Moderate exercise protects against joint disease in a murine model of osteoarthritis.

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA.

Accelerated post traumatic osteoarthritis in a dual injury murine model.

OBJECTIVE: Joint injury involving destabilisation of the joint and damage to the articular cartilage (e.g., sports-related injury) can result in accelerated post-traumatic osteoarthritis (PTOA). Destabilised medial meniscotibial ligament (DMM) surgery is one of the most commonly used murine models and whilst it recapitulates Osteoarthritis (OA) pathology, it does not necessarily result in multi-tissue injury, as occurs in PTOA. We hypothesised that simultaneous cartilage damage and joint destabilisation would accelerate the onset of OA pathology. METHODS: OA was induced in C57BL/6 mice via (a) DMM, (b) microblade scratches of articular cartilage (CS) or (c) combined DMM and cartilage scratch (DCS). Mice were culled 7, 14 and 28 days post-surgery. Microcomputed tomography (µCT) and histology were used to monitor bone changes and inflammation. Dynamic weight bearing, an indirect measure of pain, was assessed on day 14. RESULTS: Osteophytogenesis analysis via µCT revealed that osteophytes were present in all groups at days 7 and 14 post-surgery. However, in DCS, osteophytes were visually larger and more numerous when compared with DMM and cartilage scratch (CS). Histological assessment of cartilage at day 14 and 28, revealed significantly greater damage in DCS compared with DMM and CS. Furthermore, a significant increase in synovitis was observed in DCS. Finally, at day 14 osteophyte numbers correlated with changes in dynamic weight bearing. CONCLUSION: Joint destabilisation when combined with simultaneous cartilage injury accelerates joint deterioration, as seen in PTOA. Thus, DCS provides a novel and robust model for investigating multiple pathological hallmarks, including osteophytogenesis, cartilage damage, synovitis and OA-related pain.

Patient characteristics, interventions and outcomes of 1151 rapid response team activations in a tertiary hospital: a prospective study.

BACKGROUND: The characteristics of mature contemporary rapid response systems are unclear. AIM: To determine the patient characteristics, processes and outcomes, both in-hospital and post-discharge, of a well-established rapid response system in a tertiary adult hospital. METHODS: This is a prospective study of consecutive rapid response team (RRT) activations between 1 July and 25 November 2015. Variables included patient characteristics, timing, location and triggers of RRT activations, interventions undertaken, mortality and readmission status at 28 days post-discharge. RESULTS: A total of 1151 RRT activations was analysed (69.1 per 1000 admissions), involving 800 patients, of whom 81.5% were emergency admissions. A total of 351 (30.5%) activations comprised repeat activations for the same patient. Most activations (723; 62.8%) occurred out of hours, and 495 (43%) occurred within 48 h of admission. Hypotension, decreased level of consciousness and oxygen desaturation were the most common triggers. Advanced life support was undertaken in less than 7%; 198 (17.2%) responses led to transfer to higher-level care units. Acute resuscitation plans were noted for only 29.1% of RRT activations, with 80.3% stipulating supportive care only. A total of 103 (12.6%) patients died in hospital, equalling 14 deaths per 100 RRT activations. At 28 days, 150 (18.8%) patients had died, significantly more among those with multiple versus single RRT activations (24.9 vs 16.6%; odds ratio 1.66, 95% confidence interval 1.31-2.44; P = 0.013). CONCLUSION: Relatively few RRT activations are associated with acute resuscitation plans, and most interventions during RRT responses are low level. The high rate of post-RRT deaths and transfers to higher-level care units calls for the prospective identification of such patients in targeting appropriate care.

Countermeasures to driver fatigue: a review of public awareness campaigns and legal approaches.

OBJECTIVE: Driver fatigue accounts for 10-40% of road crashes and is a critical area for public health. As other major road safety issues are more successfully managed, driver fatigue becomes proportionately more important. Both public awareness and legal developments have been slow to reach the same levels as for other road safety risks. The aim of this article is to review countermeasures for non-commercial drivers that are designed to reduce the likelihood of fatigue-related crashes through education and legislation. METHODS: This review outlines information from a wide variety of sources including governments, road safety groups and the scientific literature. Educational and legislative approaches are discussed in terms of both their effectiveness and the associated implications for public health. CONCLUSIONS: Areas for improvement in education include personalising the risk to drivers and developing simple metrics for the self-assessment of fatigue. Legal implications should be more clearly defined and specific laws are needed to more effectively prosecute fatigued drivers who cause crashes. Additional research is needed to further investigate the efficacy of available countermeasures. IMPLICATIONS: Increasingly, road traffic injury is being discussed more broadly as a public health issue. However, the specific issue of driver fatigue still receives less attention than other main causes of road crashes, despite making a significant and comparable contribution to crash rates. Countries such as Australia and New Zealand have a responsibility to counter driver fatigue, as well as other causes of road crashes, and to further pursue improvements for the benefit of public health.

The impact of a week of simulated night work on sleep, circadian phase, and performance.

AIMS: To investigate factors that may contribute to performance adaptation during permanent night work. METHODS: Fifteen healthy subjects participated in an adaptation and baseline night sleep, directly followed by seven simulated eight-hour night shifts (2300 to 0700 hours). At the end of each shift they were taken outside and exposed to natural light for 20 minutes. They then slept from approximately 0800 hours until they naturally awoke. RESULTS: There was a significant increase in mean performance on a visual psychomotor vigilance task across the week. Daytime sleep quality and quantity were not negatively affected. Total sleep time (TST) for each of the daytime sleeps was reduced, resulting in an average cumulative sleep debt of 3.53 hours prior to the final night shift. TST for each of the daytime sleep periods did not significantly differ from the baseline night, nor did TST significantly vary across the week. There was a significant decrease in wake time after sleep onset and sleep onset latency across the week; sleep efficiency showed a trend towards greater efficiency across the consecutive daytime sleeps. Hours of wakefulness prior to each simulated night shift significantly varied across the week. The melatonin profile significantly shifted across the week. CONCLUSIONS: Results suggest that under optimal conditions, the sleep debt that accumulates during consecutive night shifts is relatively small and does not exacerbate decrements in night-time performance resulting from other factors. When sleep loss is minimised, adaptation of performance during consecutive night shifts can occur in conjunction with circadian adaptation.

Role of C chemokine lymphotactin in mediating recruitment of antigen-specific CD62L(lo) cells in vitro and in vivo.

In this study we investigated whether T cells expressing high or low levels of CD62L were differentially susceptible to the T cell chemokine lymphotactin. We found that lymphotactin induced preferential migration of antigen-specific (CD62L(lo)) T cells over the nonspecific (CD62L(hi)) T cells in vitro and in vivo. The differing migratory abilities correlated with higher levels of mRNA encoding the lymphotactin receptor (XCR1) on the CD62L(lo) cells compared to the CD62L(hi) cells. Thus, we have identified a coupling mechanism between the activation of T cells and acquisition of new homing properties, in this case conferred by XCR1 expression. These data confirm that at least one function of lymphotactin includes mediating the recruitment of recently activated antigen-specific T cells.

Performance, sleep and circadian phase during a week of simulated night work.

The current study investigated changes in night-time performance, daytime sleep, and circadian phase during a week of simulated shift work. Fifteen young subjects participated in an adaptation and baseline night sleep, directly followed by seven night shifts. Subjects slept from approximately 0800 hr until they naturally awoke. Polysomnographic data was collected for each sleep period. Saliva samples were collected at half hourly intervals, from 2000 hr to bedtime. Each night, performance was tested at hourly intervals. Analysis indicated that there was a significant increase in mean performance across the week. In general, sleep was not negatively affected. Rather, sleep quality appeared to improve across the week. However, total sleep time (TST) for each day sleep was slightly reduced from baseline, resulting in a small cumulative sleep debt of 3.53 (SD = 5.62) hours. Finally, the melatonin profile shifted across the week, resulting in a mean phase delay of 5.5 hours. These findings indicate that when sleep loss is minimized and a circadian phase shift occurs, adaptation of performance can occur during several consecutive night shifts.

Daytime cardiac autonomic activity during one week of continuous night shift.

Shift workers encounter an increased risk of cardiovascular disease compared to their day working counterparts. To explore this phenomenon, the effects of one week of simulated night shift on cardiac sympathetic (SNS) and parasympathetic (PNS) activity were assessed. Ten (5m; 5f) healthy subjects aged 18-29 years attended an adaptation and baseline night before commencing one week of night shift (2300-0700 h). Sleep was recorded using a standard polysomnogram and circadian phase was tracked using salivary melatonin data. During sleep, heart rate (HR), cardiac PNS activity (RMSSD) and cardiac SNS activity (pre-ejection period) were recorded. Night shift did not influence seep quality, but reduced sleep duration by a mean of 52 +/- 29 min. One week of night shift evoked a small chronic sleep debt of 5 h 14 +/- 56 min and a cumulative circadian phase delay of 5 h +/- 14 min. Night shift had no significant effect on mean HR, but mean cardiac SNS activity during sleep was consistently higher and mean cardiac PNS activity during sleep declined gradually across the week. These results suggest that shiftwork has direct and unfavourable effects on cardiac autonomic activity and that this might be one mechanism via which shiftwork increases the risk of cardiovascular disease. It is postulated that sleep loss could be one mediator of the association between shiftwork and cardiovascular health.

A week of simulated night work delays salivary melatonin onset.

In most studies, the magnitude and rate of adaptation to various night work schedules is assessed using core body temperature as the marker of circadian phase. The aim of the current study was to assess adaptation to a simulated night work schedule using salivary dim light melatonin onset (DLMO) as an alternative circadian phase marker. It was hypothesised that the night work schedule would result in a phase delay, manifest in relatively later DLMO, but that this delay would be somewhat inhibited by exposure to natural light. Participants worked seven consecutive simulated 8-hour night shifts (23:00-07:00 h). By night 7, there was a mean cumulative phase delay of 5.5 hours, equivalent to an average delay of 0.8 hours per day. This indicates that partial circadian adaptation occurred in response to the simulated night work schedule. The radioimmunoassay used in the current study provides a sensitive assessment of melatonin concentration in saliva that can be used to determine DLMO, and thus provides an alternative phase marker to core body temperature, at least in laboratory studies.

Regional distribution of potassium currents in the rabbit pulmonary arterial circulation.

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.

Similarity and inhibition in long-term memory: evidence for a two-factor theory.

Recalling a past experience often requires the suppression of related memories that compete with the retrieval target, causing memory impairment known as retrieval-induced forgetting. Two experiments examined how retrieval-induced forgetting varies with the similarity of the competitor and the target item (target-competitor similarity) and with the similarity between the competitors themselves (competitor-competitor similarity). According to the pattern-suppression model (M. C. Anderson & B. A. Spellman, 1995), high target-competitor similarity should reduce impairment, whereas high competitor-competitor similarity should increase it. Both predictions were supported: Encoding target-competitor similarities not only eliminated retrieval-induced forgetting but also reversed it, whereas encoding competitor-competitor similarities increased impairment. The differing effects of target-competitor and competitor-competitor similarity may resolve conflicting results concerning the effects of similarity on inhibition.

Posttreatment changes after successful correction of Class II malocclusions with the twin block appliance.

This investigation is a continuation of a previously published study assessing the treatment effects of the Twin Block appliance. All active treatment was carried out during the mixed dentition stage (mean starting age, 9 years 1 month) with final follow-up for the treatment group occurring in the permanent dentition (mean age, 13 years 1 month). Of the original group consisting of 28 consecutively treated severe skeletal Class II patients, 26 were available for follow-up. A comparison group of 28 untreated Class II subjects matched for age, sex, and vertical facial type was obtained from the Burlington Growth Centre according to the original study design. Of these 28 control subjects, 24 had 4-year follow-up cephalometric films available. The mean age of the controls was 12 years 11 months at the time of follow-up. During the active treatment phase, the Twin Block group experienced an average increase in mandibular unit length of 6.5 mm over a mean of 14 months (annualized rate of change of 5.6 mm per year). In comparison, the control group experienced a 2.3 mm increase in mandibular unit length during the 13-month observation period (annualized rate of 2.1 mm per year). In the posttreatment phase, the change in mandibular unit length for the Twin Block group was 6.0 mm over a 36-month period (annualized rate of change of 2.0 mm per year). The control group experienced an average increase in mandibular unit length of 6.7 mm over the posttreatment assessment period that was 34 months in duration (annualized rate of change of 2.4 mm per year). Although there was a slight reduction in mandibular growth rate after treatment, much of the significant increase in mandibular length achieved during the active phase of treatment with the Twin Block appliance was still present 3 years later when the subjects had matured into the permanent dentition stage.

Prevalence of SIDS risk factors: before and after the "Back to Sleep" campaign in North Dakota Caucasian and American Indian infants.

The objective of this study was to compare rates of infant sleeping position and other risk factors for sudden infant death syndrome from 1991 before the "Back to Sleep" campaign to rates in 1998 after the campaign. We used a cross-sectional risk factor prevalence study of risk factors for the years 1991 and 1998. In North Dakota the prevalence rates of prone sleeping declined 72% for American Indian infants and 62% for Caucasian infants. We were unable to identify a corresponding decline in SIDS in North Dakota for this time period. The relationship between sleeping position and SIDS may be more complex in rural and frontier settings and in American Indian populations than in urban and majority populations. The generalizability of this study is limited by the rural setting and small sample size. Longer term surveillance and additional reports from sites with pre "Back to Sleep" data as a baseline for both SIDS rates and sleeping position will be important to clarify the rate of prone sleeping position and SIDS.

A prevalence methodology for mental illness and developmental disorders in rural and frontier settings.

A prevalence study methodology developed for use in rural and frontier settings is described. The general method was developed over a 15 year period and has been successfully adapted and used in studies of 14 different childhood onset developmental disorders. Subjects were the 168,000 school aged children from North Dakota who were first surveyed for cases of autism--pervasive developmental disorders in 1985 and 1986. The results of the prevalence study were compared with the results of a 12-year ongoing surveillance of the cohort. The 12-year ongoing surveillance identified one case missed by the original prevalence study. Thus the original prevalence study methodology identified 98% of the cases of autism-pervasive developmental disorder in the population. This methodology may also be useful for studies of other developmental disorders in rural and frontier settings.

Screening for fetal alcohol syndrome: is it feasible and necessary?

The potential to utilize screening strategies to improve the identification and outcome of persons with fetal alcohol syndrome (FAS) is reviewed. FAS is a condition where screening and surveillance activities would be appropriate. Development of FAS screening and surveillance programs is encouraged because the disorder is expensive. People with FAS have poor outcomes as adults with less than 10% living independently. Several useful tools and models are available. Screening would improve ascertainment and prevalence estimates. Early identification could improve access to services and long term outcome, secondary disabilities and, by extension, excess disability in affected children could be decreased. Lastly, mothers who are at the highest risk to have additional children with FAS could be identified and offered treatment. While both screening and surveillance activities are discussed, the principle focus of this article is a review of the screening process. Two screening tools and several screening methodologies for FAS are available. Since no test will be appropriate in all settings, screening tests need to be selected depending on the setting and population of interest. Screening for FAS should be conducted in a variety of settings and in populations of both high and moderate risk. The results would also provide important data to influence public policy development and resource allocation. Appropriate evaluation of the efficacy, efficiency and effectiveness of FAS screening tools and methodologies would be important before utilization in screening programs.

Oxygen-sensing potassium currents in pulmonary artery.

The pulmonary vasculature is sensitive to the relative components of the respiratory gases and will vasoconstrict in response to decreased oxygen (O2) levels. This hypoxic pulmonary vasoconstriction (HPV) controls pulmonary blood flow in the fetus and serves to maximize ventilation perfusion matching in the adult lung. The exact mechanism of HPV is not fully understood but it appears to involve direct effects on both the endothelium and smooth muscle cells within the vessel wall. There is growing evidence to suggest that hypoxia mediates vasoconstriction, at least in part through the inhibition of outward potassium (K+) current in smooth muscle. A number of K+ currents present in the pulmonary vasculature have been shown to be sensitive to O2, with hypoxia acting to inhibit these currents in the majority of cases. Differences in the expression of these O2-sensitive K+ channels may explain regional and generic variations observed in the HPV response. The mechanism by which these K+ channels sense changes in O2 levels may involve changes in the cellular redox state, oxidative phosphorylation or a direct effect on the channel protein itself.

NOS inhibition potentiates norepinephrine but not sympathetic nerve-mediated co-transmission in resistance arteries.

OBJECTIVE: The in vitro interaction between sympathetic nerves and basal nitric oxide release was studied in a resistance artery, since these interact powerfully in large vessels. METHODS: The pharmacological interaction between L-NAME and vasoconstriction to field stimulation of sympathetic nerves or exogenous norepinephrine was studied in rabbit cutaneous resistance arteries in wire myographs. RESULTS: Relaxation of norepinephrine-induced tone by acetylcholine, but not sodium nitroprusside, was blocked by N omega-nitro-L-arginine methyl ester (L-NAME: 100 microM), indicating that the agonist-induced release of nitric oxide could oppose the vasoconstrictor effect of norepinephrine and confirming that L-NAME had no effect on endothelium-independent vasodilatation. L-NAME increased norepinephrine potency indicating basal NO release. With short bursts of electrical field stimulation purinergic transmission was dominant at low frequencies and adrenergic at high frequencies. L-NAME had no effect on nerve-mediated responses, even after blocking the purinergic component with alpha,beta-methylene ATP (3 microM), suggesting that the influence of spontaneously released nitric oxide does not extend to the vascular smooth muscle cells under adrenergic nervous control. CONCLUSION(S): This resistance artery exhibits a highly effective nitric oxide-mediated vasodilatation to acetylcholine. It has basal release of nitric oxide which antagonises exogenous norepinephrine. However, basal nitric oxide did not influence adrenergic nerve transmission, which contrasts with previous studies of larger arteries and veins. We speculate that in small resistance arteries there may be a spatial limitation to the zones of vascular smooth muscle influenced by the adrenergic nerves and by basal nitric oxide from the endothelium, respectively. The role of endogenous nitric oxide in modulating vascular tone may thus be less in resistance arteries than in conducting arteries or capacitance vessels and purinergic transmission appears to be particularly resistant.

Treatment effects of the twin block appliance: a cephalometric study.

A clinical study was undertaken to investigate the treatment effects of a modified Twin Block appliance. Pretreatment and posttreatment cephalometric records of 28 consecutively treated patients with Class II malocclusions were evaluated and compared with an age- and sex-matched sample of untreated Class II control subjects. The treatment group was considered to have severe skeletal Class II malocclusions and was treated using only the Twin Block appliance. Results indicated that mandibular growth in the treatment group was on average 4.2 mm greater than in the control group over the 14-month treatment period. In addition, some dentoalveolar effects in both arches contributed to the overjet correction. No statistically significant increase in the SN-mandibular plane angle occurred during treatment and, in general, the magnitude and direction of the skeletal changes were found to be quite favorable.

Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat.

1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of some antagonists suggests the presence of an inhibitory ET(A)-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activation of ET(A) receptors. SB 209670 is unique in its potency against responses to ET-1 in both control and chronically hypoxic rats, as well as human, isolated pulmonary resistance arteries.