1. The site(s) at which P2-receptor agonists act to evoke contractions of the rat isolated tail artery was studied by use of P2-receptor antagonists and the extracellular ATPase inhibitor 6-N,N-diethyl-D-b,gdibromomethyleneATP (ARL 67156). 2 Suramin (1 mM ± 1 mM) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (0.3 ± 300 mM) inhibited contractions evoked by equi-eective concentrations of a,b-methyleneATP (a,bmeATP) (5 mM), 2-methylthioATP (2-meSATP) (100 mM) and adenosine 5'-triphosphate (ATP) (1 mM) in a concentration-dependent manner. Responses to a,b-meATP and 2-meSATP were abolished, but approximately one third of the peak response to ATP was resistant to suramin and PPADS. 3 Contractions evoked by uridine 5'-triphosphate (UTP) (1 mM) were slightly inhibited by suramin (100 and 300 mM) and potentiated by PPADS (300 mM). 4 Desensitization of the P2X 1 -receptor by a,b-meATP abolished contractions evoked by 2-meSATP (100 mM) and reduced those to ATP (1 mM) and UTP (1 mM) to 15+3% and 68+4% of control. 5 Responses to a,b-meATP (5 mM) and 2-meSATP (100 mM) were abolished when tissues were bathed in nominally calcium-free solution, while the peak contractions to ATP (1 mM) and UTP (1 mM) were reduced to 24+6% and 61+13%, respectively, of their control response. 6 ARL 67156 (3 ± 100 mM) potentiated contractions elicited by UTP (1 mM), but inhibited responses to a,b-meATP (5 mM), 2-meSATP (100 mM) and ATP (1 mM) in a concentration-dependent manner. 7 These results suggest that two populations of P2-receptors are present in the rat tail artery; ligandgated P2X 1 -receptors and G-protein-coupled P2Y-receptors.
The response of pulmonary arteries to hypoxia varies as a function of vessel diameter. Small intrapulmonary resistance arteries are thought to be the main site of hypoxic pulmonary vasoconstriction (HPV), with hypoxia causing minimal contraction or even dilatation in large, conduit vessels. This has been proposed to reflect a differential distribution of morphologically and electrophysiologically distinct pulmonary artery smooth muscle (PASM) cells. We investigated longitudinal heterogeneity in smooth muscle cells isolated from five regions of the rabbit pulmonary vasculature and could find no evidence of morphological heterogeneity at the level of the light microscope. PASM cells from main (8 mm outer diameter) and branch (5 mm) arteries and large ( 400 m) intrapulmonary arteries (IPA) were similar in shape and size, as indicated by cell capacitance (25 pF). PASM cells from medium (200-400 m) and small ( 200 m) IPA were significantly smaller (15 pF), but had the same classical spindle shape. Cells from all five regions also had similar resting membrane potentials and displayed voltage-activated K+ currents of similar amplitude when recorded in standard physiological solution. Longitudinal heterogeneity in K+ current became apparent when tetraethylammonium ions (TEA; 10 mM) and glibenclamide (10 M) were added. The remaining delayed rectifier current (IK(V)) doubled in amplitude upon moving down the pulmonary arterial tree from the main artery (9 pA pF-1 at 40 mV) to the large IPA (17 pA pF-1), but remained constant throughout the intrapulmonary vasculature. The O2-sensitive, non-inactivating K+ current (IK(N)) showed a similar trend, but was significantly reduced in the smallest IPA, where its amplitude was comparable with the main artery. Thus the IK(N)/IK(V) ratio was relatively constant, at around 0.14, from the main pulmonary artery to medium IPA, but fell by 50% in the smallest vessels. The amplitude of the TEA-sensitive K+ current was similar (16 pA pF-1 at 40 mV) at all levels of the pulmonary arterial tree, except in the medium sized vessels where it was 50% smaller. These variations in K+ current expression correlate with reported variations in sensitivity to hypoxia and may contribute to the regional heterogeneity of HPV in the rabbit lung.
Background: Acute chest syndrome (ACS) is a common complication in patients with sickle cell disease (SCD) and is a leading cause of morbidity and mortality.Chest X-ray (CXR) is recommended for evaluating ACS in patients with SCD because clinical findings alone have a low sensitivity. Children with SCD are repeatedly exposed to diagnostic radiation for the evaluation of ACS. Lung ultrasound (LUS) has been compared to CXR as an alternative imaging modality for evaluating ACS, and a lung consolidation > 1 cm is sensitive and specific for diagnosing patients with ACS. Consolidations < 1 cm, or subpleural consolidations, can detect pneumonia earlier than CXR; however, the significance of these findings for evaluating ACS is unknown. We evaluated LUS with consolidations <1 cm to determine if they could identify patients with ACS. Methods: This is a prospective observational study that took place from November 2014-July 2016 in 2 urban pediatric emergency departments (EDs). The study population consisted of a convenience sample of patients with SCD from birth to 18 years of age at risk for ACS and who received a clinically-indicated CXR for suspected ACS. ACS was defined as a new pulmonary infiltrate on CXR together with the presence of fever, cough, chest pain, or respiratory symptoms. LUS were performed to evaluate for lung consolidation and determine the sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) of LUS to identify ACS. In a subanalysis, the charts of patients who had a negative CXR interpreted by a pediatric radiologist or consolidation < 1 cm on LUS at the time of enrollment were reviewed for development of ACS within 7 days of the visit. The development of ACS in patients with subpleural findings on LUS was compared to patients with negative ultrasound findings. Fischer's-Exact Test was used to determine significance between the 2 groups with α = 0.05. Results: One hundred sixty-eight patients were enrolled. ACS was diagnosed in 14% of patients, while a CXR was negative in 150 cases. The sensitivity of LUS to predict ACS was 91%, specificity was 91%, LR+ 10.5, LR- 0.1. Thirty-six cases had subpleural consolidation on LUS and 3 patients (8%) developed ACS. Of the 114 patients with negative LUS, 7 (6%) developed ACS. There was no statistical difference between these groups with p-value of 0.7. Conclusions: Patients with subpleural consolidations on LUS were no more likely to develop ACS than those patients with a negative LUS. The small number of patients who developed ACS may have failed to show a statistical difference between these groups. Further studies with serial ultrasound examinations are needed to better define the significance of this finding. Disclosures Morris: MAST: Research Funding; Pfizer: Consultancy; Calithera: Consultancy; Nourish Life: Patents & Royalties: I am the inventor of IP owned by UCSF-Benioff Children's Hospital that is licensed to NL; Endeavor: Consultancy; Nestle: Honoraria.
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