished by BQ-788 (1 μM) in 70% of the cells. In both types of arteries, the response was not modified in the presence of 100 μM La3+ or in the absence of external Ca2+ but disappeared after pretreatment of the cells with thapsigargin (1 μM) or neomycin (0.1 μM). In RPMA myocytes clamped at −60 mV, ET-1 induced an oscillatory inward current, the reversal potential of which was close to the equilibrium potential for Cl−. This current was unaltered by the removal of external Ca2+ but was abolished by niflumic acid (50 μM). In arterial rings, the ET-1 (100 nM)-induced contraction was decreased by 35% in the presence of either niflumic acid (50 μM) or nifedipine (1 μM). These results demonstrate that ET-1 via the ETA receptor only in RMPA and both ETA and ETB receptors in RIPA induce [Ca2+]ioscillations due to iterative Ca2+release from an inositol trisphosphate-sensitive Ca2+ store. Ca2+ release secondarily activates an oscillatory membrane Cl−current that can depolarize the cell membrane, leading to an influx of Ca2+, this latter contributing to the ET-1-induced vasoconstrictor effect.

The effect of chronic hypoxia (CH) for 14 days on Ca2+ signaling and contraction induced by agonists in the rat main pulmonary artery (MPA) was investigated. In MPA myocytes obtained from control (normoxic) rats, endothelin (ET)-1, angiotensin II (ANG II), and ATP induced oscillations in intracellular Ca2+ concentration ([Ca2+]i) in 85-90% of cells, whereas they disappeared in myocytes from chronically hypoxic rats together with a decrease in the percentage of responding cells. However, both the amount of mobilized Ca2+ and the sources of Ca2+ implicated in the agonist-induced response were not changed. Analysis of the transient caffeine-induced [Ca2+]i response revealed that recovery of the resting [Ca2+]i value was delayed in myocytes from chronically hypoxic rats. The maximal contraction induced by ET-1 or ANG II in MPA rings from chronically hypoxic rats was decreased by 30% compared with control values. Moreover, the D-600- and thapsigargin-resistant component of contraction was decreased by 40% in chronically hypoxic rats. These data indicate that CH alters pulmonary arterial reactivity as a consequence of an effect on both Ca2+ signaling and Ca2+ sensitivity of the contractile apparatus. A Ca2+ reuptake mechanism appears as a CH-sensitive phenomenon that may account for the main effect of CH on Ca2+ signaling.

3D molecular ultrasound using BR55 is very well suited to depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions.

No abstract

The effect of chronic hypoxia (CH; 1-4 wk) on the electromechanical properties of the rat main pulmonary artery (MPA) was investigated. MPA rings obtained from rats exposed for 14 days to hypobaric (50.5 kPa) CH exhibited spontaneous and rhythmic contractions (SRCs) that were never observed in control (normoxic) rats. SRCs were unaffected by tetrodotoxin, phentolamine, BQ-123 and BQ-788, N-nitro-L-arginine methyl ester, or endothelium removal. CH depolarized smooth muscle cells from -58.8 +/- 9 to -38.6 +/- 5.4 mV and increased the resting cytosolic Ca2+ concentration from 67.3 +/- 11.9 to 112.5 +/- 16.4 nM. CH also induced spontaneous spikelike depolarizations. All of these effects were inhibited by external Ca2+ removal or nifedipine (1 microM). Moreover, depletion of intracellular Ca2+ stores with ryanodine (1-5 microM) or cyclopiazonic acid (3 microM) progressively attenuated SRCs. This study demonstrates that CH switches the MPA from a quiescent to a spontaneously active mechanical state. Finally, the fact that SRCs precede the development of right ventricle hypertrophy and disappear when this hypertrophy reaches a maximal value (after 3-4 wk of CH) suggests that SRCs may play a role in the adaptive process of the pulmonary circulation to CH.

Imaging performance of SonoVue was similar to or slightly better than that of Definity, but it was superior to Optison for the conditions used in this study.

Ultrasound contrast imaging techniques represent a real opportunity to improve efficiency in the preclinical drug discovery and development process. Ultrasound contrast agents (UCAs) combined with specific ultrasound contrast detection modes provide real-time, high spatial resolution of both organ and lesion blood perfusion, the so-called dynamic contrast-enhanced ultrasound imaging. With the advent of targeted UCA, ultrasound molecular imaging is gaining momentum in molecular imaging, particularly because of the simultaneous real-time anatomical and functional/molecular imaging capabilities. In preclinical research, contrast-enhanced ultrasound imaging, with either nontargeted or targeted UCA, is a fast-growing imaging modality that has not yet been standardized compared with other imaging modalities. Contrast-enhanced ultrasound imaging is an operator-dependent imaging modality, requiring adherence to rigorous step-by-step protocols. In this article, which is intended for advanced, hands-on researchers, we report key factors that can lead to variability in preclinical results and recommend some preventive methods to limit or cancel their effect on the final results. Standardized procedures are a prerequisite for acceptance of new contrast-enhanced ultrasound imaging methods to eliminate factors that could distort results, improve the reproducibility between different centers and studies, and, therefore, allow translation to clinical application.