Nonadrenergic bronchodilation in adult and young guinea pigs

The contribution of the nonadrenergic inhibitory system to airway responses to infusion of 5-hydroxytryptamine (5-HT) was evaluated in anesthetized, tracheotomized, and paralyzed young (13 days) and adult (82 days) guinea pigs. Animals were mechanically ventilated by a constant flow ventilator. Compliance (C) and conductance (G) of the respiratory system were continuously monitored. Three series of experiments were performed involving intravenous pretreatment with 1) atropine (3 mg/kg) and propranolol (1 mg/kg); 2) atropine (3 mg/kg), propranolol (1 mg/kg), and phentolamine (2 mg/kg); and 3) atropine (3 mg/kg) and hexamethonium (2 mg/kg). 5-HT was then intravenously infused for 5 min at a rate of 40 ng.kg-1.s-1 in adults and 60 ng.kg-1.s-1 in young guinea pigs to obtain the same degree of bronchoconstriction in both groups. At the 3rd min of the infusion, bilateral cervical vagotomy was performed and C and G were measured at the maximal response, 1-2 min thereafter. Vagotomy increased bronchoconstriction (P less than 0.01) in both young animals and adults. Phentolamine did not modify this increase, but hexamethonium completely inhibited it. These results indicate that, in adult and young guinea pigs, 5-HT infusion induces reflex activation of the nonadrenergic inhibitory system, which in turn modulates the bronchoconstrictor responses to 5-HT. This neural modulation is not mediated by an alpha-adrenergic pathway.     

Central nervous system control of airway tone in guinea pigs: the role of histamine

The central nervous system (CNS) plays an important role in the reflex control of bronchomotor tone, but the relevant neurotransmitters and neuromodulators have not been identified. In this study we have investigated the effect of histamine. Anesthetized male guinea pigs were prepared with a chronically implanted intracerebroventricular (icv) cannula and instrumented for the measurement of pulmonary resistance (RL), dynamic lung compliance (Cdyn), tidal volume (VT), respiratory rate (f), blood pressure (BP), and heart rate (HR). Administration of histamine (2-30 micrograms) icv caused a significant (P less than 0.05) reduction of Cdyn with no change in RL, VT, and f. At a dose of 100 micrograms icv, histamine caused an increase in RL (202 +/- 78%), a reduction of Cdyn (77 +/- 9%), an increase in f (181 +/- 64%), and a reduction of VT (53 +/- 18%). There were no changes in BP and HR after 100 micrograms of icv histamine. In contrast, intravenous administration of histamine (0.1-2 micrograms/kg) caused a dose-dependent decrease in Cdyn and increase in RL that was associated with tachypnea at each bronchoconstrictor dose. Intravenous histamine (2 micrograms/kg) produced a fall in BP and an increase in HR. The bronchoconstrictor responses to icv histamine were completely blocked by vagotomy and significantly reduced by atropine (0.1 mg/kg iv), whereas vagotomy and atropine did not block the bronchospasm due to intravenous histamine. Additional studies indicated that the pulmonary responses due to icv histamine (100 micrograms) were blocked by pretreatment with the H1-antagonist chlorpheniramine (1 and 10 micrograms, icv). These data indicate that histamine may serve a CNS neurotransmitter function in reflex bronchoconstriction in guinea pigs.     

Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pigs

Pulmonary responses to intravenous leukotrienes C4, D4 and E4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD4, LTC4 and LTE4 (respective ED50 of 0.21 +/- .1, 0.64 +/- .2 and 2.0 +/- .1 microgram kg-1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-R?ssler). Bronchoconstriction was antagonized by FPL-55712 (50-200 micrograms kg-1), and indomethacin (50-200 micrograms kg-1) but was not significantly altered by mepyramine (1.0 mg kg-1), methysergide (0.1 mg kg-1), intal (10 mg kg-1) mepacrine (5 mg kg-1) or dexamethasone (10 mg kg-1). The beta adrenoceptor blocker, timolol (5 micrograms kg-1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE4 but not LTD4 or LTC4 were partially antagonized by atropine (100 micrograms kg-1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD4 and LTE4 (2.8-3.2 micrograms kg-1 min-1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE4 and LTD4 was partly reversed by intravenous FPL-55712 (1.0 mg kg-1) and atropine (100 micrograms kg-1) but was almost completely reversed by FPL-55712 (3 - 10 mg kg-1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE4 as well as a small part of the initial response to continuous infusion of LTD4 and LTE4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.     

Role of vagal C-fiber afferents in the bronchomotor response to lactic acid in the newborn dog.

We addressed the hypothesis that vagal C-fiber afferents and cyclooxygenase products are the mechanisms responsible for lactic acid (LA)-induced bronchoconstriction in the newborn dog. Perineural capsaicin and indomethacin were used to block conduction of vagal C fibers and production of cyclooxygenase products, respectively. Perineural capsaicin eliminated (85%) the increase in lung resistance (RL; 45 +/- 5.6%) due to capsaicin (25 microg/kg), whereas the increase in RL (54 +/- 6.9%) due to LA (0.4 mmol/kg) was only inhibited by 37 +/- 4.7% (P < 0.05). Atropine reduced LA-induced bronchoconstriction (42 +/- 2.1%) by an amount similar to that obtained with perineural capsaicin. However, inhibition was significantly increased when atropine was combined with indomethacin (61 +/- 2.7%; P < 0.05), implicating cyclooxygenase products in the LA-induced bronchoconstrictor response. We conclude that the mechanisms responsible for LA-induced bronchoconstriction in the newborn are 1) activation of vagal C-fibers, which, through projections to medullary respiratory centers, leads to activation of vagal cholinergic efferents; 2) production of cyclooxygenase products, which cause bronchoconstriction independent of medullary involvement; and 3) an unknown bronchoconstrictor mechanism, putatively tachykinin mediated. On the basis of our data, pharmaceutical targeting of pulmonary afferents would prevent multiple downstream mechanisms that lead to airway narrowing due to inflammatory lung disease.     

Central and local cholinergic components of histamine-induced bronchoconstriction in dogs

To determine the importance of central and local reflexes in the bronchoconstriction produced by inhaled aerosolized histamine, chloralose-urethan-anesthetized dogs were intubated with a double-lumen catheter, ventilated with a dual cylinder respirator, and instrumented for the measurements of pulmonary conductance (GL) and dynamic compliance (Cdyn) in each lung. In each dog, dose-response curves to inhaled aerosolized histamine were obtained in both lungs separately but synchronously. Four series of experiments were performed. In the first series (n = 10) the responses of the right and left lungs were compared and found to be approximately equal, indicating that one lung could be used as a control for the other. In the second and third series the dose-response curve of one lung that had either been treated with inhaled atropine sulfate (n = 6) (4 mg/ml) or vagotomized (n = 4) was compared with the contralateral control lung. At low concentrations of histamine, GL and Cdyn decreased more in the control lungs than in their atropine-treated or vagotomized counterparts, and approximately 40% of the bronchoconstriction induced was reflex in origin. At higher concentrations of histamine the responses of the control and atropine-treated or vagotomized lungs were not significantly different. In the fourth series of experiments (n = 6) histamine dose-response curves were obtained following combined bilateral vagotomy and unilateral delivery of inhaled aerosolized atropine. In these dogs GL, but not Cdyn, fell to a greater extent in the control than in the atropine-treated lung.(ABSTRACT TRUNCATED AT 250 WORDS)     

Developmental changes in vascular responses to histamine in normoxic and hypoxic lamb lungs

This study of newborn (3-10 day old) and juvenile (6-8 mo old) in situ isolated lamb lungs was undertaken to determine whether 1) histamine receptor blockade accentuates hypoxic pulmonary vasoconstriction more in newborns than in juveniles, 2) histamine infusion causes a decrease in both normoxic pulmonary vascular resistance and hypoxic pulmonary vasoconstriction in newborns, and 3) the H1-mediated dilator response to infused histamine in newborns is due to enhanced dilator prostaglandin release. Pulmonary arterial pressure (Ppa) was determined at baseline and in response to histamine (infusion rates of 0.1-10.0 micrograms.kg-1 min-1) in control, H1-blocked, H2-blocked, combined H1- and H2-blocked, and cyclooxygenase-inhibited H2-blocked lungs under "normoxic" (inspired O2 fraction 0.28) and hypoxic (inspired O2 fraction 0.04) conditions. In newborns, H1-receptor blockade markedly accentuated baseline hypoxic Ppa, and H2-receptor blockade caused an increase in baseline normoxic Ppa. In juveniles, neither H1 nor H2 blockade altered baseline normoxic or hypoxic Ppa. Histamine infusion caused both H1- and H2-mediated decreases in Ppa in normoxic and hypoxic newborn lungs. In juvenile lungs, histamine infusion also caused H2-mediated decreases in Ppa during both normoxia and hypoxia. During normoxia, histamine infusion caused an H1-mediated increase in normoxic Ppa in juveniles as previously seen in mature animals; however, during hypoxia there was an H1-mediated decrease in Ppa at low doses of histamine followed by an increase in Ppa. Combined histamine-receptor blockade markedly reduced both dilator and pressor responses to histamine infusion. Indomethacin failed to alter the H1-mediated dilator response to histamine in newborns.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of tidal volume and anesthetic agent on airway responsiveness to histamine

Dose-response relationships for bronchoconstriction in response to aerosal histamine were assessed before and after vagotomy in 11 dogs anesthetized with barbiturates and in 9 dogs anesthetized with alpha-chloralose-urethan. The dose-response relationships following vagotomy were assessed during spontaneous ventilation and during muscular paralysis and mechanical ventilation with tidal volume (VT) similar to each animal's VT prior to vagotomy. After vagotomy the spontaneous VT of both groups increased but the VT of the alpha-chloralose-urethan group was significantly less than that of the barbiturate group. The histamine responsiveness of the animals anesthetized with barbiturates was significantly greater during mechanical ventilation when VT was reduced to prevagotomy levels compared with during spontaneous ventilation. In contrast, the histamine responsiveness of the alpha-chloralose-urethan group was not significantly changed by reducing VT to prevagotomy levels. In six other dogs anesthetized with pentobarbital sodium and studied after vagotomy, responsiveness to histamine aerosol during controlled ventilation with breaths of prevagotomy VT was greater than responsiveness during mechanical ventilation with large volume breaths given immediately afterward. Thus the magnitude of VT of dogs after vagotomy may influence airway responsiveness, and the influence of anesthetic agents on airway responsiveness after vagotomy may in part be due to their effects on VT. Furthermore, bronchodilation accompanying large volume ventilation persists after vagotomy, suggesting that it is not exclusively mediated by changes in parasympathetic activity.     

Tachyphylaxis to inhaled histamine in asthmatic subjects

The bronchoconstriction induced by repeated histamine inhalation tests was studied in eight mild stable asthmatic subjects to determine whether histamine tachyphylaxis occurs in asthmatics. We also studied the specificity of histamine tachyphylaxis by examining for tachyphylaxis in response to inhaled acetylcholine in these subjects. We subsequently investigated whether indomethacin pretreatment inhibited histamine tachyphylaxis. Tachyphylaxis in response to inhaled histamine occurred in all subjects. The mean histamine provocative concentration causing a 20% fall in the forced expiratory volume in 1 s (PC20) increased from 3.04 +/- 1.9 (%SD), to 4.88 +/- 1.9, and to 6.53 +/- 2.2 mg/ml (P less than 0.0005) with successive inhalation tests. Tachyphylaxis was still present at 3 h (P less than 0.01), but not in all subjects at 6 h (P greater than 0.05). Tachyphylaxis, however, did not occur in response to inhaled acetylcholine. In addition, indomethacin pretreatment prevented histamine tachyphylaxis. Thus this study demonstrates that there is a histamine-specific mechanism that can partially protect the airways against repeated bronchoconstriction caused by histamine. This effect may occur through the release of inhibitory prostaglandins in the airway after histamine stimulation. Also when histamine inhalation tests are repeated on the same day, the tests should be separated by greater than 6 h to avoid tachyphylaxis.     

Higher sensitivity of cerebral arteries isolated from premature and newborn baboons to adrenergic and cholinergic stimulation

To find whether effects of adrenergic and cholinergic agents on cerebral artery were dependent on maturity, we examined responses of isolated cerebral artery strips harvested from premature, term newborn and adult baboons. Although cerebral arteries from many species are only mildly sensitive to norepinephrine, we found the perinatal cerebral arteries to be quite responsive to the amine. Cerebral arteries from premature and newborn baboons were significantly (P less than 0.001) more sensitive to norepinephrine than were arteries from adults; medium effective concentration (EC50) for norepinephrine were 3 X 10(-8), 6 X 10(-8) and 32 X 10(-8)M for prematures, newborns and adults, respectively. Arteries showed a similar age-dependence in the sensitivity of the response to phenylephrine, an alpha 1-adrenoceptor agonist. EC50 values for KC1 did not differ among groups, nor did the maximum response to norepinephrine. Arteries from premature and newborn baboons showed marked contractile response to acetylcholine (maximum tensions 5.9 +/- 0.6 and 6.4 +/- 0.8 g/mm2, respectively), whereas arteries from adult baboons showed little response (0.6 +/- 0.1 g/mm2). Arteries from premature and newborn animals showed a more marked relaxation response to isoproterenol than did arteries from adult animals; the degree of relaxation from an induced contraction was 63% (premature), 72% (newborn) and 10% (adult). There was no age-dependence in the relaxation response to sodium nitrite. We conclude that the events coupling alpha 1, beta or muscarinic receptor activation with cerebral arterial contraction or relaxation are more effective in perinatal than in adult baboons.     

Large-volume ventilation results in bronchoconstriction of Basenji-Greyhound dogs

We compared the effects of large-volume ventilation on airway responses to aerosolized histamine in anesthetized mongrel dogs with its effects in Basenji-Greyhound crossbred (B-G) dogs. Before bronchoconstriction, large inflations resulted in only small changes of dynamic compliance (Cdyn) and pulmonary resistance (RL) in both groups of dogs. After the induction of a moderate degree of bronchoconstriction with aerosolized histamine, large inflations had a more substantial effect; Cdyn increased by 7.5 +/- 2.3% (mean +/- SE; P less than 0.05), and RL decreased by 32 +/- 3.4% (P less than 0.001) in the mongrel dogs. In the B-G group, Cdyn increased by only 0.2 +/- 1.8% (NS), and RL increased by 29.3 +/- 9.2% (P less than 0.05); these changes differed significantly (P less than 0.05) from those observed in the mongrel dogs. Large-volume ventilation following the administration of indomethacin (10 mg/kg iv) and histamine increased Cdyn by 11.4 +/- 1.8% (NS vs. without indomethacin) and decreased RL by 43.9 +/- 3.4% (P less than 0.05) in the mongrel group. In the B-G group large-volume ventilation increased Cdyn by 7.6 +/- 1.7% (P less than 0.01) and decreased RL by 15.7 +/- 8.1% (P less than 0.05). Thus indomethacin enhanced the bronchodilator effects of large-volume ventilation in mongrel dogs and reversed the bronchoconstrictor effect of this maneuver on RL in B-G dogs.     

Distribution of bronchoconstrictor responses in isolated-perfused rat lung

We studied the effects of bronchoconstrictor stimuli administered selectively through isolated-perfused preparations of the bronchial and pulmonary circulations of 80 Sprague-Dawley rats. Dose-related contraction was elicited with infusion of acetylcholine (ACh), histamine, and serotonin (5-HT). Bolus infusion of 10(-5) mol ACh caused a 3.5-fold increase in pulmonary resistance (RL) after infusion into the pulmonary circulation (PC) and a 2.5-fold increase in the bronchial circulation (BC) (P less than 0.05 vs. control) that was blocked selectively in each circulation with atropine. Administration of 10(-5) mol 5-HT into the BC caused only a 45% increase in RL; the same dose of 5-HT caused a 5.1-fold increase in RL in the PC. A biphasic (increase at lower doses/decrease at higher doses) change in RL was elicited by histamine that was converted to dose-related constriction after H2-receptor blockade with cimetidine in both BC and PC. Response to exogenous ACh remained viable for greater than 5 h. Infusion of the mast cell degranulating agent, compound 48/80 (48/80), caused increase in RL that corresponded to quantitative recovery of histamine in the perfusates of both BC and PC. Histamine concentration in the perfusate increased from 47.2 +/- 31.8 (base line) to 624 +/- 60.1 ng/ml (2-fold increase in RL) in the BC and from 38.3 +/- 17.7 (base line) to 294.4 +/- 38.1 ng/ml (50% increase in RL) in the PC (P less than 0.001 vs. baseline concentration) after a 0.1-mg/ml dose of 48/80.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tonic activity in inspiratory muscles and phrenic motoneurons by stimulation of vagal afferents

In anesthetized rabbits, direct and integrated phrenic neurogram (Ephr) and electromyograms from the diaphragm (Edi) and intercostal (Eic) (2nd space) and transversus abdominis muscles (Etr) were simultaneously recorded in two protocols. 1) In animals breathing spontaneously, we used infinite inspiratory (RI) or expiratory (RE) resistive load and intravenous injections of carbachol, histamine, or phenyl diguanide (PDG). All circumstances except RE evoked tonic activities in Ephr, Edi, and Eic but never in Etr. Intravenous atropine abolished carbachol-induced bronchoconstriction and associated tonic inspiratory activities, but this effect persisted with RI, histamine, and PDG. Selective procaine block of conduction in thin vagal fibers (with persistence of the Breuer-Hering inflation reflex) reduced or suppressed the tonic response, which was abolished in all cases after vagotomy. 2) In rabbits artificially ventilated with open chest, passive deflation of the lung or intravenous injections of histamine or PDG also produced tonic discharge in Ephr and often in Eic. The present results demonstrate that 1) stimulation of vagal afferents and mostly thin sensory fibers elicits tonic inspiratory discharges, 2) bronchoconstriction is not necessary for the induction of the response, and 3) reflexes from the chest wall do not mediate this response in rabbits.     

Urinary N tau-methylimidazole acetic acid excretion in respiratory disease

N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.     

Effects of medium-chain triglyceride feeding or glucose infusion on glucose kinetics in the newborn rat

Hypoglycaemia which develops in starved newborn rats (0.15 +/- 0.01 mg/ml) is reversed by feeding medium-chain triglycerides (0.66 +/- 0.05 mg/ml). Despite similar glycaemia (0.71 +/- 0.07 mg/ml) starved newborns infused with glucose (10.7 mg/min/kg) show a 30% higher glucose turnover rate than medium-chain triglyceride fed animals (14.1 +/- 0.6 versus 10.6 +/- 0.3 mg/min/kg, p less than 0.01). For a comparable [6-3H]glucose turnover rate (10.5 +/- 0.3 mg/min/kg), glucose-infused (5.25 mg/min/kg) newborns have a 30% lower glycaemia (0.50 +/- 0.03 mg/ml, p less than 0.01) than medium-chain triglyceride-fed newborns. Thus, medium chain triglyceride feeding leads to a 30% decreased capacity of the tissues to utilize glucose. For a similar glucose turnover rate, medium-chain triglyceride-fed newborns have a higher blood lactate concentration than glucose-infused newborns (0.26 +/- 0.03 versus 0.15 +/- 0.02 mg/ml). However, in medium-chain triglyceride-fed newborns, the increase of blood lactate is not only due to the Cori cycle, as glucose recycling is less increased than glucose production. Thus medium-chain triglyceride increases the release of gluconeogenic precursors which are not derived from blood glucose. In presence of a glucose infusion (15.25 mg/min/kg) producing hyperglycaemia (1.35 +/- 0.05 mg/ml), endogenous glucose production is suppressed by only 37%. If 3-mercaptopicolinate, an inhibitor or gluconeogenesis, is given concomitantly, hyperglycaemia is prevented (0.72 +/- 0.08 mg/ml) and endogenous glucose production is suppressed. Glucose infusion in the hypoglycaemic newborn rat might thus lead to a precarious glucose homeostasis.     

Oxygen radical injury in the immature isolated rabbit heart.

We speculated that the increased vulnerability of the immature rabbit heart to global ischemia might be due to an increased susceptibility to free radical injury. To evaluate this, we exposed newborn (age 2.4 +/- 0.3 days, n = 20) (mean +/- SEM), juvenile (2 to 3 weeks, mean 16.6 +/- 0.5 days, n = 20), and adult (5 to 7 months old, n = 20) isolated, isovolumic, Krebs perfused rabbit hearts to oxygen radicals or cumene hydroperoxide. Control hearts showed no deterioration in left ventricular developed pressure over 60 min (newborns = 104 +/- 11%, juveniles = 101 +/- 7%, and adults = 113 +/- 12% of baseline, n = 5 for each age group). After only 30 min of oxygen radical exposure, the newborn group developed pressure decreased to 49 +/- 6% of the baseline value, while juveniles and adults were functioning at 70 +/- 10% and 83 +/- 6% of baseline, respectively (n = 10 for each age group) (P less than 0.05, newborn different from adult group). In contrast to the oxygen radical protocol, the hearts exposed to cumene hydroperoxide showed no significant difference between the age groups in deterioration of left ventricular function. There was no significant difference between the age groups in ATP content or thiobarbituric reactive substances following the oxygen radical exposure. We conclude that the newborn rabbit heart is significantly more vulnerable than the adult heart to the toxic effects of oxygen radicals. This may account, in part, for age related differences in response to global ischemia and reperfusion.     

Volutrauma activates the clotting cascade in the newborn but not adult rat

Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, we air ventilated newborn and adult rats at low (10 ml/kg) or high (30 ml/kg) tidal volume and compared them with age-matched nonventilated controls. Blood was collected at the end of the experiment for measurement of clot time, tissue factor, and other coagulation factor content. Similar measurements were obtained from lung lavage material. The newborn clot time (44+/-1) was lower and plasma tissue factor content higher (103.4+/-0.4) than adults (88+/-4 s and 26.6+/-1.4 units; P<0.01). High, but not low, tidal volume ventilation of newborns for as little as 15 min significantly reduced clot time and increased plasma tissue factor content (P<0.01). High volume ventilation increased plasma factor Xa (0.1+/-0.1 to 1.6+/-0.4 nM; P<0.01) and thrombin (1.3+/-0.2 to 2.2+/-0.4 nM; P<0.05) and decreased antithrombin (0.12+/-0.01 to 0.05+/-0.01; P<0.01) in the newborn. Lung lavage material of high volume-ventilated newborns showed increased (P<0.01) factor Xa and thrombin. No changes in these parameters were observed in adult rats that were high volume ventilated for up to 90 min. Compared with adults, newborn rats have a greater propensity for volutrauma-activated intravascular coagulation. These data suggest that mechanical ventilation promotes neonatal thrombosis via lung tissue factor release.     

Acute effects of intratracheal administration of platelet-activating factor in baboons

The bronchomotor effect of intratracheal administration of PAF-acether (60 micrograms X kg -1) was investigated in 37 curarized baboons mechanically ventilated with constant volume and frequency. PAF-acether caused an immediate bronchoconstriction as assessed by a marked increase in peak inspiratory pressure with no change in static pulmonary compliance and chest X-rays. There was a concomitant fall in arterial PO2 and a significant increase in ventilated unperfused lung zones. A decrease of circulating platelets and leucocytes was also observed. Local anesthesia with lidocaine and atropine did not prevent PAF-acether-induced bronchoconstriction although both markedly reduced the bronchial response to histamine. Albuterol significantly reduced the bronchial response to PAF-acether. Pretreatment with aspirin (80 mg X kg -1 iv) did not prevent the bronchoconstriction caused by PAF-acether, and intravenous or intratracheal arachidonic acid caused no bronchial response. Thus the role of cyclooxygenase metabolites of arachidonic acid in PAF-acether-induced bronchoconstriction is unlikely. In conclusion, an acute bronchoconstriction probably not triggered by stimulation of irritant receptors of the airways and associated with aggregation of platelet takes place subsequent to intratracheal administration of PAF-acether. These data suggest that PAF-acether might play a role in the pathogenesis of human asthma.     

Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients

Although the vasodilatory response during mental stress is blunted in heart failure (HF), the mechanisms underlying this phenomenon are not fully understood. We tested the hypothesis that sympathetic activity limits the endothelium-dependent vasodilatation during mental stress in chronic HF patients. Twenty-one HF patients (age 45 +/- 2 yr, functional classes III and IV, New York Heart Association) and 22 age-matched normal controls (NC; age 42 +/- 2 yr, P = 0.13) were studied at rest and during 4 min of Stroop color-word test with brachial intra-arterial saline, acetylcholine (endothelium dependent), phentolamine (alpha-blocker), and phentolamine plus acetylcholine infusion. Forearm blood flow was measured by venous occlusion plethysmography. Baseline forearm vascular conductance (FVC) was significantly lower in HF patients (2.18 +/- 0.12 vs. 3.66 +/- 0.22 units, P = 0.001). During mental stress with saline, the changes in FVC were significantly blunted in HF patients compared with NC (0.92 +/- 0.20 vs. 2.13 +/- 0.39 units, P = 0.001). In HF, the vasodilatation with acetylcholine was similar to saline control and significantly lower than in NC. In HF patients, phentolamine significantly increased FVC responses (1.16 +/- 0.20 vs. 2.09 +/- 0.29 units, P = 0.001), and the difference between HF patients and NC tended to decrease (2.09 +/- 0.29 vs. 3.61 +/- 0.74 units, P = 0.052). The vasodilatation with phentolamine plus acetylcholine was similar between HF and NC (4.23 +/- 0.73 vs. 4.76 +/- 1.03 units, P = 0.84). In conclusion, sympathetic activation mediates the blunted muscle endothelium-mediated vasodilatation during mental stress in HF patients.     

Effects of ozone on peripheral lung reactivity

In previous studies, we demonstrated that local exposures to the lung periphery to 0.1 ppm ozone (O3) produce increases in resistance to flow through the collateral system (Rcs) which are prevented by vagotomy, and the local exposures to 1.0 ppm O3 produces increases in Rcs which are only partially mediated by the parasympathetic system. In the present studies, we evaluated the effects of short exposures to O3 on reactions to H2O and histamine in anesthetized male dogs when no residual effects of the O3 exposures could be detected. For this purpose a fiber-optic bronchoscope was wedged in a segmental airway of anesthetized dogs and was used to deliver O3, aerosols of H2O, histamine (1.5 X 10(-4) mg), and atropine (0.1 mg). Measurements of Rcs were used to monitor responses to these agents. Responses to three successive challenges with H2O and with histamine were not different from each other. A 30-min exposure to 0.1 ppm O3 between the first and second challenge did not alter responses to histamine or H2O. However, a 10-min exposure to 1.0 ppm O3 resulted in a significant increase in responses to both H2O and histamine. No correlation was noted between the magnitude of response to O3 and the increase in response to histamine or H2O following O3 exposure. Parasympathetic blockade (atropine or bilateral cervical vagotomy) abolished the increase in response to H2O but not the increase in response to histamine following exposure to 1.0 ppm O3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of magnesium sulfate on bronchoconstriction in the lung periphery

Magnesium sulfate has been shown to be effective clinically as a bronchodilator, but its mechanism of action is unknown. We used a wedged bronchoscope technique to study the ability of MgSO4 at clinically relevant concentrations to attenuate hypocapnia-, acetylcholine- (ACh), and dry air-induced bronchoconstriction in the canine lung periphery. Control experiments demonstrated that consecutive challenges of either hypocapnia or ACh resulted in greater collateral system resistance (Rcs) after the second challenge compared with the first. Intravenous infusion of MgSO4 diminished the maximum response to a second hypocapnic challenge (Rcs = 1.59 +/- 0.29 cmH2O.ml-1.s prechallenge vs. 1.12 +/- 0.20 postchallenge) but had no effect on either ACh- or dry air-induced bronchoconstriction. Serum magnesium levels before MgSO4 administration were 1.59 +/- 0.04 meq/l and rose to 6.20 +/- 0.13 during the infusion. Previous studies demonstrated that nifedipine, like MgSO4 in this study, attenuates hypocapnia-induced bronchoconstriction in the canine lung periphery but has no effect on ACh- or dry air-induced bronchoconstriction. We conclude that these results are consistent with the idea that, like nifedipine, magnesium acts in the airway as a voltage-sensitive calcium channel blocker.