Control of shunt pathway perfusion in diffuse granulomatous lung disease

To assess the roles of cyclooxygenase inhibition and alveolar hypoxia in controlling the distribution of pulmonary perfusion in granulomatous lung injury, we studied 15 dogs (anesthetized and ventilated) 4 wk after intravenous injection of complete Freund's adjuvant (0.5-0.75 ml/kg). Base-line hemodynamic and blood gas observations were obtained at fractional O2 concentration (FIO2) 0.21 and 0.10. Observations at each FIO2 were repeated 30 min after infusion of meclofenemate (2 mg/kg; n = 10) or saline (n = 5). Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial diastolic and left atrial pressures (PDG). Distribution of blood flow between normal and diseased regions of the lung was evaluated with measurement of inert gas shunt flow. Before infusion, there were no significant differences between the two groups at either FIO2. At FIO2 0.10 PDG rose from 3 +/- 1 to 7 +/- 3 mmHg in the saline group and from 3 +/- 1 to 8 +/- 3 mmHg in the meclofenemate group, although the shunt flow increased from 8.7 +/- 7.7 to 12.2 +/- 9.2% and from 10.7 +/- 11.0 to 17.6 +/- 18.3 in the two groups, respectively. Saline induced no significant changes at either FIO2. After meclofenemate, PDG at FIO2 0.21 rose to 7 +/- 4 mmHg (P less than 0.015) while shunt flow fell to 5.2 +/- 6.2% (P less than 0.0125), whereas at FIO2 0.10 PDG rose to 15 +/- 5 mmHg (P less than 0.001) while shunt flow rose only to 14.3 +/- 16.4% (P = NS). We propose that perivascular inflammation enhanced perfusion of abnormal lung by elaborating vasodilator prostanoids. By inhibiting prostanoid biosynthesis, meclofenemate selectively increased resistance in diseased lung at FIO2 0.21 and lowered shunt flow. The persistent rise in shunt during hypoxia after meclofenemate suggests that factors other than prostanoids may account for the apparent attenuation of hypoxic vasoconstriction in diseased lung.     

Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes

We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.     

Venous occlusion pressure and vascular permeability in the dog lung after air embolization

Pulmonary edema has frequently been associated with air embolization of the lung. In the present study the hemodynamic effects of air emboli (AE) were studied in the isolated mechanically ventilated canine right lower lung lobe (RLL), pump perfused at a constant blood flow. Air was infused via the pulmonary artery (n = 7) at 0.6 ml/min until pulmonary arterial pressure (Pa) rose 250%. While Pa rose from 12.4 +/- 0.6 to 44.6 +/- 2.0 (SE) cmH2O (P less than 0.05), venous occlusion pressure remained constant (7.0 +/- 0.5 to 6.8 +/- 0.6 cmH2O; P greater than 0.05). Lobar vascular resistance (RT) increased from 2.8 +/- 0.3 to 12.1 +/- 0.2 Torr.ml-1.min.10(-2) (P less than 0.05), whereas the venous occlusion technique used to determine the segmental distribution of vascular resistance indicated the increase in RT was confined to vessels upstream to the veins. Control lobes (n = 7) administered saline at a similar rate showed no significant hemodynamic changes. As an index of microvascular injury the pulmonary filtration coefficient (Kf) was obtained by sequential elevations of lobar vascular pressures. The Kf was 0.11 +/- 0.01 and 0.07 +/- 0.01 ml.min-1.Torr-1.100 g RLL-1 in AE and control lobes, respectively (P less than 0.05). Despite a higher Kf in AE lobes, total lobe weight gains did not differ and airway fluid was not seen in the AE group. Although air embolization caused an increase in upstream resistance and vascular permeability, venous occlusion pressure did not increase, and marked edema did not occur.     

Canine bronchoconstriction, gas trapping, and hypoxia with methacholine

The effects of an intravenous methacholine infusion on cardiovascular-pulmonary function were measured in seven mongrel dogs (22.0 +/- 2.8 kg), anesthetized with chloralose and urethan and beta-adrenergically blocked with propranolol. In a volume-displacement plethysmograph, physiological measurements were made at base line and 25 min after establishing a methacholine infusion (0.1-1.0 mg X kg-1 X h-1). Methacholine significantly (P less than 0.05) increased airways resistance (1.9 +/- 0.8 to 8.2 +/- 2.9 cmH2O X l-1 X s), decreased static lung compliance (84.7 +/- 18.5 to 48.2 +/- 9.4 ml/cmH2O), depressed arterial PO2 (81 +/- 17 to 56 +/- 10 Torr), and lowered blood pressure (132 +/- 10 to 69 +/- 18 Torr) and cardiac output (5.7 +/- 1.9 to 4.1 +/- 1.2 l/min). These effects persisted during a further 80 min of methacholine infusion conducted in five of the animals. During the initial 25-min period of methacholine, the end-expired volume (volume-displacement Krogh spirometer) rose in all animals, indicating an increase in functional residual capacity from 997 +/- 115 to 1,623 +/- 259 ml (P less than 0.0005). Analysis of pulmonary pressure-volume curves revealed no change in total lung capacity but an increase in residual volume from 489 +/- 168 to 1,106 +/- 216 ml (P less than 0.001). Thus methacholine caused 617 ml of gas trapping, which was not detected by the Boyle's law principle, presumably because gas was trapped at high transpulmonary pressure. We suggest that intravenous methacholine-induced canine bronchoconstriction, which causes gas trapping and hypoxia, may be a useful animal model of clinical status asthmaticus.     

Effect of bronchial artery blood flow on cardiopulmonary bypass-induced lung injury

Cardiovascular surgery requiring cardiopulmonary bypass (CPB) is frequently complicated by postoperative lung injury. Bronchial artery (BA) blood flow has been hypothesized to attenuate this injury. The purpose of the present study was to determine the effect of BA blood flow on CPB-induced lung injury in anesthetized pigs. In eight pigs (BA ligated) the BA was ligated, whereas in six pigs (BA patent) the BA was identified but left intact. Warm (37 degrees C) CPB was then performed in all pigs with complete occlusion of the pulmonary artery and deflated lungs to maximize lung injury. BA ligation significantly exacerbated nearly all aspects of pulmonary function beginning at 5 min post-CPB. At 25 min, BA-ligated pigs had a lower arterial Po(2) at a fraction of inspired oxygen of 1.0 (52 +/- 5 vs. 312 +/- 58 mmHg) and greater peak tracheal pressure (39 +/- 6 vs. 15 +/- 4 mmHg), pulmonary vascular resistance (11 +/- 1 vs. 6 +/- 1 mmHg x l(-1) x min), plasma TNF-alpha (1.2 +/- 0.60 vs. 0.59 +/- 0.092 ng/ml), extravascular lung water (11.7 +/- 1.2 vs. 7.7 +/- 0.5 ml/g blood-free dry weight), and pulmonary vascular protein permeability, as assessed by a decreased reflection coefficient for albumin (sigma(alb); 0.53 +/- 0.1 vs. 0.82 +/- 0.05). There was a negative correlation (R = 0.95, P < 0.001) between sigma(alb) and the 25-min plasma TNF-alpha concentration. These results suggest that a severe decrease in BA blood flow during and after warm CPB causes increased pulmonary vascular permeability, edema formation, cytokine production, and severe arterial hypoxemia secondary to intrapulmonary shunt.     

Effects of thromboxane synthase inhibition on air emboli lung injury in sheep

We tested the effects of OKY-046, a thromboxane synthase inhibitor, on lung injury induced by 2 h of pulmonary air infusion (1.23 ml/min) in the pulmonary artery of unanesthetized sheep with chronic lung lymph fistula so as to assess the role of thromboxane A2 (TxA2) in the lung injury. We measured pulmonary hemodynamic parameters and the lung fluid balance. The concentrations of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma and lung lymph were determined by radioimmunoassay. Air infusion caused sustained pulmonary hypertension and an increase in pulmonary vascular permeability. The levels of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph were significantly elevated during the air infusion. TxB2 concentration in plasma obtained from the left atrium was higher than that from the pulmonary artery at 15 min of air infusion. When sheep were pretreated with OKY-046 (10 mg/kg iv) prior to the air infusion, increases in TxB2 were prevented. The pulmonary arterial pressure, however, increased similarly to that of untreated sheep (1.8 X base line). The increase in lung lymph flow was significantly suppressed during the air infusion. Our data suggest that the pulmonary hypertension observed during air embolism is not caused by TxA2.     

Oleic acid lung injury increases plasma prostaglandin levels

To determine whether lung injury causes increased plasma prostaglandin (PG) levels, 35 rabbits received oleic acid and 35 served as controls. Half of each group also received 4 ml/kg of Intralipid over one hour and at least five in each subgroup received indomethacin 7.5 mg/kg. Arterial and venous plasma concentrations of PGE2, 6-keto-PGF1 alpha, and PGF2 alpha-M were measured. Venous PGE2 was significantly higher in the oleic acid-injured than in the normal lung group, 1560 +/- 270 (Mean +/- SEM) versus 880 +/- 140 pg/ml (p less than .05). Plasma levels were reduced by 50% with indomethacin, but PGE2 levels remained significantly higher than in the normal lung group, 850 +/- 180 versus 480 +/- 60 for arterial (p less than .05) and 820 +/- 140 versus 480 +/- 80 for venous (p less than .05), respectively. PGF2 alpha-M levels were significantly higher in the lung injury group, 240 +/- 50 versus 50 +/- 40 pg/ml for arterial (p less than .05) and 220 +/- 50 versus 95 +/- 40 for venous (p less than .05), respectively. These lung injury-related increases in PGE2 and PGF2 alpha-M appear related both to increased pulmonary production and to decreased pulmonary clearance. With Intralipid infusion, however, arterial PGE2 increased by 500 +/- 260 pg/ml compared to baseline (p less than .05) with no change in venous PGE2, indicating in this instance that the increase in arterial PGE2 levels is related to increased pulmonary production.     

Adenosine prevents phorbol ester injury in rabbit lungs: role of leukotrienes and TNF.

The objective of this study was to determine whether adenosine (ADO) prevents phorbol myristate acetate- (PMA) induced lung injury by modulating peptidoleukotrienes (LT) and/or tumor necrosis factor (TNF) production. PMA significantly increased pulmonary vascular resistance (PVR, 275 +/- 4 to 447 +/- 30 cmH2O.1-1.min) and microvascular filtration coefficient.(Kf, 0.024 +/- 0.002 to 0.040 +/- 0.006 g.min-1.cmH2O-1) in isolated blood-perfused rabbit lungs. ADO (5 mumol/min) blocked the increases in PVR (257 +/- 9 to 283 +/- 26) and Kf (0.028 +/- 0.005 to 0.018 +/- 0.002). After PMA (30 min), perfusate levels of LTC4 + LTD4 increased by 15.3 +/- 2.1 pg/ml; LTE4 increased by 15.1 +/- 4.1 pg/ml. ADO reduced the increase in LTC4 + LTD4 to 2.7 +/- 6.1 pg/ml, but total LT increased by 31.9 +/- 16.6 pg/ml, implying that ADO enhanced the conversion of LTC4 and LTD4 to LTE4. MK-886 (L663,536), an LT synthesis inhibitor, blocked the increase in total LT (6.1 +/- 13.9 pg/ml) but did not reduce the PMA-induced increase in Kf (0.022 +/- 0.003 to 0.035 +/- 0.005) or PVR (238 +/- 11 to 495 +/- 21). After PMA administration, perfusate TNF levels were not different from the 10-fold increase observed in control experiments and were not reduced by ADO or MK-886. TNF production was independent of perfusate blood components and presumably due to low levels of endotoxin in the perfusate (70-90 ng/ml). These results indicate that ADO does not protect against PMA-induced acute lung injury by altering circulating levels of LT or TNF.     

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.     

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)     

Dimethylthiourea decreases acute pulmonary edema induced by phorbol myristate acetate in isolated blood-perfused lung of the rat

Acute pulmonary edema can be induced by phorbol myristate acetate (PMA). Oxygen radicals released from the neutrophils have been considered to play an important role in the pathogenesis of PMA-induced pulmonary edema. In the present experiment, we studied the effect of dimethylthiourea (DMTU) on PMA-induced pulmonary injuries in isolated perfused lungs of rats. DMTU is a potent scavenger of the hydroxyl radical and hydrogen peroxide. PMA infusion into the isolated lung increased pulmonary arterial pressure (delta PAP) by 37.8 +/- 3.9 mmHg. The lung weight gain (LWG) and lavage albumin concentration (LAC) amounted to 6.2 +/- 1.2 g and 102.0 +/- 22.9 mg/dl, respectively. DMTU (100 mM) pretreatment significantly reduced the PAP increase (delta PAP = 4.6 +/- 0.8 mmHg, p less than 0.001), LWG (0.3 +/- 0.1 g, p less than 0.01) and LAC (25.3 +/- 1.7 mg/dl, p less than 0.01). Additional in vitro experiments demonstrated that DMTU depressed the chemiluminescence released from neutrophils activated by PMA (17.9 +/- 2.6 mV.min to 2.6 +/- 0.5 mV.min, p less than 0.01). The results suggest that DMTU, a scavenger of toxic radicals, decreases the lung edema through both attenuation of pulmonary hypertension and protection of vascular permeability from PMA injury.     

Pulmonary microvascular response to LTB4: effects of perfusate composition

We examined the effects of leukotriene B4 (LTB4) on pulmonary hemodynamics and vascular permeability using isolated perfused guinea pig lungs and cultured monolayers of pulmonary arterial endothelial cells. In lungs perfused with Ringer solution, containing 0.5 g/100 ml albumin (R-alb), LTB4 (4 micrograms) transiently increased pulmonary arterial pressure (Ppa) and capillary pressure (Pcap). Pulmonary edema developed within 70 min after LTB4 injection despite a normal Pcap. The LTB4 metabolite, 20-COOH-LTB4 (4 micrograms), did not induce hemodynamic and lung weight changes. In lungs perfused with autologous blood hematocrit = 12 +/- 1%; protein concentration = 1.5 +/- 0.2 g/100 ml), the increases in Ppa and Pcap were greater, and both pressures remained elevated. The lung weight did not increase in blood-perfused lungs. In lungs perfused with R-alb (1.5 g/100 ml albumin) to match the blood perfusate protein concentration, LTB4 induced similar hemodynamic changes as R-alb (0.5 g/100 ml) perfusate, but the additional albumin prevented the pulmonary edema. LTB4 (10(-11)-10(-6) M) with or without the addition of neutrophils to the monolayer did not increase endothelial 125I-albumin permeability. Therefore LTB4 induces pulmonary edema when the perfusate contains a low albumin concentration, but increasing the albumin concentration or adding blood cells prevents the edema. The edema is not due to increased endothelial permeability to protein and is independent of hemodynamic alterations. Protection at higher protein-concentration may be the result of LTB4 binding to albumin.     

Increased leukotriene C4 in ethchlorvynol-induced acute lung injury in dogs

We investigated whether ethchlorvynol (ECV)-induced acute lung injury (ALI) is associated with an increase in leukotriene C4 (LTC4) production. In six pentobarbital sodium-anesthetized dogs, ECV (15 mg/kg iv) introduced into the pulmonary circulation resulted in a 164 +/- 31% increase in extravascular lung water 120 min after ECV administration. Concomitantly, the mean (+/- SE) concentration of LTC4 in arterial plasma measured by radioimmunoassay following 80% EtOH precipitation, XAD-7 extraction and high-pressure liquid chromatography purification was 5.0 +/- 1.3 pg/ml, unchanged from control (pre-ECV) values. In contrast, in pulmonary edema fluid 120 min post-ECV, the LTC4 concentration was 35.2 +/- 10.8 pg/ml, sevenfold greater than those values found in the arterial plasma (P less than 0.01). In six additional dogs, 120 min after unilateral ALI had been induced with ECV (9 mg/kg iv), LTC4 in the bronchoalveolar lavage (BAL) of the uninjured lung was 12.1 +/- 1.5 pg/ml, unchanged from pre-ECV values, whereas, LTC4 in the BAL of the injured lung increased from a control value of 10.2 +/- 1.6 to 24.2 +/- 3.5 pg/ml (P less than 0.01) 120 min after ECV administration. These results demonstrate that, in ECV-induced acute lung injury, LTC4 concentrations in pulmonary edema fluid are considerably greater than those found in arterial plasma in the case of bilateral acute lung injury and significantly greater in the BAL of the injured lung compared with the uninjured lung in the case of unilateral acute lung injury. The results are a necessary first step in support of the hypothesis that leukotrienes participate in the altered permeability of ECV-induced acute lung injury.     

Effects of dibutyryl cAMP on pulmonary air embolism-induced lung injury in awake sheep

To assess the role of intracellular adenosine 3',5'-cyclic monophosphate (cAMP), we tested the effects of dibutyryl cAMP (DBcAMP), an analogue of cAMP, on lung injury induced by pulmonary air embolism in awake sheep with chronic lung lymph fistula. We infused air (1.23 ml/min) in the pulmonary artery for 2 h in untreated control sheep. In DBcAMP-pretreated sheep DBcAMP was infused (1 mg/kg bolus and 0.02 mg.kg-1.min-1 constantly for 5 h); after 1 h from beginning of DBcAMP administration the air infusion was started. After the air infusion, pulmonary arterial pressure (Ppa) and lung lymph flow rate (Qlym) significantly increased in both groups. DBcAMP-pretreated sheep showed significantly lower responses in Qlym (2.7 X base line) compared with untreated control sheep (4.6 X base line); however, Ppa, left atrial pressure, and lung lymph-to-plasma protein concentration ratio were not significantly different between the two groups. Although plasma and lung lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations increased significantly during the air infusion, DBcAMP-pretreated sheep showed significantly lower responses. Thus DBcAMP infusion attenuated pulmonary microvascular permeability induced by air embolism. We conclude that pulmonary vascular permeability is in part controlled by the intracellular cAMP level.     

Temporal response of the fetal pulmonary circulation to pharmacologic vasodilators

To determine the temporal response of the fetal pulmonary circulation to pharmacologic vasodilators and to assess vasoreactivity following vasodilation, we infused either acetylcholine, histamine, or bradykinin directly into the left pulmonary artery of 21 chronically prepared fetal sheep. Blood flow (Q) to the left lung was measured by electromagnetic flow transducer. Left pulmonary artery infusion of acetylcholine at 1.5 micrograms.min-1 for 2 hr produced an increase in Q from 59 +/- 8 ml.min-1 to a peak of 113 +/- 10 ml.min-1 at 20 min into the infusion (P less than 0.001). After the peak at 20 min, Q steadily declined toward baseline to 66 +/- 7 ml.min-1 at the end of the 2-hr infusion period (P less than 0.01). Q in the 1/2-hr period following infusion was significantly less than the baseline period (47 +/- 6; P less than 0.04) with no change in pulmonary artery pressure. Similar patterns were seen with 2-hr infusions of histamine (150 ng.min-1) and bradykinin (100 ng.min-1). After a 2-hr infusion of one of the agents, a repeat infusion with that agent or a different one resulted in a diminished response. We conclude that fetal pulmonary vasodilation in response to local infusion of acetylcholine, histamine, or bradykinin is not sustained over a 2-hr period, and that following 2-hr exposure to vasodilators, pulmonary vascular resistance is increased and pulmonary vasoreactivity to pharmacologic vasodilators is decreased.     

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.     

Increased pulmonary vascular filtration pressure does not alter lung liquid secretion in fetal sheep.

The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.     

Vasopressin stimulates urinary kallikrein excretion in the isolated erythrocyte-perfused rat kidney

We have found that arginine vasopressin (AVP) (10 pg/ml) stimulates urinary kallikrein in the isolated erythrocyte perfused rat kidney. (In this model, perfusate flow rate approximates blood flow rates in vivo and morphology is normal.) Urinary kallikrein excretion rose from 6.9 +/- 0.8 to 14.9 +/- 2.4 ng/min 20 min after the addition of AVP to the perfusate, and then fell towards baseline levels over the next 30 min. 1-Desamino-8-D-AVP (8 pg/ml) caused a comparable increase in kallikrein excretion. Prostaglandin synthesis inhibition with indomethacin did not alter the stimulatory effect of AVP on kallikrein excretion. Parathyroid hormone 1-34 (144 ng/ml) and calcitonin (102 ng/ml) also increased urinary kallikrein. Kallikrein excretion rose from 9.1 +/- 2.0 to 24 +/- 4.5 ng/min in response to calcitonin and from 8.3 +/- 1.6 to 43.7 +/- 3.4 ng/min following the addition of parathyroid hormone to the perfusate. Kallikrein was found to accumulate in the perfusate in a linear fashion. Based on the slope of the relationship between perfusate kallikrein and time, the rate of release of kallikrein into the perfusate was estimated to be 0.79 ng/min in control kidneys. The rate of release of kallikrein into the perfusate in kidneys treated with AVP was the same (0.74 ng/min). Thus while kallikrein is released into the perfusate, this process is not influenced by AVP. In conclusion, AVP stimulates release of kallikrein into the urine (but not the perfusate) independently of systemic events. The effect of AVP is not mediated by prostaglandins. This effect of AVP is mediated via stimulation of the V2 receptor and also occurs in response to two other hormones (calcitonin and parathyroid hormone) that are known to stimulate adenyl cyclase in the rat distal nephron.     

Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation.

To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(ABSTRACT TRUNCATED AT 250 WORDS)