Phorbol myristate acetate-induced injury of isolated perfused rat lungs: neutrophil dependence

The effect of leukocyte depletion on acute lung injury produced by intravenous or intratracheal phorbol myristate acetate (PMA) administration was studied in isolated perfused rat lungs. Vascular endothelial permeability was assessed by use of the capillary filtration coefficient (Kf,c). A predicted pulmonary capillary pressure (Ppc,p) was calculated from measurements of postcapillary resistances. These parameters were measured before and 90 min after the administration of PMA, either intratracheally or intravascularly. When blood elements were present both intratracheal and intravascular PMA caused an increased Kf,c [0.27 +/- 0.02 vs. 0.99 +/- 0.22 and 0.25 +/- 0.05 vs. 0.64 +/- 0.15 (SE) ml.min-1.cmH2O-1.100 g-1, respectively; P less than 0.05] and an increased Ppc,p (8.3 +/- 0.4 vs. 74.7 +/- 18.3 and 8.7 +/- 0.8 vs. 74.2 +/- 25.1 cmH2O, respectively; P less than 0.05). Removal of circulating leukocytes abolished the increased Kf,c when PMA was given intratracheally (0.35 +/- 0.06 vs. 0.23 +/- 0.07 ml.min-1.cmH2O-1.100 g-1) or intravascularly (0.39 +/- 0.07 vs. 0.33 +/- 0.07 ml.min-1.cmH2O-1.100 g-1). In the absence of neutrophils, Ppc,p slightly increased with intratracheal PMA, from 6.9 +/- 0.5 to 10.5 +/- 1.1 cmH2O (P less than 0.05), but was unchanged at 90 min with intravascular PMA. Depletion of circulating neutrophils with an antineutrophil serum failed to block the Kf,c change with intratracheal PMA (from 0.24 +/- 0.03 to 0.42 +/- 0.09 ml.min-1.cmH2O-1.100 g-1; P less than 0.05). Ppc,p also increased from 6.9 +/- 0.6 to 19.8 +/- 6.7 cmH2O (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethane production rate in vivo is reduced with dietary restriction

Dietary restriction without malnutrition prolongs life and has a beneficial effect on age-related diseases and metabolic derangements. To test the effect of food restriction on ethane production rate, ethane exhalation was measured in rats with partial food restriction. Ethane production rate in room air in rats fed 60% of food consumed by ad libitum-fed animals for 2 wk was significantly reduced (3.50 +/- 0.25 vs. 5.21 +/- 0.34 pmol.min-1.100 g body wt-1, P less than 0.01). In 100% oxygen, ethane production in food-restricted rats was not different from that of ad libitum-fed rats (21.81 +/- 1.25 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Fifteen hours of fasting compared with ad libitum feeding reduced ethane production modestly in room air (4.37 +/- 0.45 vs. 5.21 +/- 0.34 pmol.min-1.100 g-1) and more significantly in 100% oxygen (12.37 +/- 0.78 vs. 19.57 +/- 1.89 pmol.min-1.100 g-1). Thus, in 100% oxygen, 15 h of fasting, compared with ad libitum feeding, resulted in an approximately 40% decrease in ethane production rate. It is concluded that short-term food restriction significantly reduces ethane exhalation rate in rats when measured in room air.     

Effect of increased Hb-O2 affinity on VO2max at constant O2 delivery in dog muscle in situ

We investigated the effect of increasing hemoglobin- (Hb) O2 affinity on muscle maximal O2 uptake (VO2max) while muscle blood flow, [Hb], HbO2 saturation, and thus O2 delivery (muscle blood flow X arterial O2 content) to the working muscle were kept unchanged from control. VO2max was measured in isolated in situ canine gastrocnemius working maximally (isometric tetanic contractions). The muscles were pump perfused, in alternating order, with either normal blood [O2 half-saturation pressure of hemoglobin (P50) = 32.1 +/- 0.5 (SE) Torr] or blood from dogs that had been fed sodium cyanate (150 mg.kg-1.day-1) for 3-4 wk (P50 = 23.2 +/- 0.9). In both conditions (n = 8) arterial PO2 was set at approximately 200 Torr to fully saturate arterial blood, which thereby produced the same arterial O2 contents, and muscle blood flow was set at 106 ml.100 g-1.min-1, so that O2 delivery in both conditions was the same. VO2max was 11.8 +/- 1.0 ml.min-1.100 g-1 when perfused with the normal blood (control) and was reduced by 17% to 9.8 +/- 0.7 ml.min-1.100 g-1 when perfused with the low-P50 blood (P less than 0.01). Mean muscle effluent venous PO2 was also significantly less (26 +/- 3 vs. 30 +/- 2 Torr; P less than 0.01) in the low-P50 condition, as was an estimate of the capillary driving pressure for O2 diffusion, the mean capillary PO2 (45 +/- 3 vs. 51 +/- 2 Torr). However, the estimated muscle O2 diffusing capacity was not different between conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal serine production in vivo: effects of dietary manipulation of serine status

Renal serine production in rats was quantitated by simultaneously measuring renal blood flow and the renal arteriovenous difference for this amino acid. The rate of synthesis was 0.24 +/- 0.02 mumol.min-1.100 g-1 in rats fed a diet containing 12% casein. This rate was not altered by the inclusion of an additional 1% serine in the diet for 7 days or by acute infusion of serine, although both protocols increased blood serine by 50%. When rats were fed a diet in which protein was entirely replaced by crystalline amino acids the rate of renal serine production was also 0.25 +/- 0.05 mumol.min-1.100g-1. Omission of serine or both serine and glycine from this diet did not alter the rate of renal serine synthesis. Renal serine production does not respond to the serine content of the diet.     

Effect of regular voluntary exercise on resting cardiovascular responses in SHR and WKY pregnant rats.

The purpose of this study was to assess the influence of regular voluntary exercise in pregnant normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats on 1) uteroplacental perfusion and mean arterial pressure in the resting conscious condition and 2) fetal number, fetal weight, and number of fetal resorptions. WKYs and SHRs were randomly assigned to standard cages [CWKY (n = 10); CSHR (n = 6)] or cages with activity wheels [EWKY (n = 7); ESHR (n = 8)]. EWKYs and ESHRs exercised for 12 wk, and then all rats were bred and experiments were conducted on gestational day 17. Resting blood flow (microspheres), heart rate (HR), and mean arterial pressure (Pa) were measured. No significant difference was found in Pa, HR, uterine blood flow (ESHRs 52 +/- 8 ml.min-1.100 g-1; CSHRs 28 +/- 6 ml.min-1.100 g-1), or maternal placental blood flow (ESHRs, 122 +/- 31 ml.min-1.100 g-1; CSHRs 78 +/- 21 ml.min-1.100 g-1) among the groups. Exercise altered the relationship between maternal placental and uterine blood flow and Pa in the SHR; SHRs with lower Pa maintained higher placental and uterine blood flow after training. Before gestation ESHRs ran on average more kilometers per week than EWKYs (43 +/- 3 vs. 34 +/- 4), but during gestation ESHRs averaged fewer kilometers per week than EWKYs (16 +/- 4 vs. 22 +/- 4). Succinate dehydrogenase activity was higher in the white vastus lateralis (1.02 +/- 0.2 mumol cytochrome c reduced.min-1.g wet wt-1) and vastus intermedius (3.1 +/- 0.5 mumol cytochrome c reduced.min-1.g wet wt-1) muscles of ESHRs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Costal vs. crural diaphragmatic blood flow during submaximal and near-maximal exercise in ponies

The present study was carried out 1) to compare blood flow in the costal and crural regions of the equine diaphragm during quiet breathing at rest and during graded exercise and 2) to determine the fraction of cardiac output needed to perfuse the diaphragm during near-maximal exercise. By the use of radionuclide-labeled 15-micron-diam microspheres injected into the left atrium, diaphragmatic and intercostal muscle blood flow was studied in 10 healthy ponies at rest and during three levels of exercise (moderate: 12 mph, heavy: 15 mph, and near-maximal: 19-20 mph) performed on a treadmill. At rest, in eucapnic ponies, costal (13 +/- 3 ml.min-1.100 g-1) and crural (13 +/- 2 ml.min-1.100 g-1) phrenic blood flows were similar, but the costal diaphragm received a much larger percentage of cardiac output (0.51 +/- 0.12% vs. 0.15 +/- 0.03% for crural diaphragm). Intercostal muscle perfusion at rest was significantly less than in either phrenic region. Graded exercise resulted in significant progressive increments in perfusion to these tissues. Although during exercise, crural diaphragmatic blood flow was not different from intercostal muscle blood flow, these values remained significantly less (P less than 0.01) than in the costal diaphragm. At moderate, heavy, and near-maximal exercise, costal diaphragmatic blood flow (123 +/- 12, 190 +/- 12, and 245 +/- 18 ml.min-1.100 g-1) was 143%, 162%, and 162%, respectively, of that for the crural diaphragm (86 +/- 10, 117 +/- 8, and 151 +/- 14 ml.min-1.100 g-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of arachidonate on permeability and resistance distribution in canine lungs

In this study, 14 canine lung lobes were isolated and perfused with autologous blood at constant pressure (CP) or constant flow (CF). Pulmonary capillary pressure (Pc) was measured via venous occlusion or simultaneous arterial and venous occlusions. Arterial and venous pressures and blood flow were measured concurrently so that total pulmonary vascular resistance (RT) as well as pre- (Ra) and post- (Rv) capillary resistances could be calculated. In both CP and CF perfused lobes, 5-min arachidonic acid (AA) infusions (0.085 +/- 0.005 to 2.80 +/- 0.16 mg X min-1 X 100 g lung-1) increased RT, Rv, and Pc (P less than 0.05 at the highest dose), while Ra was not significantly altered and Ra/Rv fell (P less than 0.05 at the highest AA dose). In five CP-perfused lobes, the effect of AA infusion on the pulmonary capillary filtration coefficient (Kf,C) was also determined. Neither low-dose AA (0.167 +/- 0.033 mg X min-1 X 100 g-1) nor high-dose AA (1.35 +/- 0.39 mg X min-1 X 100 g-1) altered Kf,C from control values (0.19 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1). The hemodynamic response to AA was attenuated by prior administration of indomethacin (n = 2). We conclude that AA infusion in blood-perfused canine lung lobes increased RT and Pc by increasing Rv and that microvascular permeability is unaltered by AA infusion.     

Separate effects of ischemia and reperfusion on vascular permeability in ventilated ferret lungs.

In systemic organs, ischemia-reperfusion injury is thought to occur during reperfusion, when oxygen is reintroduced to hypoxic ischemic tissue. In contrast, the ventilated lung may be more susceptible to injury during ischemia, before reperfusion, because oxygen tension will be high during ischemia and decrease with reperfusion. To evaluate this possibility, we compared the effects of hyperoxic ischemia alone and hyperoxic ischemia with normoxic reperfusion on vascular permeability in isolated ferret lungs. Permeability was estimated by measurement of filtration coefficient (Kf) and osmotic reflection coefficient for albumin (sigma alb), using methods that did not require reperfusion to make these measurements. Kf and sigma alb in control lungs (n = 5), which were ventilated with 14% O2-5% CO2 after minimal (15 +/- 1 min) ischemia, averaged 0.033 +/- 0.004 g.min-1.mmHg-1.100 g-1 and 0.69 +/- 0.07, respectively. These values did not differ from those reported in normal in vivo lungs of other species. The effects of short (54 +/- 9 min, n = 10) and long (180 min, n = 7) ischemia were evaluated in lungs ventilated with 95% O2-5% CO2. Kf and sigma alb did not change after short ischemia (Kf = 0.051 +/- 0.006 g.min-1.mmHg-1.100 g-1, sigma alb = 0.69 +/- 0.07) but increased significantly after long ischemia (Kf = 0.233 +/- 0.049 g.min-1 x mmHg-1 x 100 g-1, sigma alb = 0.36 +/- 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation

The systemic blood flow to the airways of the left lung was determined by the radioactive microsphere technique before and 17 h after smoke inhalation in six conscious sheep (smoke group) and six sheep insufflated with air alone (sham group). Smoke inhalation caused a sixfold increase in systemic blood flow to the lower trachea (baseline 10.6 +/- 1.7 vs. injury 60.9 +/- 16.1 ml.min-1.100 g-1) and an 11- to 14-fold increase to the intrapulmonary central airways (baseline range 9.5 +/- 1.9 to 13.5 +/- 3.7 ml.min-1.100 g-1 vs. injury 104.6 +/- 32.2 to 187.3 +/- 83.6 ml.min-1.100 g-1). There was a trend for this hyperemic response to be greater as airway diameter decreased from the trachea to 2-mm-diam central airways. In airways smaller than 2 mm, the hyperemic response appeared to diminish. The total systemic blood flow to whole lung is predominantly to small peripheral airways and showed no significant increase from its baseline level of 17.5 +/- 3.7 ml.min-1.100 g-1 in the lung homogenate. Occlusion of the bronchoesophageal artery decreased central airway blood flow 60-80% and peripheral airway blood flow 40-60% in both the sham and the smoke groups.     

Plasma glutathione turnover in the rat: effect of fasting and buthionine sulfoximine

Hepatic glutathione (GSH) plays an important role in the detoxification of reactive molecular intermediates. Because of evidence that the intrahepatic turnover of glutathione in the rat may be largely accounted for by efflux from hepatocytes into the general circulation, the quantitation of plasma GSH turnover in vivo could provide a noninvasive index of hepatic glutathione metabolism. We developed a method to estimate plasma glutathione turnover and clearance in the intact, anesthetized rat using a 30-min unprimed, continuous infusion of 35S-labelled GSH. A steady state of free plasma glutathione specific radioactivity was achieved within 10 min, as determined by high-pressure liquid chromatography with fluorometric detection after precolumn derivatization of the plasma samples with monobromobimane. The method was tested after two treatments known to alter hepatic GSH metabolism: 90 min after intraperitoneal injection of 4 mmol/kg buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, and after a 48-h fast. Liver glutathione concentration (mean +/- SEM) was 5.00 +/- 0.53 mumol/g wet weight in control rats. It decreased to 3.10 +/- 0.35 mumol/g wet weight after BSO injection and to 3.36 +/- 0.14 mumol/g wet weight after fasting (both p less than 0.05). Plasma glutathione turnover was 63.0 +/- 7.46 nmol.min-1.100 g-1 body weight in control rats, 35.0 +/- 2.92 nmol.min-1.g-1 body weight in BSO-treated rats, and 41.7 +/- 2.28 nmol.min-1.g-1 body weight after fasting (both p less than 0.05), thus reflecting the hepatic alterations. This approach might prove useful in the noninvasive assessment of liver glutathione status.     

Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung

This study evaluated the effect of ischemia-reperfusion (I-R) on pulmonary capillary permeability in isolated rabbit lungs and the roles of xanthine oxidase (XO), aldehyde oxidase (AO), and neutrophils (PMN) in producing this lung injury. Effects of XO and AO were studied by inactivation with a tungsten-enriched diet (0.7 g/kg) and inhibition of XO by allopurinol (100 microM) or AO by menadione (3.5 microM). PMN effects were studied by preventing endothelial adhesion with the monoclonal antibody IB4 (10 microM). Vascular permeability was evaluated by determining the capillary filtration coefficient (Kf,c) measured before and after I-R in all experimental conditions. Reperfusion after 2 h of ischemia significantly increased pulmonary capillary permeability (Kf,c changed from 0.096 +/- 0.014 to 0.213 +/- 0.025 ml.min-1. cmH2O-1.100 g-1), and this increase was blocked by the addition of catalase (50,000 U) at reperfusion (baseline Kf,c was 0.125 +/- 0.023 and 0.116 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). XO inactivation with the tungsten-supplemented diet and XO inhibition with allopurinol prevented the Kf,c increase observed after I-R (0.183 +/- 0.030 to 0.185 +/- 0.033 and 0.126 +/- 0.018 to 0.103 +/- 0.005 ml.min-1.cmH2O-1.100 g-1). Inhibition of AO had no effect on I-R injury (Kf,c 0.108 +/- 0.011 to 0.167 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). Preventing PMN adhesion resulted in significant attenuation of the change in Kf,c associated with I-R (0.112 +/- 0.032 to 0.090 +/- 0.065 ml.min-1.cmH2O-1.100 g-1). We conclude that XO and PMN adherence, but not AO, are involved in the increased capillary permeability associated with I-R.     

Glucose and lactate kinetics in the neonate.

To evaluate the ontogeny of neonatal glucose homeostasis, glucose production and lactate production have been measured in nine prematurely born appropriate for gestational age neonates [birth weight 1985 +/- 100 g, (SEM) gestational age 33.6 +/- 0.7 weeks] and five full term appropriate for gestational age neonates [birth weight 3254 +/- 111 g, gestational age 40.8 +/- 0.4 wks] and compared to six non pregnant, nondiabetic adults [weight of 57.7 +/- 2.2 kg, age 32 +/- 2 years]. Ra glucose (preterm) averaged 27.7 +/- 2.8 mumol.kg-1 min-1 (5.0 +/- 0.5 mg.kg-1 min-1) and Ra glucose (term) averaged 28.9 +/- 3.9 mumol.kg-1 min-1 (5.2 +/- 0.7 mg.kg-1 min-1); both were higher than the Ra glucose of the adult controls (16.1 +/- 2.8 mumol.kg-1 min-1 (2.9 +/- 0.5 mg.kg-1 min-1) (P less than 0.05 vs preterm and P less than 0.05 vs. term). Ra lactate (preterm) averaged 100 +/- 11.9 mumol.kg-1 min-1 (9.1 +/- 1.1 mg.kg-1 min-1) and Ra lactate (term) average 77.2 +/- 13.0 mumol.kg-1 min-1 (7.1 +/- 1.2 mg.kg-1 min-1); both were higher than the Ra lactate of the adult controls 35.9 +/- 6.5 mumol.kg-1 min-1 (3.3 +/- 0.6 mg.kg-1 min-1) (P less than 0.01 vs preterm and P less than 0.05 vs. term). The potential for gluconeogenesis from lactate was estimated by determining the ratio of [Ra Lactate/Ra Glucose]. The [Ra Lactate/Ra Glucose] (preterm) (187 +/- 12 (x10(-2)) was similar to that of the [Ra Lactate/Ra Glucose] (term) (136 +/- 16) (x10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of increased pulmonary vascular tone on gas exchange in canine oleic acid pulmonary edema

Pulmonary gas exchange was investigated before and after an increase in pulmonary vascular tone induced by administration of acetylsalicylic acid (ASA), indomethacin, or almitrine in 32 pentobarbital-anesthetized and ventilated (fraction of inspired O2 0.4) dogs with oleic acid lung injury. Pulmonary vascular tone was evaluated by five-point pulmonary arterial pressure (PAP)/cardiac index (Q) plots and intrapulmonary shunt was measured using a SF6 infusion. PAP/Q plots were rectilinear in all experimental conditions. In control dogs (n = 8), oleic acid (0.09 ml/kg iv) increased PAP over the range of Q studied (1-5 l.min-1.m-2). At the same Q, arterial PO2 fell from 186 +/- 11 to 65 +/- 8 (SE) Torr and intrapulmonary shunt rose from 5 +/- 1 to 50 +/- 6% 90 min after oleic acid injection. These changes remained stable during the generation of two consecutive PAP/Q plots. ASA (1 g iv, n = 8), indomethacin (2 mg/kg iv, n = 8), and almitrine (8 micrograms.kg-1.min-1 iv, n = 8) produced a further increase in PAP at each level of Q. ASA and indomethacin, respectively, increased arterial PO2 from 61 +/- 4 to 70 +/- 3 Torr (P less than 0.05) and from 70 +/- 6 to 86 +/- 6 Torr (P less than 0.05) and decreased intrapulmonary shunt from 61 +/- 5 to 44 +/- 4% (P less than 0.05) and from 44 +/- 5 to 29 +/- 4% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of maternal fasting on hepatic gluconeogenesis and glucose metabolism in fetal lambs.

In unstressed, normoglycaemic fetal lambs, the liver produces little glucose, and gluconeogenesis is insignificant. Indirect measurements have suggested that the fetus may produce glucose endogenously during hypoglycaemia induced by prolonged maternal starvation. In eight fetal lambs we directly measured total and radiolabelled substrate concentration differences across the liver to determine whether the fetal liver produces glucose after four days of fasting-induced hypoglycaemia. Simultaneously we measured umbilical glucose uptake and fetal glucose utilization. Glucose concentrations in ewes (1.78 +/- 0.44 mmol.-1) and fetuses (0.61 +/- 0.17 mmol.l-1) were decreased. Fetal glucose utilization rate (21.7 +/- 8.9 mumol.min-1.kg-1) was not significantly different from umbilical glucose uptake (17.2 +/- 8.9 mumol.min-1.kg-1). Hepatic glucose production (8.9 +/- 17.2 mumol.min-1.100 g-1) and gluconeogenesis (6.1 +/- 4.4 mumol.min-1.100 g-1) were present, but could account for only 13% and 8% of fetal glucose requirements, respectively. To determine whether glucose output by the fetal liver was limited by substrate availability, we infused lactate, acetate, and acetone into the umbilical veins of four fasted animals, increasing hepatic substrate delivery. Hepatic glucose output did not increase during infusion of gluconeogenic substrates, indicating that substrate availability did not limit gluconeogenesis. We conclude that the gluconeogenic pathway is intact in late-gestation fetal lambs and that the fetal liver is capable of gluconeogenesis. However, the primary change in fetal metabolism during maternal starvation is the reduction in fetal glucose utilization, obviating the need for substantial hepatic glucose production. The factors stimulating this modest increase in fetal hepatic glucose production remain to be elucidated.     

Effect of dihydroxyacetone and pyruvate on plasma glucose concentration and turnover in noninsulin-dependent diabetes mellitus

Consumption of dihydroxyacetone and pyruvate (DHP) increases muscle extraction of glucose in normal men. To test the hypothesis that these three-carbon compounds would improve glycemic control in diabetes, we evaluated the effect of DHP on plasma glucose concentration, turnover, recycling, and tolerance in 7 women with noninsulin-dependent diabetes. The subjects consumed a 1,500-calorie diet (55% carbohydrate, 30% fat, 15% protein), randomly containing 13% of the calories as DHP (1/1) or Polycose (placebo; PL), as a drink three times daily for 7 days. On the 8th day, primed continuous infusions of [6-3H]-glucose and [U-14C]-glucose were begun at 05.00 h, and at 09.00 h a 3-hour glucose tolerance test (75 g glucola) was performed. Two weeks later the subjects repeated the study with the other diet. The fasting plasma glucose level decreased by 14% with DHP (DHP = 8.0 +/- 0.9 mmol/l; PL = 9.3 +/- 1.0 mmol/l, p less than 0.05) which accounted for lower postoral glucose glycemia (DHP = 13.1 +/- 0.8 mmol/l, PL = 14.7 +/- 0.8 mmol/l, p less than 0.05). [6-3H]-glucose turnover (DHP = 1.50 +/- 0.19 mg.kg-1.min-1, PL = 1.77 +/- 0.21 mg.kg-1.min-1, p less than 0.05) and glucose recycling, the difference in [6-3H]-glucose and [U-14C]-glucose turnover rates, decreased with DHP (DHP = 0.25 +/- 0.07 mg.kg-1.min-1, PL = 0.54 +/- 0.10 mg.kg-1.min-1, p less than 0.05). Fasting and postoral glucose, plasma insulin, glucagon, and C peptide levels were unaffected by DHP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular reactivity and permeability to alveolar hypoxia in the dog

Hemodynamics and vascular permeability were studied during acute alveolar hypoxia in isolated canine lung lobes perfused at constant flow with autogenous blood. Hypoxia was induced in the presence (COI + Hypox, n = 6) or absence (Hypox, n = 6) of cyclooxygenase inhibition (COI) with indomethacin or meclofenamate. Hypoxic ventilation reduced blood PO2 from 143 to 25-29 Torr without a change in PCO2. During hypoxia a capillary filtration coefficient (Kf) was obtained gravimetrically as an index of vascular permeability to water. In COI + Hypox, pulmonary arterial pressure (Pa) increased from 11.5 +/- 0.7, post-COI normoxia, to a peak of 22.1 +/- 2.3 during hypoxia (P less than 0.01) without a change in capillary pressure (Pc). In contrast, hypoxia changed neither Pa nor Pc in Hypox relative to an untreated normoxic control group (Normox, n = 6, P greater than 0.05). Kfs (means +/- SE in ml.min-1.Torr-1.100 g-1) for Normox (0.070 +/- 0.014), Hypox (0.082 +/- 0.024), and COI + Hypox (0.057 +/- 0.017) did not differ from one another (P greater than 0.05). Although COI markedly enhanced the pressor response to acute alveolar hypoxia, hypoxia increased neither Pc nor vascular permeability regardless of COI.     

Hormonal interactions and renal function during mechanical ventilation and ANF infusion in humans

To investigate the influence of atrial natriuretic factor (ANF) on renal function during mechanical ventilation (MV), we examined the renal and hormonal responses to synthetic human ANF infusion in eight patients during MV with zero (ZEEP) or 10 cmH2O positive end-expiratory pressure (PEEP). Compared with ZEEP, MV with PEEP was associated with a reduction in diuresis (V) from 208 +/- 51 to 68 +/- 11 ml/h (P less than 0.02), in natriuresis (UNa) from 12.4 +/- 3.3 to 6.2 +/- 2.1 mmol/h (P less than 0.02), and in fractional excretion of sodium (FENa) from 1.07 +/- 0.02), 0.21 to 0.67 +/- 0.17% (P less than 0.02) and with an increase in plasma renin activity (PRA) from 4.83 +/- 1.53 to 7.85 +/- 3.02 ng.ml-1.h-1 (P less than 0.05). Plasma ANF levels markedly decreased during PEEP in four patients but showed only minor changes in the other four patients, and mean plasma ANF levels did not change (163 +/- 33 pg/ml during ZEEP and 126 +/- 30 pg/ml during PEEP). Glomerular filtration rate and renal plasma flow were unchanged. Infusion of ANF (5 ng.kg-1.min-1) during PEEP markedly increased V and UNa by 110 +/- 61 and 107 +/- 26%, respectively, whereas PRA decreased from 7.85 +/- 3.02 to 4.40 +/- 1.5 ng.ml-1.min-1 (P less than 0.05). In response to a 10 ng.kg-1.min-1 ANF infusion, V increased to 338 +/- 79 ml/h during ZEEP but only to 134 +/- 45 ml/h during PEEP (P less than 0.02), whereas UNa increased, respectively, to 23.8 +/- 5.3 and 11.3 +/- 3.3 mmol/h (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dependence of the parameters of microcirculation and lymph flow in the liver on the value of venous pressure

In experiments on cats the perfusion (at a constant flow and controlled venous outflow) of haemodynamic isolated liver was carried out. It was shown that at the levels of venous pressure in the liver 0, 2, and 4 mm Hg, the lymph flow (22.8 +/- 3.5, 41.8 +/- 5.7 and 57.6 +/- 8.6 mkl.min-1.100 g-1, respectively) was depended on the value of hydrostatic pressures in the sinusoids (1.4 +/- 0.1, 3.3 +/- 0.1, and 5.4 +/- 0.1 mm Hg, respectively) and did not depend on the value of sinusoidal filtration coefficient (0.421 +/- 0.029, 0.473 +/- 0.036, and 0.474 +/- 0.034 ml.min-1.mm Hg-1.100 g-1, respectively).     

Blood-brain barrier to hydrogen ion during acute metabolic acidosis in piglets

The present study investigates the integrity of the blood-brain barrier to H+ or HCO3- during acute plasma acidosis in 35 newborn piglets anesthetized with pentobarbital sodium. Cerebrospinal fluid acid-base balance, cerebral blood flow (CBF), and cerebral oxygenation were measured after infusion of HCl (0.6 N, 0.191-0.388 ml/min) for a period of 1 h at a constant arterial PCO2 of 35-40 Torr. HCl infusion resulted in decreased arterial pH from 7.38 +/- 0.01 to 7.00 +/- 0.02 (P less than 0.01). CBF measured by the tracer microsphere technique was decreased by 12% from 69 +/- 6 to 61 +/- 4 ml.min-1.100 g-1 (P less than 0.05). Infusion of 0.6 N NaCl as a hypertonic control had no effect on CBF. Cerebral metabolic rate for O2 and O2 extraction was not significantly changed from control (3.83 +/- 0.20 ml.min-1.100 g-1 and 5.7 +/- 0.6 ml/100 ml, respectively) during acid infusion. Cerebral venous PO2 was increased from 41.6 +/- 2.1 to 53.8 +/- 4.0 Torr by HCl infusion (P less than 0.02) associated with a shift in O2-hemoglobin affinity of blood in vivo from 38 +/- 2 to 50 +/- 1 Torr. Cisternal cerebrospinal fluid pH decreased from 7.336 +/- 0.014 to 7.226 +/- 0.027 (P less than 0.005), but cerebrospinal fluid HCO3- concentration was not changed from control (25.4 +/- 1.0 meq/l). These data suggest that there is a functional blood-brain barrier in newborn piglets, that is relatively impermeable to HCO3- or H+ and maintains cerebral perivascular pH constant in the face of acute severe arterial acidosis. (ABSTRACT TRUNCATED AT 250 WORDS)     

Enteral infusion of glucose at rates approximating EGP enhances glucose disposal but does not cause hypoglycemia

Portal infusion of glucose at rates approximating endogenous glucose production (EGP) causes paradoxical hypoglycemia in wild-type but not GLUT2 null mice, implying activation of a specific portal glucose sensor. To determine whether this occurs in humans, glucose containing [3-3H]glucose was infused intraduodenally at rates of 3.1 mg. kg-1. min-1 (n = 5), 1.55 mg. kg-1. min-1 (n = 9), or 0/0.1 mg. kg-1. min-1 (n = 9) for 7 h in healthy nondiabetic subjects. [6,6-2H2]glucose was infused intravenously to enable simultaneous measurement of EGP, glucose disappearance, and the rate of appearance of the intraduodenally infused glucose. Plasma glucose concentrations fell (P < 0.01) from 90 +/- 1 to 84 +/- 2 mg/dl during the 0/0.1 mg. kg-1. min-1 id infusions but increased (P < 0.001) to 104 +/- 5 and 107 +/- 3 mg/dl, respectively, during the 1.55 and 3.1 mg. kg-1. min-1 id infusions. In contrast, insulin increased (P < 0.05) during the 1.55 and 3.0 mg. kg-1. min-1 infusions, reaching a peak of 10 +/- 2 and 18 +/- 5 micro U/ml, respectively, by 2 h. Insulin concentrations then fell back to concentrations that no longer differed by study end (7 +/- 1 vs. 8 +/- 1 micro U/ml). This resulted in comparable suppression of EGP by study end (0.84 +/- 0.2 and 0.63 +/- 0.1 mg. kg-1. min-1). Glucose disappearance was higher (P < 0.01) during the final hour of the 3.1 than 1.55 mg. kg-1. min-1 id infusion (4.47 +/- 0.2 vs. 2.6 +/- 0.1 mg. kg-1. min-1), likely because of the slightly, but not significantly, higher glucose and insulin concentrations. We conclude that, in contrast to mice, selective portal glucose delivery at rates approximating EGP does not cause hypoglycemia in humans.