Pulmonary Airway Resistance Research Articles

Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia

Study objective: To determine whether long-term oral diuretic therapy would improve the pulmonary function of preterm infants with bronchopulmonary dysplasia. Design: Randomized, double-blind, placebo-controlled study. Setting: Level III intensive care nursery. Intervention: We randomly selected 43 stable patients with oxygen-dependent bronchopulmonary dysplasia to receive either orally administered spironolactone and chlorothiazide or placebo. These drugs were continued until the patients no longer required supplemental oxygen. Both groups received furosemide as needed. Measurements and results: Each infant had pulmonary function tests at study entry, 4 weeks after study entry, 1 week and 8 weeks after being weaned to room air and off study drugs, and at 1 year of corrected age. Pulmonary function tests included dynamic pulmonary compliance, airway resistance, thoracic gas volume, and maximal expiratory flow at functional residual capacity; most of the infants had functional residual capacity measured. Between the first and second pulmonary function tests (while the infants were receiving diuretic or placebo), the infants in the diuretic group had a significant improvement in dynamic pulmonary compliance (46%; p <0.001) and airway resistance (31%; p <0.05); there were no changes in compliance or resistance in the placebo group. Although patients in both the diuretic and the placebo groups required progressively less supplemental oxygen, by 4 weeks after study entry the patients in the diuretic group needed less supplemental oxygen than did those in the placebo group (p <0.01). There were no significant differences in results of serial pulmonary function tests in either group after discontinuation of diuretic therapy. Despite the significant differences in pulmonary function between the two groups, there was no significant difference between them in the total number of days that supplemental oxygen was required. Significantly more infantsin the placebo group received more than 10 doses of furosemide on an as needed basis. Conclusions: Long-term diuretic therapy in stable infants with oxygen-dependent bronchopulmonary dyslasia, after extubation, improves their pulmonary function and decreases their fractional inspired oxygen requirement, but does not decrease the number of days that they require supplemental oxygen. The improvement in pulmonary function associated with diuretic therapy is not maintained after treatment is discontinued. (J PEDIATR 1994;124:772-81)

Pulmonary effects of endogenous and exogenous nitric oxide in the pig: relation to cigarette smoke inhalation.

1. Pentobarbitone-anaesthetized pigs were challenged with cigarette smoke (unfiltered or filtered through a Cambridge glass fibre filter to remove the particulate phase including nicotine), as well as nicotine aerosol and the gas phase components nitric oxide (NO) and carbon monoxide (CO); the effects on the bronchial and pulmonary circulations, and pulmonary airway mechanics, were examined. The relative importance of endogenous NO mechanisms in the pig lung was also studied by giving the NO synthesis inhibitor NG-nitro-L-arginine (L-NOARG; 50 mg kg-1) intravenously. Mean arterial pressure and blood flow in the bronchial, pulmonary and femoral circulations were measured, the latter with ultrasonic flow probes around the supplying arteries, and vascular resistance (VR) was calculated. Changes in pulmonary airways resistance (Rpulm) and lung dynamic compliance (Cdyn) were also determined. Finally, the concentration of NO in inhaled air during cigarette smoke and NO gas challenges was continuously monitored by a chemiluminescence method and the relative contribution of NO in cigarette smoke-induced vascular effects in the pig lung was calculated. 2. Cigarette smoke challenge, with or without a Cambridge filter, caused a rapid vasodilator response in the bronchial circulation and the major part (75%) of this response was probably caused by NO present in smoke. NO challenge caused profound bronchial vasodilation with dose-response characteristics between 10 and 100 p.p.m. The small part of the cigarette smoke-induced response not explained by the NO content may be caused by CO, showing weak vasodilator effect in the bronchial circulation. The L-NOARG-induced relative increase in bronchial VR was 2-3 times higher than the changes in pulmonary, femoral and systemic VR, suggesting a strong influence of endothelial NO mechanisms on basal tone in the bronchial circulation.3. Challenge with unfiltered cigarette smoke induced variable responses in the pulmonary circulation,whereas inhalation of filtered smoke caused consistent pulmonary vasodilatation. The major part of this vasodilator response was probably caused by NO, which was a potent dilator of the pulmonary circulation with maximal effect achieved with as little as 10 p.p.m. The effect of NO may be opposed in unfiltered smoke by the particulate phase (but not nicotine), presumably by inducing sympathetic reflexes. L-NOARG caused similar relative increases in pulmonary, femoral and systemic VR.4. Cigarette smoke inhalation induced bronchodilatation in the pentobarbitone-anaesthetized pig as revealed by changes in Rpulm and Cdyn. Both NO and nicotine may contribute to this response. NO inhalation reduced Rpulm in the basal state with maximal effect at 30 p.p.m. The mechanism for NO-induced bronchodilatation may be indirect in the pig, since pretreatment with L-NOARG blocked the response. L-NOARG did not affect basal Rpulm.5. In conclusion, bronchial vasodilatation caused by continuous cigarette smoke inhalation in the pig,seems to be largely mediated (approximately 75%) by NO. The remaining part could be mediated by CO. Cigarette smoke particles, but not nicotine, may counteract NO-induced relaxation in the pulmonary circulation, thus resulting in variable effects in the pulmonary circulation during challenge with unfiltered cigarette smoke. NO also acts as a bronchodilator in the pig, but the mechanism may be indirect. Finally, endogenous NO mechanisms appear to be strongly involved in the control of basal tone in the bronchial circulation, less so in the pulmonary circulation and not at all in bronchial smooth muscle.

Aspirin effect on early and late changes in acute lung injury in sheep

There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B2 (TxB2) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep. 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i.v.) 30 min before OA, the others saline as placebo. Pulmonary and tissue gas exchange, pulmonary and systematic hemodynamics, respiratory system mechanics, TxB2 and 6-keto-PGF1 alpha, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB2 generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at approximately 1 in ASA-group compared to its fall to approximately 0.7 in controls. Our findings suggest that ASA: 1) is only effective to treat the very transient TxB2-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB2; 2) has a transient protective effect on the TxB2-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO2.

Effects of CO2 rebreathing on pulmonary mechanics in premature infants

The effects of hypercapnia produced by CO2 rebreathing on total pulmonary, supraglottic, and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk, weight at study 1,950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr, respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive, thereby improving the infant's response to CO2.

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)

A nonlinear pharmacologic model of the acute effects of ozone on the human lungs

A pharmacologic model describing the quantitative relationship between short-term exposure to ozone and pulmonary airway resistance is described. The model simulates the following processes: (1) removal of a fraction of inhaled ozone in the airways of the head; (2) ozone oxidation of membrane-bound fatty acids in the target tissue in the lower airways; (3) rupture of cell membranes, releasing inflammatory mediators into the intercellular space; (4) migration of inflammatory cells into the injured tissue, releasing additional mediators and thus amplifying the inflammatory effect of ozone in a positive feedback loop; (5) stimulation of irritant receptors by ozone directly and by inflammatory mediators leading to vagally mediated bronchoconstriction. Mathematically the model consists of a logistic equation determining losses in the head, and a set of four differential equations simulating the uptake of ozone in the target tissue and the ensuing inflammation and bronchoconstriction. The observed human response to ozone in chamber studies is nonlinear, and it was necessary to introduce a nonlinear feedback loop for inflammation in the model to replicate this. Despite limited data upon which to base the model, it successfully predicts the human response to ozone reported in a series of published short-term chamber studies and is superior to "effective dose" (the product of ozone concentration, minute ventilation, and exposure duration) used by other investigations to describe dose-response relationships. Nonlinear multicompartment pharmacologic models such as this one can exhibit very complex behavior making the estimation of model parameters difficult, but they hold promise because the physiologic processes under study are themselves complex nonlinear phenomena.

Hemodynamic and respiratory effects of thyrotropin-releasing hormone and epinephrine in anaphylactic shock

Thyrotropin-releasing hormone (TRH) has been shown to increase mean arterial pressure during anaphylactic shock. The hemodynamic mechanism of action and the effect of TRH on the respiratory system during anaphylactic shock are not known. A rabbit model of anaphylaxis was used to determine the effect of TRH, epinephrine (EPI), and normal saline (NS) on various cardiovascular and respiratory parameters during anaphylactic shock. Anaphylactic shock was induced by antigen challenge in 31 sensitized animals. After a 25% decrease in mean arterial pressure, they were randomly treated with TRH (2 mg/kg), EPI (0.005 mg/kg), or NS (10 mL/kg). Blood was drawn at baseline and at the end of the experiment for laboratory analysis. Cardiac and respiratory parameters were monitored continuously and measured at baseline, at onset of shock (time zero), and at time intervals for 30 minutes. Animals were treated with repeated doses during the first 15 minutes as needed to maintain mean arterial pressure above shock level. Five of ten TRH-, five of 11 EPI-, and six of ten NS-treated animals survived. The TRH-treated group required fewer doses than the other groups and had increased heart rate, mean arterial pressure, peripheral vascular resistance, respiratory rate, and minute ventilation as well as decreased stroke volume index and lung compliance compared with the NS-treated group. EPI treatment resulted in increased minute ventilation and decreased pulmonary airway resistance compared with NS treatment. The EPI group also had a higher postsurvival epinephrine level than the other groups. No difference in right atrial pressure, cardiac index, acid-base status, pO2, A- a gradient, lung weight, lactate, or norepinephrine levels was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Relaxant effect of the H2-receptor antagonist oxmetidine on guinea-pig and human airways.

The effects of three different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) were tested on isolated preparations of guinea-pig trachea and human bronchus against contractions induced by acetylcholine, histamine and potassium chloride (KCl). In addition, their influence on calcium concentration-response curves in guinea-pig tracheal spirals was examined in a potassium-rich solution (30 mM). Finally, their effects were studied in vivo against acetylcholine and histamine-induced bronchoconstriction in anaesthetized guinea-pigs. In guinea-pig isolated trachea, oxmetidine--in contrast to cimetidine and ranitidine, which were completely inactive--induced a concentration-dependent relaxation regardless of the excitatory stimulus: its--log EC50 values (i.e. the negative log concentration that caused a 50% relaxation) were 3.46 +/- 0.11, 4.61 +/- 0.09 and 4.20 +/- 0.12 against acetylcholine, histamine and KCl, respectively. In Ca2+-free, K+-enriched solution, the compound was able to inhibit Ca2+-induced contractions at concentrations close to those needed to counteract the spasmogenic effect of histamine in normal Krebs solution. Results obtained in the human bronchus preparation were similar to those observed in guinea-pig tracheal spirals. When tested against acetylcholine or histamine-induced bronchoconstriction in vivo, oxmetidine (10 and 30 mg Kg-1 intravenously) significantly reduced the increase in pulmonary airway resistance (Raw) induced by both agents. Once again, cimetidine and ranitidine were completely ineffective. In summary, oxmetidine displayed non-specific antispasmogenic activity on guinea-pig and human airways. This effect, which is independent of H2-receptor blockade, represents a side-effect of the drug which may be connected to its interference with Ca2+ influx and the action or release of intracellular Ca2+.

Relationship between Pulmonary Function and Sleep-Induced Respiratory Abnormalities

The relationships between pulmonary function and sleep-induced respiratory events were studied in 34 consecutive male patients with suspected sleep apnea syndrome. In view of the effects of obstructive airway disease on pulmonary volume and airway resistance (Raw), patients were divided into two groups, those with and those without obstructive airway disease. Percent predicted functional residual capacity (FRC) correlated significantly with the apnea-plus-hypopnea index (AHI) in patients with and without obstructive airway disease (r = -0.62 and p less than 0.01; and r = -0.57 and p less than 0.01, respectively) whereas percent predicted total lung capacity had a significant relationship with AHI only in patients with obstructive airway disease (r = -0.80; p less than 0.001). In patients without such disease, a significant correlation between inspiratory airway conductance (Gaw) and AHI (r = -0.47; p less than 0.05) was also present, while percent predicted FRC and Gaw did not correlate with normalized weight. These findings suggest that decreased pulmonary volume and increased Raw contribute to the severity of sleep-induced respiratory abnormalities in patients with sleep apnea syndrome regardless of the degree of obesity.

SK&F 88046: Inhibition of thromsoxane-induced bronchoconstriction in anesthetized dogs

In addition to its well-described pro-aggregatory action, thromboxane A 2 (TxA 2) has been shown to be a potent bronchoconstrictor. The present study was designed to evaluate whether SK&F 88046 [N,N′-bis-7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydroisoquinolyl disulfonylimidel had any inhibitory effects against canine bronchoconstriction induced by U-44069, a functional TxA 2 mimic. Bronchopulmonary responses were measured by computer analyses in spontaneously breathing, pentobarbital-anesthetized mongrel dogs. In a dose range of 0.3-3.0 μg/kg i.v., U-44069 produced potent, dose-related increases in pulmonary airway resistance (R L) and decreases in dynamic lung compliance (COYN), which were indicative of severe bronchoconstriction. The onset of agonist activity was prompt (1–2 min) and recovery usually occurred within 5–10 min. Pretreatment with varying doses of SK&F 88046 (1, 3 and 5 mg/kg) as a 10 min i.v. infusion, produced a significant inhibition of the R L and C DYN effects of U-44069. In addition, SK&F 88046, as well as UK 37248 (dazoxiben), a thromboxane synthetase inhibitor, was effective vs. arachidonic acid-induced decreases in C DYN; however, SK&F 88046 failed to alter significantly bronchopulmonary effects induced by other known bronchoconstrictors, e.g., PGF 2α, PGD 2, histamine or acetylcholine. Therefore, SK&F 88046 represents an antagonist of TxA 2-mediated changes in airway mechanics in the anesthetized dog.

Upper airway resistance in healthy Friesian cattle

Total pulmonary resistance (RL) and upper airway resistance (Ruaw) were measured in nine healthy unsedated Friesian cattle divided into three age groups. Mean values for these three groups of animals aged four, 188 and 1157 days were 0.32, 0.13 and 0.06 kPa litre-1 s for RL; 0.14, 0.09 and 0.05 kPa litre-1 s for Ruaw; and 0.45, 0.68 and 0.79 for the ratio Ruaw/RL respectively. Ruaw, measured with the head in the normal position, did not significantly differ from values obtained with the head in the horizontal position. Ruaw, measured with the head in the vertical position, was approximately three times greater than when measured in the two other positions.

Modulation of pulmonary stretch receptors and airway resistance by parasympathetic efferents.

Recording from pulmonary stretch receptors in the intact cervical vagus nerve revealed a novel interaction between stretch receptors and smooth muscle in the lungs of anesthetized paralyzed cats. Firing rates of pulmonary stretch receptors were modulated in step with the inflation-deflation cycle of the mechanical respirator, as expected. Firing rates of most slowly adapting receptors, but not rapidly adapting receptors, were also strongly modulated in step with the phrenic nerve activity even when the respirator was turned off and the cat motionless. The modulation of some receptors' firing rates by the inspiratory motor output was as great as the change in firing-rate in response to a lung inflation of 20 ml of air (one tidal volume). Atropine blocked the inspiratory-related modulation of slowly adapting/receptor firing rates; it did not block the inflation-related modulation. Pulmonary resistance was modulated in step with the inspiratory activity on the phrenic nerve. Hyperventilation to neural apnea (no phrenic nerve activity) reduced pulmonary resistance to its lowest level, a level equal to that produced by an injection of isoproterenol or atropine. Hypoxia during hypocapnic apnea caused bursts of inspiratory activity on the phrenic nerve accompanied by one-to-one increases in airway resistance. We conclude that the intrathoracic airway smooth muscle contracts with each neural inspiration, that the modulation of the pulmonary stretch receptors is due to a mechanical interaction with the intrathoracic airway smooth muscle, and that through the mechanical link with airway smooth muscle, stretch receptor sensitivity depends on inspiratory output, a closed loop.

Bronchopulmonary effects of phenylephrine and methoxamine in the guinea-pig. Interaction with bronchoconstrictors drugs

The bronchopulmonary effects of phenylephrine (Phe) and methoxamine (Met) were investigated in vitro on isolated guinea-pig tracheas and lung strips and in vivo on pulmonary airway resistance (Raw) in conscious guinea-pigs. Phe, but not Met, relaxed the isolated trachea precontracted with acetylcholine (ACh); this effect was inhibited by propranolol and ascribed to β-adrenergic stimulation. In the presence of propranolol, both Phe and Met contracted the isolated trachea (-log EC 50 were 3.80±0.37 and 3.04±0.25 respectively ( n=5) and this effect was competitively antagonized by phentolamine. Phe and Met contracted the isolated lung strips more strongly than the trachea (-log EC 50 were 5.14±0.23 and 4.30±0.14 respectively (n =5)). In contrast with the letter, the maximum response was equivalent to that induced by ACh; this effect was also antagonized by phentolamine. In the conscious guinea-pig, Phe (100 and 300 μg/kg) and Met (1 and 3 mg/kg) had no effect on Raw but significantly reduced the bronchoconstriction induced by ACh (25 μg/kg), histamine (20 μg/kg) and serotonin (15 μg/kg); this protective effect was unmodified by propranolol (2 mg/kg), yohimbine (1 mg/kg) or piperoxan (0.3 mg/kg) but was significantly inhibited by prazosin (30 μg/kg) or AR-C239 (50 μg/kg). These result suggest that α-adrenergic vasoconstriction with subsequent shrinkage of the bronchial mucosa is responsible for the protective effect of Phe and Met against ACh-induced bronchoconstriction. In isolated lung strips, vasoconstriction would increase tension.

Bronchopulmonary effects of clonidine on the bronchomotor responses of the guinea-pig

In conscious guinea-pigs, clonidine (10 and 100 ωg/kg i.v.) lowered diastolic (−7.9±3.5 and −12.4±5.2%) and systolic (−8.6±3.0 and −11.9±4.2%) arterial pressure and reduced heart rate (−14.5±3.9 and −27.7±3.8%), but did not significantly modify pulmonary airway resistance. Hypotension was suppressed by yohimbine and bradycardia was partially suppressed by atropine and yohimbine, which demonstrates in this animal an α 2-adrenergic effect for hypotension and a mixed cholinergic and α 2-adrenergic effect for bradycardia. Clonidine (10 and 100 ωg/kg i.v.) enhanced the bronchoconstrictor effects of histamine 20 ωg/kg (+80.0±22.5 and 89.1±26.5%), acetylcholine 25 ωg/kg (+66.4±19.8 and +95.4±25.4%) and serotonin 15 ωg/kg (+68.5±23.2 and +81.4±34.1%). The duration of this effect was comparable to that of the hypotensive and cardiac effects of clonidine. The effects of clonidine were suppressed after pretreatment with propranolol, reserpine or pentobarbitone, all drugs which enhance the bronchoconstrictor effect of ACh. Yohimbine (1 mg/kg), piperoxan (0.3 mg/kg) or prazosin in high dosage (0.3 mg/kg) inhibited the potentiation of clonidine of ACh-induced bronchoconstriction, whereas prazosin in lower doses (0.03 mg/kg) or AR-C 239 (0.05 mg/kg) had no action. A specific involvement of α 2-adrenoceptors stimulated by clonidine with subsequent reduction of the adrenergic activity associated with bronchospasm could therefore be demonstrated in the conscious guinea-pig during bronchomotor reactions.

The release of prostanoids during the acute pulmonary response to E. coli endotoxin in anaesthetized cats.

1 The administration of E. coli endotoxin (2 mg/kg i.v.) to anaesthetized cats results in a characteristic acute pulmonary response. This consists of increases in pulmonary artery pressure and airways resistance and a reduction in lung compliance. 2 Plasma concentrations of prostaglandin E2 (PGE2), PGF2 alpha, thromboxane B2 and 6-keto PGF1 alpha were measured by radioimmunoassay in aortic and pulmonary arterial blood samples before, during and after the acute pulmonary response to endotoxin. 3 Endotoxin administration resulted in the rapid release of PGF2 alpha and thromboxane B2 from the lungs. The time course of this release was parallel to that of the pulmonary hypertensive and airways responses to endotoxin. PGE2 and 6-keto PGF1 alpha were released more gradually and with greater variations between individual animals. 4 During the delayed shock phase (2 h after endotoxin) the concentrations of PGE2, PGF2 alpha and 6-keto PGF1 alpha were once again elevated in both the aorta and pulmonary artery. Thromboxane B2 concentrations were not increased at this time. 5 These results suggest that PGF2 alpha and thromboxane A2 may be mediators of the acute pulmonary responses to endotoxin.

Sodium cromoglycate, verapamil and nicardipine antagonism to leukotriene D4 bronchoconstriction.

1--The effects of nicardipine, verapamil and sodium cromoglycate (SCG) on the increase in pulmonary airway resistance(RAw) and decrease in pulmonary dynamic compliance (CDyn) induced by leukotriene D4 (LTD4) 0.5 micrograms kg-1 and acetylcholine (ACh) 3 micrograms kg-1 were investigated in anaesthetized guinea-pigs. The effects of these three agents on the contractile effects of LTD4 and ACh were tested on isolated tracheal preparations of the guinea-pig. 2--Nicardipine and verapamil (0.3 and 1 mg kg-1), as well as SCG (3 and 10 mg kg-1), partially but significantly inhibited the effects of LTD4 on RAw. Partial inhibition of the effect of LTD4 on CDyn was only observed with verapamil (0.3 and 1 mg kg-1). Nicardipine and verapamil had no effect on ACh-induced bronchoconstriction in vivo. 3--In concentrations higher than 10(-5) M, nicardipine and verapamil inhibited the contractile effects of LTD4 and ACh on guinea-pig isolated trachea. SCG had no effect on this preparation. 4--These results suggest that nicardipine, verapamil and SCG partially reduce the component of bronchoconstriction associated with stimulation of irritant receptors by LTD4. However, the site and mechanism of action of Ca2+-entry antagonists remain uncertain.

Problems with plethysmographic estimation of lung volume in infants and young children.

In 57 infants and very young children, less than 2 yr of age and with a variety of cardiopulmonary illnesses, problems were encountered in the estimation of lung volume with the plethysmographic technique. In 19 subjects calculated thoracic gas volume (TGV) was found to be consistently larger when airway occlusions were performed at low lung volumes than when performed at higher lung volumes. In 13 infants, changes in intraesophageal pressure (Pes) during airway occlusions were found to be larger than simultaneous changes in mouth pressure. In 25 subjects in whom none of the above changes were observed, total pulmonary resistance (TPR) and airway resistance (Raw) did not differ significantly [mean TPR, 50.1 +/- 27.5 cmH2O X l-1; mean Raw, 48.1 +/- 26.5 (P greater than 0.5)]. In the 13 subjects in whom the delta Pes-to-delta Pm occlusion ratio exceeded 1.05, closest agreement with specific resistance (sRaw) and TPR derived lung volume was found when TGV was calculated with delta Pes rather than mouth pressure change (delta Pm). A similar close agreement with the sRaw TPR derived volume was obtained when TGV was calculated during airway occlusions at the higher lung volume. Two separate lung models are proposed to explain these observations, one with a segmental airway closure and the other with more a generalized airway closure. If plethysmographic techniques are to be used in these young subjects for the estimation of lung volume and airway resistance, possible errors may be reduced by performing airway occlusions at lung volumes above functional residual capacity and noting the delta Pes-to-delta Pm ratio obtained during the occlusion.

Histamine-releasing properties of hydroxy-9-methyl-2-ellipticinium acetate.

Previous work on Hydroxy-9-methyl-2-ellipticinium acetate indicated a bronchoconstrictor activity which could be partially offset by antagonists of the H1 histamine receptors, and the absence of any direct effect on smooth muscle. OH-9-CH3-2-E at concentrations of 10 micrograms/ml and 500 micrograms/ml produced a moderate and a variable release of histamine when placed in contract with whole human blood and lung fragments, respectively. In addition, at a dose of 3 mg/kg in the guinea pig, pulmonary airway resistance was raised and the blood histamine level lowered. A significant correlation was found between these two effects. These results demonstrate that OH-9-CH3-2-E possesses a histamine-releasing potency which is partly responsible for its bronchial effects, implying that precautions may have to be taken when it is used as a therapeutic agent in sensitive subjects. However, the moderate intensity of this potency has not so far precluded therapeutic use of the preparation.

Contributions of prostaglandin F 2α and thromboxane A 2 to the acute cardiopulmonary changes of pulmonary embolism

The contributions of prostaglandin F 2α (PgF 2α) and thromboxane A 2 (TXA 2) to the acute cardiopulmonary changes of pulmonary embolism (PE) have been evaluated in dogs. Six dogs (Group I) received an LD 50 autologous whole-blood-clot embolus. Twelve dogs (Group II) received 15 mg/kg of imidazole, a selective thromboxane synthetase inhibitor, intravenously 5 min prior to the LD 50 embolus. Six dogs (Group III) received only imidazole intravenously. Pulmonary artery, left atrial, femoral artery, and tracheal pressures and cardiac output were recorded. Tracheal resistance and lung compliance were calculated. PgF 2α was assayed in pre- and postembolization blood samples obtained simultaneously from the left atrium, pulmonary artery, and femoral artery. Characteristic changes of increased pulmonary arterial and airway resistance were similar in Groups I and II and were accompanied by significant increases in PgF 2α. The PgF 2α response to pulmonary embolism was not significantly different in the Group I and II dogs, indicating that while imidazole inhibits thromboxane synthetase, it does not inhibit cyclooxygenase. The Group III dogs demonstrated increases of PgF 2α suggesting that endoperoxide intermediates usually metabolized to TXA 2 may have been utilized for the synthesis of PgF 2α. It is speculated that PgF 2α and TXA 2 produced in response to pulmonary embolism are protective in nature with PgF 2α and TXA 2 helping to maintain arterial pressure and PgF 2α reducing ventilation to nonperfused alveoli during the acute insult.

Assessment of total pulmonary airway resistance under mechanical ventilation

We propose a procedure for assessing the pulmonary airway resistance of patients under mechanical ventilation with a volume-cycled respirator having a sine-wave flow curve and inspiration/expiration (I/E) ratio of 1/2. This simplified procedure requires only the respirator's manometer and spirometer. The method is based on Ohm's Law, dividing the pressure difference (as shown on the manometer) between the peak value and that obtained by occluding the expiratory outlet by one-tenth of the minute volume (Vm). The relationship between the Vm and flow is obtained by calculating the height of the triangle formed by the sine wave, given that the area approximates total volume and the base is derived from the frequency and I/E ratio. This method was tested in 296 measurements on 106 patients using as a control the determination of resistance with a pneumotachograph and differential manometer placed between the patient and respirator. There was a high correlation (r = 0.96) between both procedures. To further facilitate bedside use, we have prepared a graph relating common values of Vm and pressure to resistance.