Centrally Acting ACE Inhibitor Use and Physical Performance in Older Adults.

BACKGROUND: There is conflicting evidence regarding the role of angiotensin-converting enzyme inhibitors and physical function. While some studies show improvements in muscle strength and physical function, others show no significant difference or decreased performance. This ambiguity could be due to differential effects of angiotensin-converting enzyme inhibitor subtypes which can be categorized as centrally or peripherally-acting based upon their ability to cross the blood-brain barrier. OBJECTIVE: The objective of this study is to compare physical performance measures among angiotensin-converting enzyme inhibitor subtype users. METHODS: Design: Cross-sectional Setting: Ambulatory Participants: Performed in 364 participants in the Health and Retirement Study cohort who were ≥ 65 years (median age (IQR) 74.00 (69-80) years. MEASUREMENTS: Average difference in hand grip (kg), gait speed(m/s) and peak expiratory flow (L/min). RESULTS: Compared to participants on a peripherally-acting angiotensin-converting enzyme inhibitor (113 (31%)), those on a centrally-acting agent (251(69%)) had stronger grip strength 28.9 ±1.0 vs 26.3±1.0, p=.011 and higher peak expiratory flow rates 316.8±130.4 vs. 280.0±118.5, p= .011 in unadjusted analysis. After multiple adjustments the difference in PEF remained statistically significant (Estimate(CI) 26.5, 95% CI 2.24, 50.5, p = 0.032). CONCLUSION: Our results suggest that in older adults the use of centrally-acting angiotensin-converting enzyme inhibitors compared to a peripherally acting angiotensin-converting enzyme inhibitors was associated with better lung function in older individuals.

The Effect of Nasal High Flow Therapy on Minute Ventilation in Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Nasal high-flow therapy (HFT) has been shown to improve daytime breathing mechanics in healthy adults as well as the lung function and quality of life in chronic obstructive pulmonary disease (COPD) patients. METHOD: We hypothesized that improved breathing mechanics with HFT may further reduce minute ventilation (i.e. decreased work of breathing) during sleep in patients with COPD. In COPD participants we examined the dose effect of HFT (within night randomization of HFT level; 0, 10, 20 and 30L/min) on minute ventilation, oxyhemaglobin saturation and transcutaneous carbon dioxide during wake and sleep. We assessed overnight polysomnography with and without HFT on two separate nights. Paired t-tests were used to compare overnight sleep quality with and without HFT. The association between ventilatory variables and HFT level was assessed using regression analysis. RESULTS: During sleep, HFT decreased minute ventilation by 0.63±0.02L/min per 10L/min nasal airflow by reducing tidal volume (37±6mL per 10L/min; p<0.001) without affecting respiratory rate (p=0.9) or arterial CO2 (p=0.7). In contrast, during wakefulness reductions in minute ventilation (0.85±0.04L/min per 10L/min) was due to respiratory rate reduction along with prolongation in expiratory time. CONCLUSION: The reduction in minute ventilation is greater with higher dead-space volumes (r=0.50; p<0.02) and during wakefulness suggesting that ventilatory responses to HFT are mediated through a reduction in dead-space ventilation. The reduction in ventilation in response to HFT is large enough to reduce respiratory loads. Reducing respiratory loads may avert muscle fatigue, preserve respiratory function, or prevent development of respiratory failure.

Leptin receptor polymorphisms and lung function decline in COPD.

Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.

Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis.

Persistent directional movement of neutrophils in shallow chemotactic gradients raises the possibility that cells can increase their sensitivity to the chemotactic signal at the front, relative to the back. Redistribution of chemoattractant receptors to the anterior pole of a polarized neutrophil could impose asymmetric sensitivity by increasing the relative strength of detected signals at the cell's leading edge. Previous experiments have produced contradictory observations with respect to receptor location in moving neutrophils. To visualize a chemoattractant receptor directly during chemotaxis, we expressed a green fluorescent protein (GFP)-tagged receptor for a complement component, C5a, in a leukemia cell line, PLB-985. Differentiated PLB-985 cells, like neutrophils, adhere, spread, and polarize in response to a uniform concentration of chemoattractant, and orient and crawl toward a micropipette containing chemoattractant. Recorded in living cells, fluorescence of the tagged receptor, C5aR-GFP, shows no apparent increase anywhere on the plasma membrane of polarized and moving cells, even at the leading edge. During chemotaxis, however, some cells do exhibit increased amounts of highly folded plasma membrane at the leading edge, as detected by a fluorescent probe for membrane lipids; this is accompanied by an apparent increase of C5aR-GFP fluorescence, which is directly proportional to the accumulation of plasma membrane. Thus neutrophils do not actively concentrate chemoattractant receptors at the leading edge during chemotaxis, although asymmetrical distribution of membrane may enrich receptor number, relative to adjacent cytoplasmic volume, at the anterior pole of some polarized cells. This enrichment could help to maintain persistent migration in a shallow gradient of chemoattractant.

Galphai is not required for chemotaxis mediated by Gi-coupled receptors.

Pertussis toxin inhibits chemotaxis of neutrophils by preventing chemoattractant receptors from activating trimeric G proteins in the Gi subfamily. In HEK293 cells expressing recombinant receptors, directional migration toward appropriate agonist ligands requires release of free G protein betagamma subunits and can be triggered by agonists for receptors coupled to Gi but not by agonists for receptors coupled to two other G proteins, Gs and Gq. Because activation of any G protein presumably releases free Gbetagamma, we tested the hypothesis that chemotaxis also requires activated alpha subunits (Galphai) of Gi proteins. HEK293 cells were stably cotransfected with the Gi-coupled receptor for interleukin-8, CXCR1, and with a chimeric Galpha, Galphaqz5, which resembles Galphai in susceptibility to activation by Gi-coupled receptors but cannot regulate the Galphai effector, adenylyl cyclase. These cells, unlike cells expressing CXCR1 alone, migrated toward interleukin-8 even after treatment with pertussis toxin, which prevents activation of endogenous Galphai but not that of Galphaqz5. We infer that chemotaxis does not require activation of Galphai. Because chemotaxis is mediated by Gbetagamma subunits released when Gi-coupled receptors activate Galphaqz5, but not when Gq- or Gs-coupled receptors activate their respective G proteins, we propose that Gi-coupled receptors transmit a necessary chemotactic signal that is independent of Galphai.

Receptors induce chemotaxis by releasing the betagamma subunit of Gi, not by activating Gq or Gs.

Many chemoattractants cause chemotaxis of leukocytes by stimulating a structurally distinct class of G protein-coupled receptors. To identify receptor functions required for chemotaxis, we studied chemotaxis in HEK293 cells transfected with receptors for nonchemokine ligands or for interleukin 8 (IL-8), a classical chemokine. In gradients of the appropriate agonist, three nonchemokine Gi-coupled receptors (the D2 dopamine receptor and opioid mu and delta receptors) mediated chemotaxis; the beta2-adrenoreceptor and the M3-muscarinic receptor, which couple respectively to Gs and Gq, did not mediate chemotaxis. A mutation deleting 31 C-terminal amino acids from the IL-8 receptor type B quantitatively impaired chemotaxis and agonist-induced receptor internalization, but not inhibition of adenylyl cyclase or stimulation of mitogen-activated protein kinase. To probe the possible relation between receptor internalization and chemotaxis, we used two agonists of the mu-opioid receptor. Morphine and etorphine elicited quantitatively similar chemotaxis, but only etorphine induced receptor internalization. Overexpression of two betagamma sequestering proteins (betaARK-ct and alphat) prevented IL-8 receptor type B-mediated chemotaxis but did not affect inhibition of adenylyl cyclase by IL-8. We conclude that: (i) Nonchemokine Gi-coupled receptors can mediate chemotaxis. (ii) Gi activation is necessary but probably not sufficient for chemotaxis. (iii) Chemotaxis does not require receptor internalization. (iv) Chemotaxis requires the release of free betagamma subunits.

Lipid synthesis by isolated Chlamydia psittaci.

The isolated cells of the host-dependent meningopneumonitis agent, Chlamydia psittaci, were shown to incorporate radioactive carbon from aspartate, isoleucine, and glucose-6-phosphate into cell lipids. The nature of this incorporation was investigated. Radioactivity was found only in the fatty acids and primarily in the phosphatidyl ethanolamine, and, to a lesser extent, in the phosphatidyl choline fractions. Branched-chain fatty acids, not found in host lipid, were shown to constitute a large proportion of the fatty acid content of phosphatidyl ethanolamine. The reasons why only fatty acid synthesis took place under the conditions of our experiments with isolated meningopneumonitis agent cells remain obscure.

Influence of gas environment on catabolic activities and on reoxidation of reduced nicotinamide adenine dinucleotide phosphate in Chlamydia.

We investigated the effect of the gas environment on the enzymatic reactions of intact isolated cells of the agents of trachoma and of meningopneumonitis of the host-dependent genus Chlamydia. In comparison with the reactions taking place in a gas phase of air, O(2) depressed CO(2) production from pyruvate and glutamate by trachoma and from glutamate by meningopneumonitis. O(2) enhanced the degradation of pyruvate by meningopneumonitis, but this effect was due to increased H(2)O(2), and was reversed by added catalase. Both dehydrogenation of alpha-ketoglutarate and was reversed by added catalase. Dehydrogenation of alpha-ketoglutarate by both agents and production of CO(2) from C(1) of glucose-6-phosphate were stimulated by O(2) and depressed in N(2). The latter activity was stimulated in air, O(2), and N(2) by nicotinamide adenine dinucleotide phosphate (NADP) in relation to the amount added, and also in air or O(2), but not in N(2), by moderate amounts of NADP and an excess of oxidized glutathione with concomitant formation of H(2)O(2). A small but significant amount of O(2) was consumed during the course of these reactions. It is suggested that glutathione reductase activity can occur only when accompanied by an oxidative reaction, and that this close link between the two reactions represents a mechanism of electron transport which transfers hydrogen to molecular O(2).