Mediators of acute lung injury in endotoxaemia.
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Animals↗
Biomedical subjects
I W Rodger
Publications and source records attributed to I W Rodger.
Characterisation of receptors mediating the contractile effects of prostanoids in guinea-pig and human airways.
Receptors mediating the contractile effects of prostanoids in the airways of guinea-pig and man have been compared using a range of selective agonists and antagonists. In guinea-pig and human lung parenchymal strips, contractile responses to all prostanoid agonists were blocked by EP092 and AH23848 (antagonists of thromboxane-sensitive receptors) but were unaffected by the EP1 receptor antagonist, AH6809. In guinea-pig tracheal rings responses to the thromboxane mimetic U46619 were antagonised by EP092 and AH23848. AH6809 was ineffective, but did antagonise responses to 16,16-dimethylPGE2 and PGF2 alpha in this tissue. In the human bronchiolar ring responses to U46619 were poorly antagonised by AH23848, EP092 and AH6809. The results suggest that prostanoid contractile agonists act through thromboxane receptors in guinea-pig and human lung parenchymal strips and through thromboxane and EP1 receptors in guinea-pig trachea. A novel prostanoid receptor type, or subtype, mediating contractile effects may be present in human bronchioles.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Calcium ion mechanisms in airway smooth muscle: potential targets for novel symptomatic drugs for asthma.
Calcium ions (Ca2+) are fundamental to the processes responsible for the initiation and maintenance of contraction of airway smooth muscle cells. Recent developments in our understanding of signal transduction mechanisms relating to intracellular Ca2+ release have extended our knowledge of excitation-contraction coupling mechanisms in airway smooth muscle. Furthermore, these developments open up potential targets for the development of new drugs, with novel mechanisms of action, for the symptomatic treatment of asthma. This article reviews these recent advances and focusses upon those calcium ion mechanisms that are possible targets for drug action.
Animals↗
Concentration-related differences in the effects of the Ca2+ agonist Bay K 8644 in human bronchus in vitro.
1. In human isolated bronchial muscle Bay K 8644 (1 nM-1 microM) increased the force of contraction. In concentrations greater than 1 microM (in sensitized tissues), and 10 microM (in control), Bay K 8644 relaxed tissues to below their pretreatment baseline tension. 2. In control tissues contracted with methacholine or LTD4, Bay K 8644 (10 microM) produced a further small contraction; Bay K 8644 (100 microM) relaxed the tissues below baseline. 3. In tissues contracted with histamine, Bay K 8644 (10-100 microM) produced only relaxation. 4. Bay K 8644 therefore has both Ca2+ agonist and Ca2+ antagonist properties, the calcium agonist activity is more pronounced in sensitized tissues.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Effects of leukotriene D4 on the mechanical and electrical properties of guinea-pig isolated trachealis.
1. The effects of leukotriene D4 (LTD4) on mechanical and electrical activity were examined in guinea-pig isolated trachealis muscle and compared with two other bronchoconstrictors, methacholine and potassium chloride (KCl). 2. LTD4 elicited concentration-dependent increases in tension in trachealis muscle which were slower in time course than responses induced by either methacholine or KCl. The maximum response to LTD4 was approximately 85% of the methacholine maximum. 3. At a concentration close to the EC50 for tension changes, LTD4 had no significant effect on either transmembrane potential or slow wave activity recorded in single trachealis cells. 4. At a concentration close to the EC90 for tension changes, LTD4 caused significant membrane depolarization, transiently reduced the amplitude and increased the frequency of slow wave discharge and ultimately abolished slow wave discharge. LTD4-induced depolarization was less marked, and developed more slowly, than that evoked by either methacholine or KCl. 5. These results show that LTD4 can elicit substantial increases in tension without altering transmembrane potential and are consistent with the view that LTD4 initiates contraction mainly through potential-independent mechanisms. However, at high concentrations the depolarization evoked by LTD4 allows the possibility that potential-dependent mechanisms may contribute to the spasm.
Airway Resistance↗
Structure:action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat.
The hypothesis that the neuromuscular blocking potency of pancuronium and vecuronium depends on the two acetylcholine moieties present at positions 3 and 17 was tested in cats by examining the neuromuscular profile of several desacetoxy analogues. Blockade of sciatic nerve-induced contraction of the tibialis and soleus muscles, as well as the effects on vagal-induced bradycardia and on sympathetically induced contractions of the nictitating membrane, were studied. The bis-desacetoxy analogue of pancuronium (ORG 7931) was one-fifth as potent as the parent compound as a neuromuscular blocking drug and as a vagolytic agent, but the neuromuscular block was faster in onset and shorter in duration than that produced by pancuronium. The desacetoxy analogues of vecuronium (ORG 8730 and ORG 8764) also were less potent neuromuscular blocking drugs, and, in addition, produced more vagal block than did vecuronium itself. The neuromuscular block produced by these desacetoxy analogues was of more rapid onset and shorter duration than that produced by vecuronium. The results thus showed that the greater neuromuscular blocking potency of pancuronium and vecuronium is lost after removal of one or both of the acetylcholine moieties. An analysis of the relationship between neuromuscular blocking dose and duration of action revealed that it was reciprocal, and it is suggested that a nondepolarizing equivalent of suxamethonium, when discovered, may necessarily be a drug of relatively low potency.
Animals↗
Electrophysiological and other aspects of excitation-contraction coupling and uncoupling in mammalian airway smooth muscle.
In this article the electrophysiological events which are believed to underly agonist-induced contraction and relaxation of airway smooth muscle are reviewed, with special emphasis on the indispensable role of the Ca ion. The contribution made by Na, K, Ca and Cl to, and the role that the electrogenic Na:K-dependent ATPase plays in, the maintenance of the resting membrane potential in both normal and sensitised airway smooth muscle cells is described together with the permeability changes that occur in the plasmalemma in response to excitatory and inhibitory agonists. In addition, the currently available evidence for the existence of potential-sensitive and receptor-operated Ca channels in respiratory smooth muscle, and how such channels may be involved in the regulation of airway calibre, is critically assessed.
Animals↗
In vivo and in vitro human airway responsiveness to leukotriene D4 in patients without asthma.
We have examined the in vivo airway responsiveness to leukotriene (LT) D4 in 11 patients without asthma who were to undergo thoracotomy and compared this responsiveness with in vitro sensitivity and in vitro contractility of bronchial smooth muscle to LTD4. In vivo responses were measured by the provocation concentration producing a 10% fall in FEV1, a 30% fall in partial flow rate at 30% of total lung capacity from a partial forced expiratory maneuver, and a 35% fall in specific airway conductance. In vitro sensitivity was measured as the concentration of LTD4 producing a 50% of maximum contraction and maximum-induced tension. The smooth muscle content of the bronchial strip was estimated microscopically, and the absolute quantity of muscle strip was compared with the maximum tension generated by that bronchial smooth muscle sample. In vivo results varied over 2 log units, and in vitro sensitivity, over 1 log unit. The absolute amount of smooth muscle present in bronchial strips correlated with maximal LTD4-induced tension. There was no relationship between in vivo responsiveness and in vitro sensitivity nor between in vivo responsiveness and maximum tension generated, even when this was corrected for the proportion of smooth muscle present in each bronchial strip. These results suggest that in vivo airway responsiveness to LTD4 is not determined by airway smooth muscle sensitivity or its ability to generate tension alone. Other factors must be influencing the response of the airway to LTD4. Nevertheless, the finding of a positive correlation between the absolute amount of smooth muscle present in bronchial strips and maximal LTD4-induced tension suggests that hypertrophy and/or hyperplasia of airway smooth muscle may contribute to in vivo airway hyperresponsiveness.
Aged↗
Sr2+ may differentiate high and low affinity Ca2+ stores in guinea-pig trachealis.
1. In guinea-pig trachealis Ca2+ are mobilized from different stores to produce the contractions to various agents. 2. Sr2+ can substitute for Ca2+ and maintain responses to KC1 but not responses to A23187 or agents acting via drug-receptor interaction. 3. Resting tone and responses to KC1 are supported by low affinity Ca2+. 4. Responses to the other agents are supported by high affinity Ca2+.
Animals↗
Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle.
1. The effects of three phosphodiesterase inhibitors (papaverine, isobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2. The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation of histamine-induced contractions of the trachealis. 3. Papaverine-induced relaxation was associated with concentration-related increases in the levels of both cyclic nucleotides. 4. IBMX at low concentrations (1 mumol l-1) produced significant relaxation (36%) of histamine-contracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX-induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels. Only at the highest concentration tested (100 mumol l-1) did IBMX increase cyclic AMP levels significantly. 5. SKF 94120 (1 mumol l-1) elicited a 23% relaxation of the contracted trachealis without altering the tissue content of either cyclic nucleotide. At the two higher concentrations tested (10 and 100 mumol l-1), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6. In the skinned trachealis Ca2+ (10 and 20 mumol l-1)-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 mumol l-1) and by cyclic AMP (10 mumol l-1), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 mumol l-1) and cyclic GMP (10 mumol l-1). 7. Papaverine (100 mumol l-1) significantly inhibited (31 +/- 6%) the Ca2+-induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. It is concluded that cyclic nucleotide-dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase- inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.
1-Methyl-3-isobutylxanthine↗
Does thromboxane mediate the indirect contractile action of leukotriene D4 in guinea-pig isolated lung parenchyma under equilibrium conditions?
The role that thromboxane A2 plays in contractions induced by leukotriene D4 in guinea-pig isolated lung parenchyma was investigated under equilibrium conditions. Lung tissue generated thromboxane A2 and prostacyclin spontaneously as evidenced by the slow accumulation of their biologically inactive metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, in the bathing buffer. Challenge of guinea-pig lung parenchyma with a high concentration (EC90 for tension generation) of leukotriene D4 (200 nM) produced a biphasic contraction of the tissue that consisted of an initial rapid increase in isometric tension followed by a slowly developing, well-sustained contracture. In addition, leukotriene D4 (200 nM) effected a transient increase (over basal) in the generation of thromboxane A2 and prostacyclin that lagged significantly behind the tension response. Kinetic analysis of the mechanical and eicosanoid-generating effect of leukotriene D4 revealed that tension development could be suitably fitted to a biexponential function, whilst the release of both eicosanoids from the lung occurred monoexponentially. Pretreatment of the lung with the cyclooxygenase inhibitor, flurbiprofen, which effectively abolished both the spontaneous and the leukotriene D4-stimulated eicosanoid biosynthesis, significantly reduced both the first order rate coefficient of the first exponent and the maximum amplitude of this function with respect to control. This change in the kinetics describing leukotriene D4-induced contractions was explained by the fact that the initial rate of tension development was markedly reduced following pretreatment of the lung with flurbiprofen. Neither the inhibitor of thromboxane synthetase, dazmegrel, which selectively inhibited (by 95%) leukotriene D4-stimulated thromboxane A2 formation, nor blockade of 11 alpha,9 alpha-epoxymethano-prostaglandin H2 (U-46619)-sensitive (thromboxane A2) receptors with either AH 23848 or EP 092 affected the profile of leukotriene D4-induced tension development in guinea-pig lung. It is concluded that a high concentration of leukotriene D4 (200 nM) contracts guinea-pig lung by both a direct and indirect mechanism. Initially, a rapid short-lived contraction of the lung is manifest which is dependent, in part, upon the synthesis and release of cyclooxygenase product(s) other than thromboxane A2. This initial response occurs coincidently with, and is subsequently followed by, the development of a tonic well-sustained contracture that is the result of a direct action of leukotriene D4 on the contractile cells that comprise the lung.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Airway smooth muscle and disease workshop: calcium channels.
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Animals↗
Leukotriene antagonist FPL 57231 prevents the acute pulmonary effects of Escherichia coli endotoxin in cats.
We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
The dependence of airway smooth muscle on extracellular Ca2+ for contraction is influenced by the presence of cartilage.
Isolated guinea-pig and rabbit airway smooth muscle preparations lacking cartilage are less able to contract, in response to methacholine, histamine and K+, in the absence of extracellular Ca2+ than cartilage-containing preparations removed from the same animal. Cartilage apparently provides utilizable Ca2+ for contraction of airway smooth muscle. The presence of cartilage, therefore, affects the apparent dependence of the isolated smooth muscle on extracellular Ca2+ for contraction.
Animals↗
Agonist-induced contractile responses of human bronchial muscle in vitro: effects of Ca2+ removal, La3+ and PY108068.
The effects of reducing the extracellular Ca2+ concentration ([Ca2+]0), the effects of La3+ and the dihydropyridine Ca2+ entry blocker PY108068 on contractile responses in human isolated bronchial strips have been compared. Reducing [Ca2+]0 or the presence of La3+ (1 mM) caused a reduction in basal tone, whereas PY108068 (1 microM) had no effect on unstimulated preparations. Response to KCl and A23187 were, in general, more markedly depressed by reducing the entry of extracellular Ca2+, with La3+ or PY108068 than were those to histamine, methacholine and LTD4. The effects of reducing [Ca2+]0, La3+ and PY108068 on responses to the receptor-mediated agents suggest that intracellular Ca2+ may be mobilized upon receptor activation, whereas responses to KCl and A23187 appear to be dependent upon the influx of extracellular Ca2+. More than one source of activator Ca2+ can therefore be involved in the development of contractions in human airway smooth muscle. These findings are in accord with those observed for in vitro airways preparations from experimental animals.
Bronchi↗
Desensitization of platelet alpha 2-adrenoceptors after short term infusions of adrenoceptor agonist in man.
The effect of intravenous infusion of catecholamines and related drugs on human platelet alpha 2-adrenoceptor number and function was investigated. Short (60-120 min) infusions of catecholamines with alpha 2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. Acute infusions of alpha 2-adrenoceptor agonists may alter the coupling of the platelet alpha 2-adrenoceptor to adenylate cyclase.
Adolescent↗
Does naloxone induce relaxation of guinea-pig airway smooth muscle?
The effects of the opiate receptor antagonist naloxone were investigated on isolated preparations of guinea-pig trachealis contracted with either histamine, methacholine or KCl. The commercially available solution of naloxone (Narcan) induced concentration-dependent relaxation of the contracted airway preparations. In stark contrast, aqueous solutions of naloxone were without any significant relaxant effect. Aqueous solutions of the preservatives (methyl and propyl hydroxybenzoate) present in the vehicle used in the commercial formulation of naloxone mimicked exactly the relaxant effects induced by Narcan. Thus, naloxone does not directly induce relaxation of airway smooth muscle. The effects of Narcan can be solely attributed to the activity of the preservatives present in the vehicles. The mechanism underlying the bronchodilator activity of methyl and propyl hydroxybenzoate is unknown but is not related to receptor blockade or to alterations in the intracellular levels of cyclic AMP.
Animals↗
In vitro and in vivo effect of verapamil on human airway responsiveness to leukotriene D4.
The mechanism by which leukotriene D4 (LTD4) induces airway narrowing in man is unclear. We have investigated this by examining the effect of the calcium channel blocker verapamil on the sensitivity of in vitro preparations of human bronchi to LTD4 and methacholine, and on the bronchoconstriction induced in normal subjects by these agonists in vivo. In vitro smooth muscle sensitivity was assessed by the concentration of LTD4 and methacholine causing a 50% of maximum contraction (EC50) and as the maximum tension generated. Verapamil did not alter baseline tension or the response to LTD4 but did inhibit contractile responses to methacholine. In vivo studies were performed in six normal subjects; they inhaled increasing concentrations of LTD4 (0.4-50 micrograms/ml) or methacholine (2-64 mg/ml). Airway responsiveness in vivo was expressed as the provocation concentration (PC) of agonist producing a 35% fall in specific airways conductance (PC35sGaw) and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Verapamil did not alter baseline sGaw or V30(p). One subject did not respond to LTD4 on either day. In contrast to the in vitro results, verapamil produced a greater than 10 fold reduction in LTD4 induced bronchoconstriction, but had no effect on methacholine induced bronchoconstriction. These results suggest that in normal subjects bronchoconstriction induced by inhaled LTD4 is due to a combination of direct and indirect mechanisms.
Adult↗