Contraction Of Lung Parenchymal Strips Research Articles

Bradykinin-induced contraction of guinea pig lung in vitro.

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea-pig: importance of the booster injection.

1. BN 52021, an antagonist of platelet activating factor (PAF), was inactive against bronchoconstriction in guinea-pigs sensitized with low amounts of ovalbumin (OA) injected twice, at a 14 day interval and challenged i.v. 7 days later. 2. Serum IgG titers increased for 7 weeks after the booster injection at day 14 and returned to low levels at day 96. 3. Administered by the intratracheal (i.t.) route at 1 mg, BN 52021 failed to inhibit bronchoconstriction induced by the i.t. administration of OA to guinea-pigs tested 7, 28, 56 and 84 days after the booster injection, even when the titers of circulating IgG had declined with time. BN 52021 was also inactive against bronchoconstriction in guinea-pigs boosted at day 98 and tested 7 days later and against contractions and thromboxane (Tx) B2 and histamine release induced by OA-challenged parenchymal lung strips from the boosted guinea-pigs. 4. Sensitized unboosted guinea-pigs displayed reduced IgG serum titers. Used 21 or 70 days after the sensitizing injection, they did develop bronchoconstriction upon the i.t. instillation of OA, which was blocked by BN 52021. The latter also inhibited OA-induced contractions of lung parenchymal strips from these unboosted guinea-pigs. 5. When boosted and non-boosted guinea-pigs received OA i.t. and bronchoalveolar lavage fluid was collected 10 min later, the number of eosinophils increased markedly in boosted, but not in non-boosted guinea-pigs. 6. The booster injection of antigen thus modifies the response of the lung and PAF appears to be relevant for antigen-induced bronchoconstriction in unboosted animals, but loses its major role following the booster injection.

Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig.

1. The effects of REV 5901 on the platelet activating factor (Paf)-induced (a) bronchoconstriction, (b) contraction of lung parenchymal strips and (c) increased airways responsiveness to histamine, were assessed in the guinea-pig. REV 5901 is a 5-lipoxygenase inhibitor and competitive peptidoleukotriene antagonist which does not inhibit multiple forms of phosphodiesterase. 2. In urethane/pentobarbitone anaesthetized animals, REV 5901 (10 or 30 mg kg-1, i.v.) substantially inhibited the bronchoconstriction, measured as changes in airways resistance (RL) and dynamic lung compliance (Cdyn), induced by leukotriene D4 (2.5 micrograms kg-1, i.v.) but did not attenuate that induced by Paf (50 ng kg-1, i.v.). 3. Paf contracted the lung parenchymal strip in a concentration-dependent manner. REV 5901 (25 microM) neither altered the magnitude of the contractions nor the tissue sensitivity to Paf. The sustained contraction induced by Paf was not affected when REV 5901 was added after the response had reached a plateau. 4. Contractions of parenchymal strips to Paf (50 nM) were prevented by pretreatment with the competitive Paf antagonists, SRI 63441 and WEB 2086. Also WEB 2086, but not SRI 63441, reversed established Paf-induced contractions and relaxed parenchymal strips from intrinsic tone in the absence of Paf. 5. Paf (20 ng kg-1, i.v.) caused an acute increase in airways responsiveness to histamine (4-12 micrograms kg-1, i.v.) which was attenuated by REV 5901 at 10 mg kg-1, i.v. and abolished by 30 mg kg-1, i.v. 6. These data suggest that leukotrienes do not participate in Paf-induced bronchoconstriction or contraction of the lung parenchymal strip, but may play a role in the increased responsiveness of the airways to histamine observed after Paf challenge in the guinea-pig.

Effect of Desmodium adscendens fractions on antigen- and arachidonic acid-induced contractions of guinea pig airways.

Three fractions (n-butanol, F2, and L5), isolated from an aqueous extract of Desmodium adscendens, a plant used in Ghana for the management of asthma, were evaluated for their pharmacological activity using ovalbumin and arachidonic acid-induced contractions of guinea pig airways. All three fractions inhibited the ovalbumin-induced contractions of indomethacin-pretreated tracheal spirals from sensitized animals dose dependently, but only L5 and n-butanol inhibited such contractions in the absence of indomethacin. The concentrations required to inhibit ovalbumin-induced contractions of lung parenchymal strips were threefold higher than with trachea. The contractile response over a 60-min period was divided into three phases. F2 and n-butanol inhibited all phases, whereas L5 inhibited only the late phase. n-Butanol and L5 inhibited arachidonic acid-induced contractions on indomethacin-pretreated tracheal spirals, a leukotriene-dependent reaction. There was no inhibition of arachidonic acid-induced contractions of lung parenchymal strips, which is largely a thromboxane-dependent reaction. The results suggest that D. adscendens contains several pharmacologically active substances that can inhibit allergic airway smooth muscle contraction at multiple sites, including the synthesis and (or) activity of the bronchoconstrictor leukotrienes.

Inhibition of antigen-induced contractions of ileum segments and lung parenchymal strips of actively sensitized guinea pigs by different anti-allergic agents in vitro.

Different types of anti-allergic agents have been compared for their ability to inhibit the antigen-induced contraction of isolated lung parenchymal strips and ilea of guinea pigs. Extremely low concentrations of the lipoxygenase inhibitor NDGA inhibit the contraction of the lung parenchymal strips and higher concentrations block the ileal phase II-contraction (both predominantly caused by the developing SRS-A), but do not inhibit ileal phase I-contraction (caused by released histamine). The H1-antihistamine clemastine predominantly antagonizes phase I of the ileum contraction, and the anti-allergic drug oxatomide reduces all three types of contraction. The degranulation inhibitor DSCG does not influence the contraction of the lung strip, but produces a slight inhibition of both ileal contractions. The PAF-antagonist BN 52021 influences these three contractions in the opposite way to DSCG. As these various types of anti-allergic agents influence these three contractions in a different manner, the models can be used for judging the mechanism of action of a new anti-allergic compound.

Dose–response effects of one subfraction of Desmodium adscendens aqueous extract on antigen‐ and arachidonic acid‐induced contractions of guinea‐pig airways

AbstractDesmodium adscendens is used in Ghana for the management of asthma. The first fraction (F1), isolated from an aqueous extract of the plant material by flash chromatography, was evaluated for its anti‐allergic properties using ovalbumin (OA)‐ and arachidonic acid (AA)‐induced contractions of tracheal spirals and lung parenchymal strips from guinea pigs. F1 inhibited OA‐ and AA‐induced contractions in both tissues dose‐dependently. In the AA‐induced contractions, F1 was more effective on the tracheal spirals than on the lung parenchymal strip. On the OA‐induced contractions of tracheal spirals, there was enhancement of the early phase of the contraction in the absence of indomethacin. This effect, which was biphasic, was not seen when the tissues were pretreated with indomethacin. Higher concentrations of F1 were required to effect the same inhibition in the absence of indomethacin than in its presence. F1 inhibited all phases of OA‐induced contractions of lung parenchymal strips by >80% at the highest concentration used (0.9 mg/mL). The results suggest that F1 inhibits both the cyclo‐oxygenase and the lipoxygenase pathways of AA metabolism. F1 also appears to inhibit the release of arachidonic acid.

Effects of gossypol on guinea pig airway responsiveness: in vitro and in vivo studies

AbstractThe actions of the naturally occurring polyphenol, gossypol, on guinea pig lung parenchymal strip preparations, bronchoconstriction in anaesthetized guinea pigs and platelet aggregation were examined. At concentrations between 0.2 and 20 μg/ml gossypol markedly inhibited contraction of lung parenchymal strips induced by LTB4 and LTD4, but was less effective against histamine‐induced contraction. Gossypol also inhibited contraction induced by platelet‐activating factor‐acether (PAF‐acether) but was not as effective as BN52021, a specific PAF‐acether antagonist. In addition, gossypol failed to antagonize PAF‐acether‐induced bronchoconstriction in anaesthetized guinea pigs or the histamine‐dependent bronchoconstriction response to ovalbumin in passively sensitized animals. Gossypol was minimally effective in inhibiting PAF‐acether‐induced platelet aggregation. This polyphenol displays a similar spectrum of effects to the radical scavenger NGDA, suggesting that, in common with other phenolic antioxidants, it may interfere with the formation of cyclo‐oxygenase products in the guinea pig lung.

Different Ability of Verapamil to Inhibit Agonist-Induced Contraction of Lung Parenchymal Strips from Control and Sensitized Guinea Pigs

There is increasing interest in the therapeutic potential of calcium channel blockers in asthma, but the basic mechanism of this beneficial effect is not fully understood. In the present work we have compared the effect of verapamil on contractions of lung parenchymal strips induced by various agonists (CaCl2, KCl, acetylcholine and histamine) in control (unsensitized) and actively sensitized guinea pigs. Concentration-response curves to CaCl2 were constructed in the presence of a depolarizing (K+ 30 mM) Ca2+-free Tris-physiological salt solution. Verapamil produced a concentration-dependent antagonism of the CaCl2, KCl, acetylcholine and histamine concentration-related responses in control and sensitized preparations. Verapamil inhibited KCl-induced contractions to a greater extent than those induced by acetylcholine and histamine in control and sensitized specimens. The ability of verapamil to inhibit CaCl2-, KCl-, acetylcholine- and histamine-induced contractions was substantially reduced in sensitized tissues compared to control. These results may be interpreted as supporting the hypothesis of an increased Ca2+ influx linked to airway hyperreactivity and point to the contribution of other sites of action, besides airways smooth muscle, to the beneficial effect of calcium channel blockers in asthma.

Pharmacological alteration of antigen-induced contraction of lung parenchymal strips isolated from the actively sensitized guinea pig

Several drugs, known to influence the action or formation of histamine and SRS-A, were examined for their abilities to alter antigen (ovalbumin)-induced contractions of guinea-pig isolated lung parenchymal strips. Cumulative dose-response effects of ovalbumin were obtained on paired parenchymal strips, one used as control and the other drug treated. When used alone, mepyramine, 10 −6 M, phenoxybenzamine, 3 × 10 −5 M and FPL55712, 10 −5 M, did not alter ovalbumin-induced contractions. 5,8,11,14-eicosatetraynoic acid (ETYA), 10 −4 M, produced a small (2.5-fold) rightward shift of the dose-response curves to ovalbumin and histamine. Indomethacin, 5 × 10 −6 M, produced a small increase in the maximum response to ovalbumin and a small (2-fold) rightward shift of the histamine dose-response curve. The effect of indomethacin on ovalbumin-induced contraction was not seen in the presence of phenoxybenzamine and may therefore be due to an increase in histamine release. Combination of indomethacin with FPL55712 or ETYA did not alter antigen-induced contractions. The effect of ETYA on the histamine dose-response curve was not seen in the presence of indomethacin. Combination of phenoxybenzamine with FPL55712 or ETYA caused a marked reduction of the maximum contractile response to ovalbumin. The effect of phenoxybenzamine and ETYA was not observed in the presence of indomethacin. The results suggest that the ability of ETYA to reduce antigen responses in the absence or presence of phenoxybenzamine as well as histamine-induced contraction is related to inhibition of contractile product(s) of cyclooxygenase metabolism of arachidonic acid. Even though substantial antagonism of antigen-induced contractions of guinea-pig parenchymal strips could only be achieved with a combination of drugs, the magnitude of the antagonism was not as large as observed in other pulmonary smooth muscle preparations. This may reflect the existence of other contractile mediators, different interactions between known mediators of immediate hypersensitivity reactions or relative insensitivity of parenchymal strips to effects of the drugs.

Effects of C5a on guinea pig lung: Histamine release and mechanism of contraction

C5a, a product of complement system activation, causes a significant contraction of the isolated guinea pig trachea, and the antihlstamine diphenhydramine does not altter the rate, amplitude, or duration of the contraction (Regal et al., 1980). The present study demonstrates that over the ronge of C5a concentrations investigated, the C5a-induced contractile response of the trachea maximized, whereas the contraction of lung parenchymal strips and the release of histamine from chopped lung did not. In addition, the antihistamines, diphenhydramine and pyrilamine, caused a significant delay in the onset of the C5a-Induced contraction of lung parenchymal strips. When parenchymal strips from nonperfused lung were used, the maximum of the contraction was also reduced by pyrltamine. Aspirin and indomethacin effectively inhibited the C5a-induced contraction of tuns parenchymal strips, and Inhibition by a combination of aspirin and pyrilarnine was the mm of the inhibition by aspirin and the Inhibit ton by pyrilamine. The SRS-A antagonist, FPL 55712, caused a more rapid retaxation of the C5a-induced response over control. These studies suggest that products of the cyclo-oxygenase pathway are mediators involved in the C5a-Induced contraction of lung parenchyma, with histamine and leukotrienes contributing as well.

Effect of inhibition of arachidonic acid metabolism on anaphylaxis of guinea pig lung strips.

The effect of inhibitors of the cyclooxygenase and/or lipoxygenase pathways of arachidonic acid metabolism on the anaphylactic contraction of lung parenchymal strips from ovalbumin sensitized guinea pigs was studied. Indomethacin, a selective cyclooxygenase inhibitor, significantly enhanced the anaphylactic contraction at 10(6) M with no effect at 10(-5) or 10(-4) M. By contrast, nordihydroguaiaretic acid (Ndga, 10(-5) or 10(-4) M, a lipoxygenase inhibitor, and 1-phenyl-3-pyrazolidinone (phenidone, 10(-4) M), an inhibitor of both the cyclooxygenase and lipoxygenase markedly inhibited the anaphylactic contractile response. The pattern of inhibition was similar to that produced by FPL 55712, an antagonist of slow reacting substance of anaphylaxis (SRS-A), and was characterized by a decrease in the maximum tension and in the duration of the contraction. The results suggest that inhibition of the lipoxygenase pathway reduced anaphylactic contraction of guinea pig lung strips possibly by inhibiting the synthesis and release of SRS-A.