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PubMed1999

Chloride transport in the ferret trachea.

A net secretion of chloride stimulated by carbamylcholine was observed in whole trachea. Luminal anthracene-9-carboxylic acid inhibited the net secretion of chloride and the transepithelial potential difference across the isolated trachea. Submucosal ouabain inhibited the net secretion of chloride and submucosal ouabain, or submucosal bumetanide inhibited the transepithelial potential difference across the isolated trachea. Short-circuited flat sheets of trachea manifested a net secretion of chloride induced by carbamylcholine. Serosal ouabain inhibited the short-circuit current and net chloride flux across isolated flat sheets of trachea.

Animals↗
PubMed2002

Increased function of inhibitory neuronal M2 muscarinic receptors in trachea and ileum of diabetic rats.

1. Release of acetylcholine from parasympathetic nerves is inhibited by neuronal M(2) muscarinic receptors. The effects of streptozotocin-induced diabetes on prejunctional M(2) and postjunctional M(3) muscarinic receptor function in rat trachea and ileum were investigated in vitro. 2. Neuronal M(2) muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of trachea and ileum. Concentration-response curves to pilocarpine and methoctramine were shifted to the left in both to a greater degree in diabetics than controls. 3. In trachea, post-junctional M(3) muscarinic receptor function was increased since maximum contractile responses to the muscarinic agonists acetylcholine and carbachol were greater in diabetics than controls. This increase offset the increased function of the inhibitory neuronal M(2) muscarinic receptors since EFS-induced, frequency-dependent contraction was equal in control and diabetic rats. 4. In contrast, post-junctional M(3) muscarinic receptor function was unchanged by diabetes since concentration-response curves to acetylcholine and carbachol were not different between groups. Thus, EFS-induced contractions of the ileum were decreased in diabetics versus controls. 5. In conclusion, inhibitory M(2) muscarinic receptors on parasympathetic nerves in the trachea and ileum are hyperfunctional in diabetic rats. The function of post-junctional M(3) muscarinic receptors in the trachea, but not the ileum, is also increased in diabetes. 6. The dysfunction of inhibitory, neuronal M(2) muscarinic receptors in the airways may protect against hyperreactivity and in the ileum may contribute to gastrointestinal dysmotility associated with diabetes.

Animals↗
PubMed1997

Effects of noise stress on EFS-mediated cholinergic and inhibitory NANC responses in tracheae from normal and sensitized guinea-pigs.

1 The aim of the present research was to study the cholinergic and inhibitory non-adrenergic-non-cholinergic (NANC) responses obtained with electrical field stimulation (EFS) of tracheal tissues from sham- and noise-exposed guinea-pigs. A comparison was also made between normal and ovalbumin (OA)-sensitized animals. 2 In proximal tracheae pretreated with indomethacin (3 microM), propranolol (1 microM), alpha-chymotrypsin (2 U ml-1) and L-NAME (0.1 mM), frequency-dependent responses to EFS (0.1 ms width; 20 V, 0.1-100 Hz, 15 s train duration) were obtained, both contractile and relaxing in nature. The contractile responses were abolished by atropine (1 microM), and did not vary significantly between sham- and noise-exposed guinea-pigs, or between normal and sensitized animals. The NANC relaxing responses, present in spite of the pre-treatment of the tissues with L-NAME and alpha-chymotrypsin, and almost completely abolished by tetrodotoxin (TTX) treatment (10 microM), appeared to be enhanced in noise-exposed guinea-pigs, with respect to sham-exposed animals, but only when the animals were not OA-sensitized. 3 In distal tracheae contracted with histamine (10 microM), the study of the whole inhibitory NANC response (pre-treatment with propranolol, but not with alpha-chymotrypsin and L-NAME), which was mainly TTX-sensitive, revealed a statistically non-significant difference between sham- and noise-exposed guinea-pigs, both normal and OA-sensitized. When distal tracheae were preincubated with alpha-chymotrypsin (2 U ml-1) and L-NAME (0.1 mM), in addition to propranolol, a significant residual inhibitory NANC response to EFS was observed. Surprisingly, in this case, similarly to the evidence obtained in proximal tracheae, a significantly enhanced response was revealed in noise-exposed guinea-pigs with respect to sham-exposed animals. 4 The noise-induced enhancement of the relaxant response disappeared when the tissues were pretreated with the A2 purinergic antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 1 microM), while it persisted in the presence of the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM). 5 The above data indicate that, while not modifying the cholinergic and the whole inhibitory NANC response to EFS, noise stress selectively influences an inhibitory component of the NANC system in guinea-pig trachea with a mechanism probably involving an enhanced neurally mediated release of adenosine, which relaxes the smooth muscle via A2 receptors. This effect appears to be lacking or masked in sensitized guinea-pigs.

Acetylcholine↗
PubMed2000

Influence of the epithelium on acetylcholine release from parasympathetic nerves of the rat trachea.

1. The present study was undertaken to investigate the influence of the airway epithelium on the release of acetylcholine (ACh) from parasympathetic nerves of the rat trachea. Epithelium-intact and epithelium-denuded preparations of rat trachea were incubated with [3H]-choline to incorporate [3H]-ACh into the cholinergic transmitter stores. Release of radiolabelled transmitter ACh was evoked by electrical field stimulation (60 s trains of 1 ms pulses, 5 Hz, 15 V). 2. Field stimulation both of epithelium-intact and epithelium-denuded radiolabelled tracheal preparations evoked an increase in the efflux of radioactivity; however, the mean stimulation-induced (S-I) efflux from epithelium-denuded preparations (2932 +/- 190 d.p.m., n = 9) was approximately 60% of that from epithelium-intact preparations (4802 +/- 820 d.p.m., n = 11). We have shown previously that, in epithelium-intact (but not epithelium-denuded) tracheal preparations, a substantial proportion of the S-I efflux is resistant to tetrodotoxin (1 microM) and to the removal of extracellular Ca2+, indicating that much of the S-I efflux is not caused by exocytotic release of neuronal [3H]-ACh. In epithelium-denuded tracheal preparations, superfused individually, phosphorylcholine (1 and 100 microM) did not alter S-I efflux. In epithelium-intact tracheal preparations, both in the absence and in the presence of atropine (1 microM), neither N(G)-nitro-L-arginine (100 microM), superoxide dismutase (100 units ml(-1)), indomethacin (10 microM), capsaicin (30 microM) nor alpha-chymotrypsin (1 unit ml(-1)) altered S-I efflux. 3. Experiments were also performed using two tracheal preparations superfused in series. When unlabelled epithelium-intact preparations were present in the upper chamber (superfused first), the S-I efflux from radiolabelled epithelium-denuded preparations in the lower chamber (superfused second) did not differ significantly from radiolabelled epithelium-denuded preparations superfused individually. Moreover, there was no significant difference in the S-I efflux from radiolabelled epithelium-denuded preparations in the lower chamber between experiments in which the upper chamber contained epithelium-intact or epithelium-denuded preparations. 4. Field stimulation of epithelium-intact tracheal preparations in the upper chamber with 90, 120 and 300-s periods (trains of 1 ms pulses, 5 Hz, 15 V) did not significantly alter the S-I efflux from radiolabelled epithelium-denuded tracheal preparations in the lower chamber. 5. When introduced into the upper (unlabelled epithelium-intact) and subsequently allowed to superfuse the lower (radiolabelled epithelium-denuded) tracheal preparations, the stable cholinomimetic carbachol (3 microM) markedly reduced the S-I efflux whereas ACh (0.1 and 1 microM) had no significant effect. However, in the presence of the anti-cholinesterase neostigmine (1 microM), ACh (1 microM) significantly reduced S-I efflux, indicating that ACh is subject to rapid hydrolysis by cholinesterase enzymes. When atropine (10 microM) was only exposed to radiolabelled epithelium-denuded preparations in the lower chamber, the inhibitory effects of ACh (1 microM) and carbachol (3 microM) on S-I efflux were prevented. 6. In conclusion, the findings of the present study do not support the notion that the airway epithelium exerts an inhibitory influence on ACh release from parasympathetic nerves of the rat trachea. Alternatively, if epithelium-dependent modulation of cholinergic transmission does occur in the rat trachea, then the mechanism does not appear to involve phosphorylcholine, nitric oxide, superoxide radicals, cyclo-oxygenase products of arachadonic acid, capsaicin-sensitive neuropeptides or vasoactive intestinal peptide. Moreover, the inhibitory effect of carbachol and ACh on transmitter ACh release in the rat trachea appears to be due solely to activation of prejunctional inhibitory muscarinic cholinoceptors on parasympathetic nerves and does not involve the liberation of a putative epithelium-derived inhibitory factor.

Acetylcholine↗
PubMed1983

Indications for endoscopic Nd-YAG laser surgery in the trachea and bronchus.

Nd-YAG laser surgery via the fiberoptic bronchoscope can vaporize lesions causing airway obstruction or stenosis located from the trachea to segmental bronchi with minimized danger of bleeding, and improve ventilatory disturbances. 35 lesions in the trachea and bronchus consisting of 27 malignant lesions and 8 benign lesions were treated with endoscopic Nd-YAG laser surgery. The procedures were performed under local anesthesia, and no significant side effects were recognized. The lesions was irradiated with 20-80 W. power. In most cases a continuous wave was used, but in cases of early stage squamous cell carcinoma intermittent irradiation of 0.5 second laser spots were used. In 21 of 35 cases effective results were obtained. The non-effective results obtained in 14 cases were considered to be due to inexact preprocedural evaluation of the extent of the lesions. Effective results were obtained in 11 of 13 lesions located in the trachea, in 3 of 5 lesions in the trachea and bronchus and in 7 of 17 lesions in the bronchus. Tumor in the trachea with severe ventilatory disturbance is a good indication for Nd-YAG laser surgery to rapidly alleviate symptoms. But in cases of lung cancer, indications even as a palliative procedure are limited to those cases in which the lung parenchyma distal to the stenotic portion is viable. However, the indications for this procedure as a curative modality are extremely limited.

Adult↗
PubMed2001

Seven Wnt homologues in Drosophila: a case study of the developing tracheae.

Sequencing of the Drosophila genome has revealed that there are "silent" homologues of many important genes-family members that were not detected by classic genetic approaches. Why have so many homologues been conserved during evolution? Perhaps each one has a different but important function in every system. Perhaps each one works independently in a different part of the body. Or, perhaps some are redundant. Here, we take one well known gene family and analyze how the individual members contribute to the making of one system, the tracheae. There are seven DWnt genes in the Drosophila genome, including wingless (wg). The wg gene helps to pattern the developing trachea but is not responsible for all Wnt functions there. We test each one of the seven DWnts in several ways and find evidence that wg and DWnt2 can function in the developing trachea: when both genes are removed together, the phenotype is identical or very similar to that observed when the Wnt pathway is shut down. DWnt2 is expressed near the tracheal cells in the embryo in a different pattern to wg but is also transduced through the canonical Wnt pathway. We find that the seven DWnt genes vary in their effectiveness in specific tissues, such as the tracheae, and, moreover, the epidermis and the tracheae respond to DWnt2 and Wg differently. We suggest that the main advantage of retaining a number of similar genes is that it allows more subtle forms of control and more flexibility during evolution.

Animals↗
PubMed2002

L-carnitine does not exert any in vitro relaxant effect in Guinea pig trachea, lung parenchyma and human bronchial tissue.

The aim of the present study was to investigate the probable in vitro relaxant effect of carnitine in guinea pig trachea, guinea pig lung parenchymal strips, and human bronchial tissue. It was suggested by an in vivo study that carnitine pretreatment prevented the subclinic bronchospasm in children who underwent chronic hemodialysis. Tracheal and lung parenchymal preparations of 10 guinea pigs and 5 human bronchial tissues were prepared and mounted in 20-mL organ baths. In the first series of experiments, contractions to carbachol and histamine (10(-9) to 10(-3) M) were compared after the tissues were incubated with different concentrations of L-carnitine (10(-6) to 10(-4) M). pD(2) values were compared with analysis of variance (ANOVA) and P <.05 was considered as significant. In the second part of experiments, the inhibitory effect of L-carnitine (10(-9) to 10(-3) M) was investigated on the sustained contractions of preparations to carbachol (10(-6) M) and histamine (10(-5) M). In the first part of the study pD(2) values obtained with carbachol were 6.48 +/- 0.09, 5.42 +/- 0.05, and 6.48 +/- 0.02 for guinea pig trachea, guinea pig lung parenchymal strips, and human bronchial tissues, respectively. pD(2) values obtained with histamine were 5.34 +/- 0.10, 5.74 +/- 0.06, and 6.32 +/- 0.03 for guinea pig trachea, guinea pig lung parenchymal strips, and human bronchial tissues, respectively. No significant difference was observed between the pD(2) values before and after incubation with carnitine (P >.05). In the second part of the study, only 10(-4) M L-carnitine exerted an insignificant relaxant effect (6.16% +/- 1.22% on carbachol induced contractions and 4.48% +/- 0.85% on histamine induced contractions) in guinea pig trachea. Our results show that L-carnitine exerts no in vitro relaxant effect in guinea pig trachea, guinea pig lung parenchymal strips, and human bronchial preparations.

Animals↗
PubMed1990

Mechanism of thiopental-induced constriction of guinea pig trachea.

The authors studied the effects of thiopental on baseline airway tone in intact guinea pig tracheas using a preparation where the epithelial (inside) and serosal (outside) surfaces were isolated. Whole tracheas were excised, cannulated, and mounted in 50-ml tissue baths. The serosal and epithelial surfaces were perfused via separate circuits with Krebs-Henseleit solution. All data were expressed as a percent of constriction produced by 2 X 10(-6) M carbachol (a concentration that elicited a 90 + % of maximal constriction). Thiopental elicited a dose-dependent constriction in all 25 tracheas. Increases in tone were first seen at 10(-5) M (14.3 +/- 1.84%; mean +/- SEM) and reached a peak at 10(-3) M (29 +/- 3.16%; P less than .0001). Responses to thiopental were similar when the epithelium was removed, when thiopental was added to the inner perfusate, and when tracheas were pretreated with 10(-5) M pyrilamine. Constriction was entirely inhibited by pretreatment with indomethacin 10(-5) M. The authors conclude that thiopental, at concentrations in the clinical range, causes a reproducible dose-dependent constriction of guinea pig trachea. This effect is mediated by constrictor prostaglandins.

Animals↗
PubMedDate not supplied

Experimental study of bioactive polyurethane sponge as an artificial trachea.

An artificial trachea that has tissue reconstructive activity and elasticity that matches a biologic trachea was fabricated using a polyurethane sponge (PS). The inner surfaces of the PS were modified by immobilizing collagen, fibronectin, RGD peptide, a coating of collagen, and apatite. Two PS pore sizes were prepared, 150 to 350 microns (small pore) and 350 to 710 microns (large pore). When they were implanted in the subcutaneous tissue of rats, study of the implantation showed severe inflammatory cell infiltration with the treated PS, especially with collagen and collagen coating. Infiltration and maturity of fibroblasts inside the PS were noted with fibronectin. Infiltration of inflammatory cells and fibroblasts was noted with small pore PS compared with large pore PS. Partial tracheal defects were patched with PS. Better epithelization of PS patches was observed with fibronectin and apatite compared with the others. The artificial trachea made of PS was transplanted into the tracheas of dogs. No separation of the anastomosis and tissue reconstruction of the artificial trachea wall were observed; however, sputum absorption and tracheal granulation were seen.

Amino Acid Sequence↗
PubMed2000

Lymphocytic infiltration in the chicken trachea in response to Mycoplasma gallisepticum infection.

A prominent feature of disease induced by Mycoplasma gallisepticum is a lymphoproliferative response in the respiratory tract. Although this is also seen in other mycoplasma infections, including Mycoplasma pneumoniae, the phenotype of the lymphocytes infiltrating the respiratory tract has not been determined. In this study, the numbers and distribution of lymphocytes in the tracheas of chickens infected with a virulent strain of M. gallisepticum were examined. Three groups of chickens were experimentally infected with M. gallisepticum and three unchallenged groups were used as controls. One infected and one control group were culled at 1, 2 and 3 weeks post infection. Tracheas were removed and examined for the presence and number of T cells carrying CD4, CD8, TCRgamma7, TCRalphabeta1 or TCRalphabeta2 markers. There was no significant difference in the number of CD8+ cells in the upper, middle and lower trachea. High numbers of both CD4+ and CD8+ cells were found with variable numbers of TCRalphabeta1+ and TCRalphabeta2+, but no TCRgammadelta+, cells throughout the time course. The distribution of CD4 cells was dispersed, while the CD8+ cells were clustered in follicular-like arrangements. No difference was detected in the distribution of TCRalphabeta1+ and TCRalphabeta2+ cells. The titre of mycoplasma genomes in the trachea decreased significantly from 1 to 2 weeks, while the mucosal thickness of the trachea increased significantly from 1 to 2 weeks then decreased from 2 to 3 weeks, indicating resolution of the lesions following control of infection. This study is the first to examine the phenotypes of T lymphocytes infiltrating the respiratory tract during mycoplasma infections. The findings suggest involvement of specific stimulation of CD8+ cells, particularly in the acute phase of disease.

Animals↗
PubMedDate not supplied

Antagonism by manganese of isoprenaline dilatation of the guinea-pig isolated trachea.

Manganese (0.5-100 mumol/l) was found to be a potent inhibitor of the dilator effect of isoprenaline on the isolated tracheal muscle of the guinea-pig. Above these concentrations the inhibitory action of Mn2+ diminished and no inhibition occurred above 1000 mumol/l Mn2+. Thus a bell-shaped dose-response curve resulted for the inhibition of isoprenaline by Mn2+. The antagonism was surmountable but apparently noncompetitive. Dilation of the isolated trachea caused by theophylline or nitroprusside was not inhibited by Mn2+ at concentrations of 12.5 to 750 mumol/l. At the dose range which could be tested manganese did not antagonize isoprenaline bronchodilatation in vivo. However, manganese at doses between 0.5 and 2.0 mumol/kg inhibited increased in pulmonary resistance caused by acetylcholine, histamine or serotonin. At concentrations above 250 mumol/l Mn2+ inhibited constrictor responses to histamine, acetylcholine and serotonin in guinea-pig isolated ileum and trachea, and inhibited serotonin and prostaglandin E2 contractions in rat fundus. Co2+, Fe2+, Fe3+ and Zn2+ were also tested for their action against isoprenaline on the isolated trachea. Co2+ was similar in effect to Mn2+ but had only 1/50 of the potency. Up to the highest concentrations which could be tested, namely 1000 mumol/l, the other trace metals produced negligible effects. Thus Mn2+ showed selective inhibition of the relaxant effect of isoprenaline on the guinea-pig isolated trachea, at concentrations of Mn2+ well below those shown previously to inhibit constrictor responses by block of transmembrane Ca2+ entry. It is suggested that Mn2+ may interfere with intracellular Ca2+ fluxes in the isolated trachea.

Animals↗
PubMed1986

Physiological and pharmacological characterization of an in vitro vagus nerve-trachea preparation from guinea-pig.

The trachea with the vagus nerves attached was isolated from guinea-pigs. Contractile responses to nerve stimulation or to drugs were measured as pressure changes in the fluid-filled lumen. Electrical stimulation of the vagus nerves caused a prompt increase in the intratracheal pressure with an optimum frequency of stimulation between 20 and 30 Hz. The response to the left vagus was somewhat stronger than the response to the right vagus. Carbachol caused a maximum pressure increase which was about twice that achieved by bilateral stimulation of the vagus nerves at 20 Hz. In the presence of physostigmine the two sources of stimuli were equally effective. The excitatory response to stimulation of the vagus nerves was completely inhibited by hexamethonium, atropine and terbutaline. This indicates that the excitatory response is mediated via ganglia with end-organ responses mediated exclusively by muscarinic receptors and functionally antagonized by stimulation of beta 2-adrenoreceptors. The trachea preparation exhibited an intrinsic tone which was reduced by terbutaline and indomethacin but not by atropine or hexamethonium. It is probable that prostaglandins are involved in the generation of intrinsic tone. Noradrenaline caused a concentration dependent inhibition of the vagally mediated contractions of the trachea which was antagonized by propranolol and yohimbine. When tracheal tone was induced by carbachol only propranolol was effective thus indicating both pre- and postsynaptic effects of noradrenaline. The present study has shown that the isolated vagus nerve-trachea is a stable and useful preparation for the evaluation of drugs acting at various levels of the contractile responses of the trachea.

Animals↗
PubMed1988

Comparison of the muscarinic receptors of the guinea-pig oesophageal muscularis mucosae and trachea in vitro.

1. The muscarinic receptor profile of the guinea-pig oesophageal muscularis mucosae has been compared to that of the trachea in vitro. There was no significant difference in the potency of the following muscarinic agonists at muscarinic receptors in the two tissues: carbachol, RS-86, ethoxyethyltrimethyl-ammonium, bethanechol and pilocarpine. RS-86 was 6-fold more potent at receptors in the muscularis mucosae in comparison to the trachea. There was no difference in the affinity of either carbachol or RS 86 at receptors in the two tissues. 2. The affinities (pA2) of the majority of antagonists (atropine, 4 diphenylacetoxy-N-methylpiperidine methiodide, AF-DX 116, silabenzhexol, methoctramine and gallamine) were similar at receptors in the muscularis mucosae and trachea. In contrast, the affinity of pirenzepine was approximately 5-fold greater at receptors in the muscularis mucosae (pA2 = 7.4) in comparison to receptors in the trachea (pA2 = 6.8). 3. It is concluded that the muscarinic receptor profile of the oesophageal muscularis and trachea are similar and only differ slightly with respect to the affinity of pirenzepine. Consequently, it is difficult to justify receptor heterogeneity in these two tissues.

Animals↗
PubMed1977

The use of functional antagonism to determine whether beta-adrenoceptor agonists must have a lower efficacy than isoprenaline to be trachea-atria selective in vitro in guinea-pigs.

1 The relative efficacies of three trachea-atria selective beta-adrenoceptor agonists, fenoterol, Me 506 and Me 454, compared to isoprenaline, were determined on both trachea and atria of guinea-pigs. 2 On tracheal preparations the beta-adrenoceptor agonists were used as functional antagonists of carbachol and a comparison of the maximum shifts in the carbachol concentration-response line produced by each of the beta-adrenoceptor agonists provided a comparison of their efficacies. 3 On atrial preparations carbachol was used as a functional antagonist of the beta-adrenoceptor agonists and comparison of the maximum responses to the beta-adrenoceptor agonists in the presence of carbachol provided a comparison of their efficacies. 4 On trachea and atria the order of efficacy of the compounds was Me454 greater than Me506 greater than or equal to isoprenaline=fenoterol. 5. The results indicated that high efficacy in a non-catechol beta-adrenoceptor agonist is possible provided there is a favourable N-substituent group. 6 Since Me 454, Me 506 and fenoterol, which are trachea-atria selective, have effficacies equal to or greater than that of isoprenaline, which is non-selective, it is concluded that low efficacy in a compound is not essential for it to show trachea-atria selectivity in vitro in guinea-pigs.

Adrenergic beta-Agonists↗
PubMed1980

A study of some propranolol analogues for selective beta-adrenoceptor antagonism using A2 values on isolated trachea and atria from guinea-pig.

1 PA2 values for beta-adrenoceptor antagonists were obtained on isolated preparations of guinea-pig trachea (intrinsic tone) and atria (rate), with isoprenaline, noradrenaline (beta 1-selective) and fenoterol (beta 2-selective) as agonists. Uptake mechanisms and alpha-adrenoceptors were inhibited. The antagonists studied were (+/-)-threo-alpha-methylpropranolol. (+/-)-1(4-benzimidazoloxy)-3-isopropylamino-2-propanol (4-BIP) and (+/-)-1-(5-benzimidazoloxy)-3-isopropylamino-2-propanol (5-BIP). 2 4-BIP was a potent beta-adrenoceptor antagonist but it was not selective for trachea (pA2 on trachea 7.88 and on atria 7.73, fenoterol as agonist). 5-BIP was less than one tenth as active as 4-BIP and was therefore not studied in detail. 3 alpha-Methylpropranolol was potent and it was also selective for trachea (pA2 on trachea 8.24 and on atria 7.56, fenoterol as agonist). This selectivity was not seen with isoprenaline as agonist. In tracheal preparations contracted by carbachol the slope of the Schild plot for alpha-methylpropranolol was less than 1.0 (isoprenaline as agonist). 4 alpha-Methylpropranolol, although not highly selective for beta 2-adrenoceptors, is considerably more potent than the alternative beta 2-selective antagonists available at present. Therefore, it may be useful in studies designed to classify beta-adrenoceptor subtypes in tissues.

Adrenergic beta-Antagonists↗
PubMed1983

The effects of 2-nicotinamidoethyl nitrate on smooth muscle cells of the dog mesenteric artery and trachea.

The effects of 2-nicotinamidoethyl nitrate (nicorandil; 2-NN), a synthesized coronary vasodilator, on smooth muscle cells of dog mesenteric artery or trachea were investigated using microelectrode, double sucrose gap and isometric tension recording methods. Nicorandil hyperpolarized the smooth muscle membrane of the mesenteric artery (5 X 10(-6)M) and the trachea (5 X 10(-5)M). In both these smooth muscle cells, the nicorandil-induced hyperpolarization remained constant in various concentrations of [Cl-]o, but changed with various concentrations of [K+]o. This hyperpolarization was partly inhibited following pretreatment with tetraethylammonium (TEA greater than 1 mM) and was completely inhibited following pretreatment with procaine (1 mM or 5 mM), indicating that the nicorandyl-induced hyperpolarization is due to increase in the K-conductance, in both these membranes. Following pretreatment with TEA (5 mM), outward current pulses evoked an action potential in tracheal smooth muscle cells. Nicorandil inhibited the generation of action potential due to the hyperpolarization of the membrane but not due to inhibition of the spike generating mechanism. Nicorandil (10(-6)M) inhibited the contracture evoked by excess [K]o, in both tissues. The contracture evoked by noradrenaline or repetitive field stimulation with short duration (50 microseconds) pulses was also inhibited in the mesenteric artery, while a higher dose of nicorandil (10(-5)M) was required to inhibit the contracture evoked by acetylcholine or repetitive field stimulation in the trachea. Excitatory junction potentials (e.j.ps) evoked by field stimulation in the mesenteric artery due to the release of noradrenaline, or in the trachea due to release of acetylcholine, were suppressed by 10(-5)M or 5 X 10(-5)M nicorandil, respectively. The reduction in the amplitude of e.j.p. was mainly due to the hyperpolarization of the membrane with increase in the membrane conductance. In the mesenteric artery, following pretreatment with TEA (1 mM) an action potential was generated on the e.j.p.. Nicorandil suppressed the generation of the action potential by reduction in the amplitude of the e.j.p., below the threshold required for generation of the action potential. These results indicate that nicorandil hyperpolarizes the membrane by increasing K-conductance and inhibits the generation of contraction, in both tissues. Higher concentrations of nicorandil are required to suppress the mechanical response in the trachea than in the mesenteric artery. Depression of the mechanical responses in both tissues is partly due to suppression of Ca-mobilization inside the muscle cells and partly to hyperpolarization of the membrane.

Animals↗
PubMed1989

Endotoxin-induced hyperreactivity of the guinea-pig isolated trachea coincides with decreased prostaglandin E2 production by the epithelial layer.

1. Pretreatment of guinea-pigs with endotoxin (1 mg kg-1 b.w., i.p., 4 days before the experiments) results in respiratory airway hyperreactivity in vitro. Dose-response curves with either arecoline or histamine on isolated tracheae from these animals display increased maximal contractions, and decreased EC50 values. 2. Tracheae denuded of epithelium respond with a similar hyperreactivity to histamine as observed in preparations from endotoxin pretreated animals. Removal of the epithelial layer of tracheae from endotoxin pretreated guinea-pigs did not additionally affect the histamine dose-response curve. 3. The cyclo-oxygenase inhibitor indomethacin (10 microM) induces histamine hyperreactivity which is equal in intact and epithelium-denuded tracheae from saline or endotoxin pretreated guinea-pigs. Similar results are obtained with the combined lipoxygenase/cyclo-oxygenase inhibitor nordihydroguaiaretic acid (10 microM). 4. Histamine (0.1 mM) induces an increase in prostaglandin E2 (PGE2) formation by the tracheal spiral in vitro, which is reduced by 34% by endotoxin pretreatment, and by about 60% following epithelium removal irrespective of endotoxin pretreatment. 5. Arachidonic acid (AA, 22 microM) stimulation of the guinea-pig trachea in vitro induces a relaxation, and an increase in PGE2 production. In preparations lacking the epithelium, AA induces a contraction which coincides with a 60% reduced increase in PGE2 formation. These effects are not altered by endotoxin pretreatment. 6. It is concluded that the endotoxin-induced respiratory airway hyperreactivity may be caused by a disturbed ability of epithelial cells to synthesize PGE2. The decreased formation of this prostaglandin is rather the consequence of a diminished liberation of AA from the phospholipid stores than a dysfunction of the cyclo-oxygenase enzyme.

Airway Resistance↗
PubMed1990

Distribution of beta 1- and beta 2-adrenoceptors in mouse trachea and lung: a quantitative autoradiographic study.

1. Binding and quantitative autoradiography were used to detect [125I]-iodocyanopindolol (I-CYP) associated with beta 1- and beta 2-adrenoceptors in mouse tracheal epithelium and airway smooth muscle as well as in lung parenchymal tissue. 2. Specific I-CYP binding to slide-mounted tissue sections of both trachea and parenchyma was of high affinity (KD = 49.0 pM, n = 3, trachea; KD = 118.9 pM, n = 3, parenchyma) and saturable, involving single populations of non-interacting binding sites (Hill coefficient nH = 1.00 +/- 0.02, trachea; nH = 0.99 +/- 0.03, parenchyma). 3. Direct measurement of tissue radioactivity also showed that specific I-CYP binding was competitively inhibited in the presence of the beta-adrenoceptor antagonists (-)-propranolol (non-selective), CGP 20712A (beta 1-selective) and ICI 118,551 (beta 2-selective). Analysis of the competition binding curves for the two selective antagonists revealed mixed populations of beta 1- and beta 2-adrenoceptors in the approximate proportions 33% and 67% respectively in mouse trachea and 28% and 72% respectively in mouse lung parenchyma. 4. Densities of autoradiographic grains derived from specific I-CYP binding to alveolar wall tissue and to tracheal epithelium and airway smooth muscle were quantified by a computer-assisted image analysis system, which allowed the construction of competition binding curves in the presence of the selective beta-adrenoceptor antagonists CGP 20712A and ICI 118,551. Analysis of these data demonstrated that in alveolar wall, beta 1- and beta 2-adrenoceptors co-existed in the proportions 18% and 82%, respectively. 5. Quantitative autoradiographic analyses also showed that beta 1- and beta 2-adrenoceptors were differentially distributed in tracheal epithelium and airway smooth muscle. The beta 2-adrenoceptor subtype accounted for 71% of all beta-adrenoceptors in epithelium. Conversely, beta l-adrenoceptors which mediate relaxant responses of mouse trachea to beta,-adrenoceptor agonists (Henry & Goldie, 1990), accounted for 69% of all beta-adrenoceptors in the airway smooth muscle.

Adrenergic beta-Antagonists↗