Sodium transport by isolated bullfrog small intestine. Effect of prostaglandin E1.

Addition of 446 micron prostaglandin E1 (PGE1) to the serosal medium of isolated short-circuited bullfrog small intestine elicited small increases transmural potential difference and short-circuit current while addition of PGE1 to the mucosal medium caused no change in the electrical parameters. Addition of 100 micron indomethacin to the mucosal medium inhibited both potential difference and short-circuit current with a resultant increase in steady-state tissue resistance. In the presence of mucosal 100 micron indomethacin, serosal 60 micron PGE1 markedly stimulated transmural potential difference and short-circuit current with a resultant decrease in steady-state tissue resistance. Serosal arachidonic acid (330 micron) stimulated transmural potential difference and short-circuit current and this effect was abolished by the addition of 100 micron indomethacin to the mucosal medium. Serosal 60 micron PGE1 only stimulated the M (mucosa) leads to S (serosa) unidirectional flux of sodium. These results strongly suggest that the PGE1 action is mediated either via a series of metabolic reactions which possibly increase the permeability of the mucosal membrane to sodium or via direct stimulation of rheogenic sodium pump activity.

Concentration-activity profile of the modulation of cyclooxygenase product formation by reduced glutathione in microsomal fractions from the goat lung.

Age-related changes in pulmonary formation of arachidonic acid (AA) metabolites are thought to play an important role in regulating cardiopulmonary function. This study addresses the potential role of reduced glutathione (GSH) in modulating cyclooxygenase product formation in the developing lung. Prostaglandin H2 (PGH2) metabolism was studied in microsomal fractions isolated from the lungs of unventilated fetal, neonatal and adult goats. GSH-dependent PGH2 to PGE2 isomerase activity in microsomal fractions from the perinatal (fetal and neonatal) goat lung was not saturable with respect to GSH and can respond to changes in GSH concentration over the range of 0.01 to 30 mM, which encompasses the full range the intracellular GSH levels reported in the literature. However, in fractions from the adult, a lower rate of PGE2 formation is observed at higher GSH concentrations. In addition, the tissue levels of GSH exhibited developmental stage-related differences with fetal being higher than neonatal or adult. The present observations may have physiologic relevance, in that decreases in pulmonary GSH levels after birth may contribute to decreases in plasma PGE2 levels by decreasing pulmonary PGE2 synthesis, thereby contributing to closure of the ductus arteriosus; conversely, increased GSH levels associated with hyperoxia may contribute to persistence of ductal patency. Formation of 6-keto-PGF1 alpha and of TXB2 (the stable metabolites of prostacyclin and TXA2) was decreased when PGE2 formation was increased by GSH activation of PGE2 isomerase in fractions isolated from all three developmental stages. A similar pattern of product formation was observed when AA was employed as substrate. These data suggest the possibility that changes in GSH concentration may modulate eicosanoid formation in cells that contain GSH-dependent PGE2 isomerase, as well as either or both prostacyclin or thromboxane synthase(s).

Nitric oxide administration using constant-flow ventilation.

Nitric oxide (NO) gas is known as both a vasodilator and a toxin. It can react with oxygen to form compounds more toxic than itself, such as nitrogen dioxide (NO2). The reactions are time dependent; thus, infusing NO into breathing circuits as close to ventilated subjects as possible may help minimize toxic byproduct exposure. Unfortunately, flow rates commonly used with mechanical ventilation favor laminar gas flow (streaming) within the breathing circuits. Streaming could delay mixing of NO with other inhaled gases. This mixing delay may interfere with accurate monitoring and/or delivery of NO. We tested the hypothesis that streaming of NO infused by constant flow into the inspiratory limb of a constant-flow mechanical ventilation system can lead to NO concentration delivery estimate errors. We then compared the NO2 concentrations at the ventilator Y-piece with three different NO mixing methods: blending the gases before they reach the breathing circuit inspiratory limb, infusing NO directly into the breathing circuit inspiratory limb far enough from the Y-piece to ensure thorough mixing, and infusing NO directly into the breathing circuit inspiratory limb immediately before the gases reach an in-line mixing device placed close to the Y-piece. Our results indicate that streaming can lead to NO concentration delivery estimate errors and that these errors can be characterized by measuring NO concentration variations across the inspiratory tubing's luminal diameter. NO2 concentration measured at the ventilator Y-piece were dependent on NO concentrations (p < 0.0001), NO delivery methods (p < 0.0001), and interactions between NO concentrations and NO delivery methods (p < 0.0001). We conclude that gas streaming and toxic byproduct exposure should be considered together when choosing an NO delivery method.

Thromboxane synthase inhibition and perinatal pulmonary response to arachidonic acid.

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Amiloride inhibits arginine vasopressin-induced decrease in fetal lung liquid secretion.

The effects of arginine vasopressin (AVP) and amiloride were studied in 16 unanesthetized fetal sheep (129-135 days of age) with indwelling catheters. Secretion was measured by an impermeant tracer technique. Control fetuses showed no change in lung liquid secretion over a 5-h period with an average secretion rate of 3.6 +/- 0.31 ml.kg-1.h-1. Infusion of AVP (23.4 +/- 2.23 mU.kg-1.min-1) in seven fetuses (134-140 days of age) produced significant decreases (from control) in the secretion rate over a 5-h period: the secretion rate decreased by 68% in the last hour. Amiloride placed in the lung liquid during infusion of AVP, but after AVP effects had taken place, reversed the AVP-induced decrease in lung liquid secretion. AVP in conjunction with other hormones that are elevated during the stress of birth (epinephrine and cortisol) may be important in the removal of lung fluid at birth.

Endothelin-1-induced pulmonary arterial dilation is reduced by N omega-nitro-L-arginine in fetal lambs.

Endothelin-1 (ET-1) is a pulmonary vasodilator in the unventilated fetal lamb. The site and mechanism of this vasodilator response were investigated in isolated blood-perfused lungs from nine fetal lambs delivered at 127-140 days gestation. The vascular occlusion technique was used to partition the total pulmonary pressure gradient into pressure gradients across large and small arteries (delta PLA and delta PSA, respectively) and veins (delta PV). Injection of ET-1 (74 ng/kg) into the pulmonary artery significantly decreased delta PLA from 12.4 +/- 2.1 to 5.2 +/- 1.1 mmHg and delta PSA from 49.2 +/- 2.7 to 31.3 +/- 4.9 mmHg. The pressure measured by double occlusion, an estimate of pulmonary capillary pressure, was not altered by ET-1 (15.5 +/- 1.0 vs. 14.8 +/- 1.0 mmHg), indicating that ET-1 had no effect on pulmonary veins. Addition of N omega-nitro-L-arginine (estimated perfusate concentration 2-6 mM), an analogue of L-arginine that inhibits the production of endothelium-derived relaxing factor (EDRF), significantly attenuated the dilator responses to acetylcholine (10 micrograms) and ET-1 (74 ng/kg) by 35 and 56%, respectively. These results in unventilated fetal lungs indicate that 1) ET-1 dilates both large and small pulmonary arteries with no effect on pulmonary veins, and 2) this effect is mediated in part through the action of the EDRF pathway.

Estimation of lung liquid production in fetal sheep with blue dye dextran and radioiodinated serum albumin.

Lung liquid production and reabsorption rates and lung volumes were measured in 99 fetal sheep (119-148 days of gestation) by indicator-dilution methods with the simultaneous use of blue dye dextran (BDD) and radioiodinated serum albumin (RISA). There were no significant differences between rates of lung liquid production or reabsorption by the two methods (n = 71 pairs; paired t-test; Wilcoxon test; ANOVA); this was equally true for rates in milliliters per hour or milliliters per kilogram body weight per hour and was independent of age. Volumes measured by both methods showed a close linear relationship (r = 0.97; for slope P < 0.0001; n = 99), whether expressed as milliliters or milliliters per kilogram body weight. Either method could give the higher volume. Values differed by only approximately 4%, independent of age or parameter (ml or ml/kg body wt; volumes regressed to original volume, or as measured in untreated control hours). However, this small difference was significant by paired t-test or Wilcoxon test when all data were combined irrespective of age; it was not significant after allowance for gestational age (two-way ANOVA). Both indicators showed the same increase in lung volume toward birth and the same fall when related to body weight (slopes significant P = 0.0003-0.0004; r = 0.93). Two-way ANOVA showed that the declines were significant (P = 0.003). The data suggest that 1) there was no significant difference in production or reabsorption rates measured by BDD or RISA, 2) differences in volumes measured by the two indicators were only significant if gestational age was ignored and were too small to have physiological importance, and 3) although BDD and RISA each may have methodological weaknesses, for purposes of measuring lung liquid volumes both are sufficiently accurate and reproducible to obtain meaningful physiological results.

Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ.

Pulmonary vascular responses to endothelin (ET-1), a peptide derived from endothelial cells in culture, were investigated in the ovine fetus delivered by cesarean section from chloralose-anesthetized ewes with intact umbilical circulation. Circulation to the lower left lobe of the fetal lung was isolated in situ and perfused at constant flow with blood withdrawn from the inferior vena cava. Injection of graded doses of ET-1 into the left pulmonary artery decreased pulmonary arterial perfusion pressure in a dose-related manner. At doses of 100, 300, and 1,000 ng, pulmonary vascular resistance per kilogram body weight (PVR/kg) was decreased 30, 40, and 42%, respectively. However, when fetuses were ventilated with 100% oxygen, 100- and 300-ng doses of ET-1 decreased PVR/kg by 5 and 9%, respectively. In contrast, injection of 1,000 ng of ET-1 resulted in a reversal of the response, and PVR/kg was increased by 70%. Ventilation of the right lung alone resulted in a similar reversal of the vasodilator response to 1,000 ng of ET-1, and a 138% increase in PVR/kg was recorded. These studies demonstrate for the first time that ET-1 has vasodilator activity in the normally high-tone ovine fetal pulmonary circulation. In addition, these results show that ET-1 has vasoconstrictor activity in the newly ventilated low-tone pulmonary vasculature. The present data indicate the pulmonary vascular responses to ET-1 are tone dependent in the ovine fetal pulmonary circulation.

Do inhibitors of lipoxygenase and cyclooxygenase block neonatal hypoxic pulmonary vasoconstriction?

Lipoxygenase products have been suggested as mediators of the hypoxic pulmonary pressor response in newborn animals. Data supporting this suggestion are equivocal, since lipoxygenase and leukotriene receptor antagonists that have been used may produce vasodilation because of phosphodiesterase inhibition. We used a leukotriene receptor antagonist L 649923, which appears not to have smooth muscle relaxant activity. L 649923 blocks pressor responses to leukotriene D4 (LTD4) without diminishing the pressor response to hypoxia. Also, BW 755C did not block the pressor response to hypoxia in newborn sheep and goats, whereas the pressor response to LTD4 (75 ng/kg) was depressed significantly. In newborn sheep there was an augmented response to hypoxia with BW 755C, which is consistent with cyclooxygenase inhibition. Finally, the thromboxane receptor antagonist SQ 29548 was investigated in both species. With this agent the pressor response to LTD4 in contrast to that of hypoxia was completely inhibited. We conclude that thromboxanes are involved in the pressor response to LTD4 in newborn lambs and goats. These data do not support the view that leukotrienes are involved in the ovine or caprine neonatal pulmonary pressor response to hypoxia.

Leukotrienes and prostaglandins in fetal lung liquid.

Several recent studies have suggested that peptidoleukotrienes are involved in or responsible for the pulmonary pressor response to hypoxia as well as the normally high pulmonary vascular resistance of fetal lambs. The present studies were carried out to test these hypotheses. Fetal lambs were prepared with indwelling vascular catheters and tracheal catheters for access to lung liquid. We measured lung liquid levels of leukotrienes C4 (LTC4) and D4 (LTD4) in control unanesthetized fetal lambs with blood gases and pH in the normal range. In the control series, LTC4 and LTD4 were either not detectable or their levels were close to the limit of resolution (LTC4, less than 80 pg/ml; LTD4, less than 50 pg/ml) of the techniques utilized. Leukotriene E4 was measured in a separate study by using pooled samples, and it was also found to be below the detection limit of that assay (10 pg/ml). In a second series of animals, a level of acute hypoxia was induced to decrease fetal arterial PO2 to 12 Torr for 20 min. After hypoxia, tracheal fluid levels of leukotrienes were again below detection limits of the assays used (LTC4, less than 80 pg/ml; LTD4, less than 142 pg/ml). In another study, methodology was altered to lower the detection limits of leukotrienes in lung fluid and to allow the measurement of total peptidoleukotriene concentrations. In this study, even when hypoxia was extended for up to 1 h, leukotriene levels were consistently below the limit of detection of the assay (less than 20 pg/ml for the sum of all leukotrienes).(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of lung liquid secretion in immature fetal sheep: hormonal interaction.

The present studies were designed to test the hypothesis that arginine vasopressin (AVP) can interact with hydrocortisone and 3,5,3'-triiodothyronine (T3) to induce maturation of lung liquid reabsorptive processes in fetal sheep < 130 days gestation. Lung liquid production rates were measured in chronically catheterized thyroidectomized fetal sheep during eight different experimental treatments. Each experiment consisted of a 2-h control period followed by a 5-h treatment period. Net secretion or reabsorption of lung liquid was measured by using impermeant marker dilution techniques. AVP alone (50 mU/kg bolus plus 5.0 mU.kg-1.min-1 i.v. infusion) does not alter lung liquid secretion in fetal sheep 125 +/- 0.72 (SE) days gestation. In contrast, AVP (same dose as above) with T3 (30 micrograms) and hydrocortisone (6.94 mg/min) depressed lung liquid secretion and caused reabsorption of fluid. T3 alone, T3 and hydrocortisone, T3 and AVP, hydrocortisone alone, hydrocortisone and AVP, and saline did not result in net lung liquid reabsorption over a 5-h treatment period. These investigations demonstrate that AVP, T3, and hydrocortisone interact to cause lung liquid reabsorption in immature fetal lungs.

Carboxy- and oxyhemoglobin in pregnant ewe and fetus after inhalation of marijuana, marijuana placebo and tobacco cigarette smoke.

We measured carboxyhemoglobin (HbCO) and oxyhemoglobin (HbO2) percent saturations and blood gases in four near-term pregnant ewes and their fetuses, during and for 6 hours after 9-12 minutes of smoke inhalation from one high-potency marijuana cigarette (M), a marijuana placebo cigarette (P), and a reference tobacco cigarette (T). Maternal HbCO reached maximum levels at or soon after the exposure (M, 2.8%; P, 3.5%; T, 6.3% above baseline) and fell to baseline values by 6 hours. Fetal HbCO rose slowly reaching a plateau at 3 hours (M, 0.7%; P, 1.1%; T, 2.0% above baseline) which was maintained for at least three additional hours. Reductions in maternal and fetal HbO2 after exposure to marijuana placebo and reference tobacco cigarettes reflected these rises in HbCO. After exposure to marijuana cigarettes, however, fetal HbO2 dropped precipitously by 17% of baseline and showed a prolonged rate of return to presmoking HbO2 levels. Although P exposure caused a greater change in HbCO in the fetus than did M, it had a less-profound effect on fetal oxygenation.

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations.

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Calculating vascular resistances.

Vascular resistance calculations often affect decisions regarding therapeutic options encountered by physicians and their patients. However, many of the terms, units, and methods used when calculating vascular resistances are ambiguous. This report attempts to clarify some of these ambiguities and suggests methods for predicting normal vascular resistances.

In utero lung growth of fetal sheep with diaphragmatic hernia and tracheal stenosis.

The observation that tracheal ligation produces pulmonary hyperplasia even in animals with surgically induced diaphragmatic hernia (DH) has led to rapid application of the technique to human fetuses with DH. The aim of this study was to determine how rapidly fetal lung volume increases after creation of a high-grade tracheal stenosis in fetal sheep with surgically created DH. Twenty-three fetal sheep were prepared with a left thoracotomy at 90 days' gestational. Six had creation of a DH with tracheal stenosis (DHTS) over an 18-gauge cannula, which was then removed. Ten had DH alone, and seven control animals (CT) had a thoracotomy without DH. Thirty days later, vascular and tracheal loop catheters were inserted in all animals and tunneled out the ewes' flank. Between 125 and 140 days' gestation, lung volumes and lung liquid production were measured in awake, unanesthetized animals using a standard double-marker dilution technique. Average lung volumes (in milliliters) were 150.9 +/- 13.9 for CT, 29.3 +/- 4.4 for DH, and 414.5 +/- 88 for DHTS (p < 0.01). Mean lung liquid production varied from 6.00 +/- 2.23 mL/h in DH animals before 130 days to 16.69 +/- 8.29 mL/h in DHTS animals after 135 days' gestation. DH animals had lower lung liquid production (8.51 +/- 1.4 mL/h) than CT (12.4 +/- 0.8 mL/h) or DHTS animals (12.4 +/- 2.2 mL/h)(P < .01). The rate constant gamma (h-1) for lung liquid production was significantly higher in DH animals than in either CT or DHTS animals (P < .01). Tracheal stenosis in this model causes rapid lung growth before 130 days' gestation. The authors speculate that short periods of incomplete stenosis might reverse the pulmonary hypoplasia associated with DH. To achieve this goal, the timing and duration of treatment and the optimal degree of stenosis must be defined.

Young injectors: a comparative analysis of risk behaviour.

This study compares the injecting and sexual risk-behaviour of young injectors, with injectors over the age of 25. All respondents presented for the first time at the Merchants' Quay Health Promotion Unit between May 1st 1997 and February 28th 1998. Analysis revealed that the young injectors were significantly more likely to report recently borrowing and lending used injecting equipment, and injecting paraphernalia. Regarding sexual risk behaviour, younger respondents were proportionately more likely to report being sexually active, having multiple sexual partners, and having a regular partner who is an injecting drug user. However, they were significantly more likely than older clients to report condom use. The suggestion is that the harm minimisation message, which reached its zenith in the early 1990s, has now been somewhat de-emphasised in both policy and practice. Consequently, it is not reaching the young injectors who have recently initiated intravenous drug use. Additional strategies are needed this group of drug users, in order to promote positive behaviour changes.

Syringe exchanges: a public health response to problem drug use.

This paper presents the findings of the first ever Irish follow-up study to establish the effectiveness of syringe exchanges as a harm reduction strategy in the context of public health. The study was conducted in collaboration with 370 injecting drug users who attended the Merchant's Quay Project's Health Promotion Unit between May 1st 1997 and October 31st 1998. Data was collected from respondents by means of a structured interview at first visit and three-months after initial contact. Evidence from the study demonstrates that syringe exchanges play an important contributing role in significantly reducing the numbers reporting both the use of heroin as a primary drug (n=41; McNemar x2=10.1;p<0.01), and its frequency of use (n=70; McNemar x2=4.13;p<0.05) at follow-up. Moreover, there were significant reductions in the reported borrowing (n=60; McNemar x2=10.1;p<0.01) and lending (n=42: McNemar x2=7.9;p<0.01) of used injecting equipment. There was however no significant change in the reported sharing of injecting paraphernalia or in levels of reported condom use. The results of this study illustrate that low threshold services such as the Health Promotion Unit have the ability to attract injecting drug users not in contact with other drug treatment services. Furthermore, this type of service has been shown to be effective in maintaining contact with injecting drug users and promoting safer drug use among attendees. Even though the distribution of sterile injecting equipment reduces the situational sharing, this is hampered by the limited availability of sterile injecting equipment in Dublin. There is a need to continue to develop strategies to prevent HIV and hepatitis C transmission. One such approach would be to develop effective outreach as a means of reaching greater numbers of drug users earlier in their injecting histories. Other areas for future HIV and HCV prevention include discouraging the transition from smoking to injecting, and among those who inject, encouraging further reductions in sharing, sustaining risk reduction over time, and encouraging the adoption of safer sexual behaviour.

Psychiatric predictors of surgery non-completion following suitability assessment for bariatric surgery.

BACKGROUND: Bariatric surgery is recognized as a treatment for severe obesity; however, little is known about factors influencing patient surgery non-completion. This study explored the relationship between psychiatric factors and patient non-completion during the pre-bariatric surgery suitability assessment. METHODS: A total of 367 individuals underwent a structured psychiatric interview and were classified as either surgery completers (SC) or surgery non-completers (SNC) if they attended at least one pre-surgery assessment appointment but did not receive surgery. RESULTS: The results showed that in comparison to the SC group, the SNC group had significantly higher rates of overall past Axis I psychiatric disorders (58.1 vs. 46.6 %, p = 0.035), past anxiety disorders (17.4 vs. 9.4 %, p = 0.03), and past substance use disorders (8.7 vs. 3.7 %, p = 0.03). For specific past psychiatric disorders, the SNC group exhibited significantly higher rates of a past post-traumatic stress disorder (PTSD) (5 vs. 1 %, p = 0.029) and past substance dependence disorder (7 vs. 1 %, p = 0.005). Although overall current psychiatric disorders did not significantly differ between groups, the SNC group had significantly higher rates of current PTSD (2 vs. 0 %, p = 0.049) and current generalized anxiety disorder (4 vs. 0 %, p = 0.005). CONCLUSIONS: A past history of an anxiety or substance use disorder may play a role in patients not completing the assessment component of the bariatric surgery process. Additional psychosocial support, such as cognitive behavioral therapy or targeted psychoeducation, may help improve patient completion of the pre-surgery assessment phase.