Tracheal Chain Research Articles

Actions of 16-aryloxy analogues of prostaglandin F2alpha on preparations responsive to prostaglandin endoperoxides.

On four prostaglandin endoperoxide-sensitive preparations, namely human platelets in vitro, rabbit aortic strip, guinea-pig tracheal chain and pig blood pressure, ICI 79939 and its 11-oxo analogue mimicked the actions of 11,9-(epoxymethano) prostaglandin H2, and were considerably more active than either prostaglandin F2alpha or ICI 81008. It is suggested that this activity of ICI 79939 may contribute to its toxicity in experimental animals.

Mechanism of relaxant action of prostaglandin F 2α on the guinea-pig isolated trachea

Prostaglandin F 2α consistently produced a dose-related triphasic response in guinea-pig isolated tracheal chain preprations. The response consisted of an initial transient contraction followed by a transient relaxation, followed by a further contraction. The relaxant action was not due to adrenergic or histaminergic transmission, but might be due to a PG-like material released by the PGF 2α-induced contraction.

Experimental study of the sensitizing activity of Neisseria perflava

The sensitizing activity ofNeisseriaperflava isolated from the bronchial mucosa of patients with infectious asthma was studied in experiments on guinea pigs. It was shown that Ovary's passive cutaneous anaphylaxis test and the tracheal chain contraction test can be reproduced withNeisseria antigens. High sensitizing activity ofN.perflava was found compared with two other microorganisms:Klebsiellapneumoniae andStaphylococcusaureus, inhabiting the bronchi of patients with infectious asthma.

The effects of some bronchodilator and anti-inflammatory drugs on prostaglandin F2alpha-induced contraction of guinea-pig isolated trachea.

1. The bronchodilator drugs isoprenaline, salbutamol, theophylline and prostaglandin E1 (PGE1) relaxed the guinea-pig isolated tracheal chain preparation dose-dependently and their potencies were compared by EC50 values. 2. The non-steroid anti-inflammatory drugs flufenamate, mefenamate and phenylbutazone also relaxed the preparation dose-dependently, but were less potent than the sympathomimetic drugs and PGE1. 3. The contractile response to a submaximal concentration of prostaglandin F2alpha (PGF2alpha) was antagonized by flufenamate, mefenamate, phenylbutazone, aspirin, theophylline, isoprenaline, salbutamol and PGE1, at concentrations similar to or less than the clinical peak plasma levels in man. A relatively higher concentration of indomethacin was required. 4. The antagonism was relatively specific for PGF2alpha in the case of the fenamates, which did not cause comparable reductions in responses to equi-effective concentrations of histamine and carbachol. The other anti-inflammatory drugs, theophylline and the sympathomimetic drugs were less or non-specific. 5. The nature of the shifts in the long dose-response curve for PGF2alpha caused by increasing concentration levels of flufenamate indicates a dual competitive/non-competitive type of antagonism.

Effect of acetylated derivatives of some sympathomimetic amines on the isolated auricles and tracheal chain of the guinea-pig.

The effects of acetylation of sympathomimetic amines, tyramine, amphetamine, ephedrine, phenylephrine, orciprenaline, and salbutamol, and their O- and N-acetyl derivatives and the effects of reserpine or physostigmine pretreatment on the isolated auricles and tracheal chain of guinea-pigs have been studied. All the parent drugs relaxed the tracheal chain and had a positive inotropic and chronotropic effect on the isolated auricles; only amphetamine, on the contrary, contracted the tracheal chain. O-acetylation of these sympathomimetic amines generally decreased less chronotropic than iontropic action on the isolated auricles. O-acetylation of tyramine however: actually increased the positive chronotropic activity of drug. As a rule, O-acetylation also decreased the beta-adrenergic effect of these compounds on the tracheal chain, but not so markedly as on the isolated auricles. N-acetylation generally abolished the adrenergic effects of these sympathomimetic amines on the isolated auricles and decreased those effects on the tracheal preparation. N,O-triacetylation of salbutamol abolished the stimulating effect of the parent drug on the auricles but increased the relaxant activity on the trachea. Physostigmine antagonized the effects of O-acetyltyramine and O-triacetylorciprenaline but not those of tyramine and orciprenaline on the trachea preparation. It is concluded that among the sympathomimetic amines acetylation may be utilized for the development of specific bronchodilators and O-acetylation for inducing drug latentiation.

STUDIES ON THE ACTION POTENTIAL ORIGINATED FROM NERVE ELEMENTS IN GUINEA PIG URETER

The interrelation of the inhibitory effect of aspirin-like drugs on the resting tonus of tracheal chain in guinea pigs, arachidonic acid-induced contraction in rat stomach fundus strips and bradykinin-induced bronchoconstriction in guinea pigs in vivo was investigated. All the drugs tested produced a dose-related inhibitory action on the resting tonus of the tracheal chain in comparatively low doses. Diclofenac was the most potent of all the drugs and was equal in activity to isoproterenol, followed in descending order by flufenamic acid, mefenamic acid, indomethacin, ibuprofen, phenylbutazone, oxyphenbutazone and aspirin. These aspirin-like drugs also inhibited arachidonic acid-induced contraction in rat stomach fundus strips. A highly significant correlation was observed between the potency of inhibition of the arachidonic acid-induced contraction and the relaxant effect on the tracheal chain. Moreover, the drugs antagonized bradykinin-induced bronchoconstriction in guinea pigs in vivo and the order of potency roughly paralleled that of the tracheal chain. These results suggest that the aspirin-like drugs produce a reduction in resting tonus of the isolated guinea pig tracheal chain by inhibition of intramural biosynthesis of prostaglandin endoperoxides.

The selective action of beta-adrenoceptor blocking drugs and the nature of beta1 and beta2 adrenoceptors.

1 Purified membranes retaining a catecholamine responsive adenylate cyclase have prepared from rabbit heart, lung and (pseudo-pregnant) uterus. 2 These preparations have the characteristics of plasma membranes and both heart and lung respond to beta-adrenoceptor agonists in the order: (+/-)-isoprenaline greater than (-)-noradrenaline greater than (-)-adrenaline greater than (+)-isoprenaline greater than salbutamol. The sensitivity of the adenylate cyclase to beta-adrenoceptor stimulation is improved by pre-treatment of the animals with reserpine and syrosingopine. 3 Dose-ratios for several concentrations of propranolol (non-selective beta-adrenoceptor blocker), practolol and atenolol (cardio-selective beta-adrenoceptor blockers) have been measured on all three membrane preparations. Schild plots of log (dose ratio -1) vs. log dose were virtually coincident for heart and lung with a dissociation constant (Kb) for propranolol very close to the pharmacological value. The ratio of Kb values was 0.65 for practolol and 1.23 for atenolol compared with pharmacological cardio-selectivity ratios (measured on isolated atria and tracheal chain) of 67.6 and 110 respectively. The uterus/heart Kb ratio was 51.5 for atenolol. Inhibition of the uterus by practolol gave a Schild plot with slope significantly less than 1, indicating a different mechanism of action from the heart. 4 Kb values obtained by measuring adenylate cyclase stimulation in chopped tissue (including preparations of bronchial tree and alveolar tissue as well as whole lung) resembled the membrane values rather than those found in whole organs. 5 The results show that the pharmacological selectivity of practolol and atenolol is maintained at the receptor-adenylate cyclase level, at least as far as heart and uterus are concerned, though the smaller selectivity ratios in the biochemical system suggest that receptor differences is not the only factor and that phase distribution of the drug may also be important. Membranes prepared from whole lung show that phase distribution of the drug may also be important. Membranes prepared from whole lung show an overall beta1 response which may simply reflect the predominance of beta1 cell types containing beta1-adrenoceptors over bronchial smooth muscle.

Potentiation of beta-sympathomimetics with alpha-adrenoceptor blocking drugs in guinea pig trachea and human bronchus preparations.

The actions of beta-sympathomimetics alone and in various combinations with alpha-adrenoceptor blocking agents were studied in guinea pig tracheal chain and in some preparations of human bronchi taken in operations. All the alpha-adrenoceptor blockers caused 50-100% potentiation of the effects of the beta-sympathomimetics studied in both preparations, had no effects of their own in the rather low concentrations used (10(-10) --10(-6) mol/l). The results show that guinea pig and human tracheobronchial smooth muscle react similarly to these drugs and may contain adrenergic alpha-receptors.

Effects of salsolinol on smooth muscle responses to various biogenic amines

Isolated smooth muscle tissues from rats, guinea pigs and rabbits were used to investigate pharmacological effects of salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline). By itself, salsolinol did not produce any profound or sustained sympathomimetic or 5-hydroxytryptamine-like activity in the concentrations used in these experiments (7.7 and 77 μM). Salsolinol was found to antagonize the contraction of the rabbit aorta induced by noradrenaline but did not affect the adrenaline-induced relaxation of the guinea pig tracheal chain. On both the rat fundus and oestrus rat uterus, salsolinol exhibited significant anti-5-hydroxytryptamine activity but responses of these tissues to acetylcholine and histamine remained unaffected, indicating that the action was not non-specific. These results suggest that in vivo formation of salsolinol after ingestion could produce significant pharmacological effects.

ChemInform Abstract: SYNTHESIS AND BIOLOGICAL PROPERTIES OF SOME NOVEL HETEROCYCLIC HOMOPROSTANOIDS

AbstractÖlsäure (I) wird zu (IIa) hydroxyliert und über den Methylester (IIb) oder direkt in die Cyclisierungsprodukte (III) und (IV) übergeführt.

Synthesis and biological properties of some novel heterocyclic homoprostanoids.

In the search for prostaglandin-like structures capable of exerting specific and desirable biological properties, a variety of simple heterocyclic homoprostanoidal derivatives was synthesized from readily available stearic acid derivatives. Compounds 5b and 5e were found to be more than 100 times as potent as PGE1 and PGE2 in a tracheal chain bioassay and, like 6, 9, and 12, inhibited PGE2-induced diarrhea. Derivatives 6 and 7a showed significant PG-synthetase inhibitor activity.

Some evidence for the maturity of peripheral adrenergic nerves in new-born guinea-pigs.

The fluorescence histochemical technique of Falck and Hillarp revealed a similar distribution and density of peripheral adrenergic nerves in new-born and adult guinea-pigs. The accumulation of tritiated noradrenaline by tracheae from new-born guinea-pigs, assumed to be uptake into adrenergic nerves, was not less than the accumulation by tracheae from adult animals. There was equal potentiation by cocaine (1 x 10(-5)M) of responses to noradrenaline on tracheal chain preparations taken from new-born and adult guinea-pigs. The evidence supports the hypothesis that the guinea-pig has a functional, well differentiated peripheral adrenergic nervous system at birth. This would account for the apparent inability to produce a long-lasting sympathectomy by administration of 6-hydroxydopamine to new-born guinea-pigs.

ChemInform Abstract: ANTAGONISM OF SLOW REACTING SUBSTANCE IN ANAPHYLAXIS (SRS‐A) AND OTHER SPASMOGENS ON THE GUINEA PIG TRACHEAL CHAIN BY HYDRATROPIC ACIDS AND THEIR EFFECTS ON ANAPHYLAXIS

Chemischer InformationsdienstVolume 6, Issue 20 Isocyclic Compounds ChemInform Abstract: ANTAGONISM OF SLOW REACTING SUBSTANCE IN ANAPHYLAXIS (SRS-A) AND OTHER SPASMOGENS ON THE GUINEA PIG TRACHEAL CHAIN BY HYDRATROPIC ACIDS AND THEIR EFFECTS ON ANAPHYLAXIS M. E. GREIG, M. E. GREIGSearch for more papers by this authorR. L. GRIFFIN, R. L. GRIFFINSearch for more papers by this author M. E. GREIG, M. E. GREIGSearch for more papers by this authorR. L. GRIFFIN, R. L. GRIFFINSearch for more papers by this author First published: May 20, 1975 https://doi.org/10.1002/chin.197520228Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume6, Issue20May 20, 1975 RelatedInformation

Antagonism of slow reacting substance in anaphylaxis (SRS-A) and other spasmogens on the guinea pig tracheal chain by hydratropic acids and their effects on anaphylaxis.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAntagonism of slow reacting substance in anaphylaxis (SRS-A) and other spasmogens on the guinea pig tracheal chain by hydratropic acids and their effects on anaphylaxisMargaret E. Greig and Robert L. GriffinCite this: J. Med. Chem. 1975, 18, 1, 112–116Publication Date (Print):January 1, 1975Publication History Published online1 May 2002Published inissue 1 January 1975https://doi.org/10.1021/jm00235a027RIGHTS & PERMISSIONSArticle Views61Altmetric-Citations20LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (595 KB) Get e-Alerts Get e-Alerts

The effects of 6-hydroxydopamine and guanethidine on peripheral adrenergic nerves in the guinea pig

Chemical sympathectomy was achieved in guinea pig trachea 24 hr after a single dose of 50 mg/kg (i.v. or i.p.) 6-hydroxydopamine (6-OHDA). This was shown by (a) the dissapearance of fluorescent nerve terminals (b) decreased uptake-with-retention of radioactivity following incubation in (−)- 3H-noradrenaline (50 nM) and (c) the supersensitive response of the isolated tracheal chain preparation to noradrenaline. The susceptibility of the adrenergic nerve terminals in the lung of 6-OHDA resembled that of trachea, in that complete dissapearance of fluorescent nerve terminals was achieved with the above doses, whereas doses higher than 100 mg/kg were required to produce this in heart and iris. Chronic treatment of guinea pigs with guanethidine (25 or 30 mg/kg daily by i.p. injection for up to 6 weeks) did not produce destruction of adrenergic nerves in peripheral tissues.

TRACHEAL SMOOTH MUSCLE RELAXANT EFFECT OF KETAMINE

Ketamine is claimed to decrease airways resistance in patients suffering from broncho-constriction. Investigations of its mechanism of action were undertaken using the guineapig tracheal chain, a preparation which reacts to drugs in a manner similar to that of the smooth muscle of human bronchioles. Ketamine was found to possess a direct relaxant effect on the tracheal chain, to antagonize the spasmogenic effects of carbachol and potentiate the antispasmodic effects of adrenaline. Reduction in airway resistance after ketamine anaesthesia is probably the result of a direct relaxant effect on bronchial smooth muscle and a changed response to endogenous humoral substances.

Comparison of the bronchodilator and cardiovascular actions of isoprenaline, Th 1165a, terbutaline and salbutamol in cats and isolated organ preparations

In anesthetized cats the bronchodilator action of isoprenaline (IPN), Th 1165a, terbutaline and salbutamol was measured by the method of Konzett and Rosler. Determined were in addition the following cardiovascular effects: increase indp/dt max of the left ventricular pressure and heart rate as well as decrease of mean arterial pressure (MAP). In order to compare the bronchodilator and the cardiovascular efficacy, the negative logarithms of the EC50 were calculated for the parameter aforementioned. — Further experiments were performedin vitro on the isolated electrically driven guinea-pig atrium and on the tracheal chain at 37°C in order to estimate the affinities of theβ sympathomimetics.

Beta-adrenolytic, antiarrhythmic and local anaesthetic effects of phenylephrine.

The β-sympathomimetic effect of phenylephrine was investigated on the electrically driven atrium, as well as on the tracheal chain of the guinea pig. 1. Phenylephrine (PE) was found to be less effective than isoprenaline (IPN) with regard to its positive inotropic effect on the guinea-pig atrium and to its relaxing action on the tracheal chain. The intrinsic activity for PE amounted to 0.75 on the tracheal chain and to 0.45 on the atrium, when compared with IPN. 2. From these low intrinsic activities, PE was assumed to be a partial β-agonist, exerting a competitive dualism in action to IPN. This dualism could be confirmed by dose-response curves for PE in the presence of IPN and vice versa: PE behaved as a β-agonist as well as a β-antagonist. 3. The intrinsic activity of PE steadily decreased with prolongation of the incubation period. After 1 h PE had almost lost its intrinsic activity. Under these conditions the dose-response curves for IPN on the tracheal chain, as well as on atrium, were shifted to the right in a parallel manner, i.e. PE behaved as a competitive β-antagonist. 4. High concentrations of PE (10−3 M) protected the electrically driven guineapig atrium against arrhythmias induced by k-strophanthoside. The onset of both the first extrasystoles and of heart standstill, which occurred after infusion of k-strophanthoside, were delayed after preincubation with PE. 5. Phentolamine was without any influence on these antiarrhythmic properties of PE. Therefore, it could be excluded that the antiarrhythmic effect of phenylephrine is due to a stimulation of myocardial α-adrenoceptors. 6. The local anaesthetic activity of phenylephrine, as tested on the rabbit cornea, was 4 times higher than that of propranolol. 7. The effective concentrations for the β-adrenolytic, antiarrhythmic, and local anaesthetic activities of PE were clearly different. We concluded, therefore, that the different actions produced by phenylephrine were not associated with each other.

POTENTIATION OF OXYTOCIN AND PROSTAGLANDINS-EVOKED RESPONSES BY ( + ) INPEA ON ISOLATED RAT UTERUS: ITS SPECIFICITY AND SELECTIVITY

The effect of (+) INPEA on various stimulant drugs was examined on isolated rat uterus. Addition of (+) INPEA (lxl<~'g/ml) to the organ bath, produced marked potentiation in the contractile responses of oxytocin and prostaglandins. Potentiation was less significant to 5-HT, vasopressin, angiotensin and bradykinin. (+) INPEA did not potentiate the responses of oxytocin on isolated rat mammary strip and the responses of prostaglandins on rat stomach (fundus) strip, guineapig tracheal chain and guinea-pig ileum. The significance of these findings has been discussed.

Effects of oxyfedrine on isolated portal vein and other smooth muscles

1. Oxyfedrine (0.01-1.0 mug/ml), inhibited spontaneous myogenic activity in rat isolated portal vein and carbachol-induced contractions of rat isolated uterus, and relaxed the rabbit duodenum and the guinea-pig tracheal chain preparation. These actions were prevented by the beta-adrenoceptor blocking drug alprenolol. Oxyfedrine was a relatively weak beta-adrenoceptor stimulant (10-100 times less active than isoprenaline) but its actions were more prolonged.2. In the same concentrations, oxyfedrine reduced or prevented the inhibition of myogenic activity of the rat portal vein induced by isoprenaline and by repeated doses of oxyfedrine itself, acting as a partial agonist at beta-adrenoceptor sites.3. Oxyfedrine, 1-12 mug/ml increased myogenic activity in the rat portal vein. This effect was not due to direct or indirect stimulation of alpha-adrenoceptors (because it was unaffected by phentolamine) or to potentiation of acetylcholine or 5-hydroxytryptamine.4. Oxyfedrine (>20 mug/ml) inhibited spontaneous myogenic activity in the portal vein and relaxed the saphenous vein contracted with noradrenaline. This spasmolytic effect of the drug was not due to beta-adrenoceptor stimulation or to inhibition of phosphodiesterase since it was unaffected by alprenolol and by concentrations of imidazole which antagonized the effects of the active phosphodiesterase inhibitor, papaverine. In the portal vein this effect of oxyfedrine was similar to that of the calcium inhibitor iproveratril; some of the effects of oxyfedrine on venous smooth muscle may be mediated through effects on calcium transport.