leukotriene-d4 and Bronchial-Spasm

1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Bronchi; Bronchial Spasm; Capillary Permeability; Cyclopropanes; Histamine; Histamine H1 Antagonists; Leukotriene D4; Male; Methysergide; Ovalbumin; Pyrilamine; Quinolines; Rats; Rats, Inbred BN; Respiratory Hypersensitivity; Serotonin; Serotonin Antagonists; Sulfides; Trachea

YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previous report, we indicated that YM976 has less emetogenicity, a major adverse effect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administered exhibited inhibition of antigen-induced bronchoconstriction, airway plasma leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR), with ED(50) values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstriction and plasma leakage. Theophylline moderately suppressed bronchoconstriction and edema, but neither eosinophil infiltration nor AHR. YM976 suppressed the peroxidase activity in the bronchoalveolar lavage fluid, and elevated the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also the activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC(30) = 83 nM), and exerted a little relaxation on LTD(4)-precontracted tracheal smooth muscle (EC(50) = 370 nM). Rolipram exhibited a potent tracheal relaxation activity (EC(50) = 50 nM). In vivo studies indicated that the inhibitory effect of YM976 on LTD(4)-induced bronchospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that YM976, unlike rolipram, showed the inhibition of antigen-induced airway responses due to anti-inflammatory effects, but not to direct tracheal relaxation. In conclusion, YM976 may have potential therapeutic value in the treatment of asthma through its anti-inflammatory activities.

Topics: Animals; Anti-Asthmatic Agents; Bronchial Hyperreactivity; Bronchial Spasm; Bronchoconstriction; Eosinophils; Guinea Pigs; In Vitro Techniques; Leukotriene D4; Lung; Male; Phosphodiesterase Inhibitors; Pyridines; Pyrimidinones; Superoxides

Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for most of the early phase bronchospasm in asthma. However, activation of the smooth muscle CysLT1-receptor plays a major role in asthmatic bronchospasms. CysLT-receptor antagonists or CysLT-synthesis inhibitors are efficacious in asthma but do not completely abolish asthmatic bronchospasms. A recent clinical study showed that combined antagonists loratadine (H1) and zafirlukast (CysLT1) were more effective against allergic bronchospasms than either drug alone. We examined the combined efficacy of H1- and CysLT1-receptor antagonists in allergic human bronchus. The H1- and CysLT1-receptor antagonists chlorpheniramine (CTM; 1 microM) and MK-571 (0.03 microM), were tested alone and in combination, against anti-human IgE antibody (Ab)-induced contractions of passively sensitized isolated human bronchus. Ab-induced allergic contractions were reduced 15% and 36% by CTM (1 microM) and MK-571 (0.03 microM), respectively. Combined CTM (1 microM) and MK-571 (0.03 microM) significantly inhibited the Ab response by 87%. Mechanistic investigations in isolated human bronchus and cultured human cord blood mast cells suggest that H1- and CysLT-receptor interactions likely occur at the airway smooth muscle level. CTM and MK-571 synergistically inhibited human allergic bronchospasm in the present in vitro model. The mechanism underlying this synergistic activity requires further investigation.

Topics: Adult; Bronchi; Bronchial Spasm; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Female; Histamine; Histamine H1 Antagonists; Humans; Immunization, Passive; Immunoglobulin E; In Vitro Techniques; Leukotriene Antagonists; Leukotriene D4; Male; Mast Cells; Membrane Proteins; Middle Aged; Muscle Contraction; Muscle, Smooth; Propionates; Quinolines; Receptors, Leukotriene

We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anti-Asthmatic Agents; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids; Enzyme Inhibitors; Guinea Pigs; Histamine; In Vitro Techniques; Leukotriene D4; Muscle Contraction; Nitriles; Ovalbumin; Trachea

1-[3-(4-Benzhydryl-1-piperazinyl)propyl]-3-(1H-imidazol-1-ylmethyl )- 1H-indole-6-carboxylic acid (CAS 172544-75-1, KY-234) was characterized pharmacologically. KY-234 (10(-9)-10(-6) mol/l) and ozagrel (10(-8)-10(-5) mol/l) inhibited the production of thromboxane A2 (TXA2) in rabbit platelets. KY-234 and pyrilamine at concentrations of 10(-9)-10(-6) mol/l relaxed the isolated guinea pig trachea contracted with histamine, while neither drug attenuated the heart rate increased by histamine. Cimetidine antagonized histamine in the right atrium but not in the trachea. KY-234 (10(-8)-10(-5) mol/l) and ozagrel (10(-7)-10(-4) mol/l), but not pyrilamine, attenuated the contraction induced by leukotriene D4 (LTD4) and platelet-activating factor in the lung parenchymal strips. In anesthetized guinea pigs, KY-234 (1-10 mg/kg p.o.) inhibited the LTD4- and histamine-induced bronchoconstriction. Ozagrel and terfenadine inhibited only the LTD4- and histamine-induced constrictions. KY-234 (3-30 mg/kg p.o.) inhibited the anaphylactic bronchoconstriction continuously for 15 min after antigen-challenge. Terfenadine (3-30 mg/kg p.o.) inhibited the constriction more strongly within the first 5 min (fast phase) than it did within 5 to 15 min (slow phase) after the challenge. Ozagrel (100 mg/kg p.o.) slightly attenuated only the constriction during the slow phase. These findings demonstrated that KY-234 has a selective TXA2 synthetase-inhibitory and H1-blocking activity and protects against anaphylactic bronchospasm more effectively than a TXA2 synthetase inhibitor or H1-blocker alone.

Topics: Anaphylaxis; Animals; Bronchial Spasm; Bronchoconstriction; Enzyme Inhibitors; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Indoles; Leukotriene D4; Lung; Male; Methacrylates; Platelet Activating Factor; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Trachea

Selective inhibition of phosphodiesterase (PDE) isozymes has been shown to inhibit inflammatory cell function and relax airway smooth muscle and, thus, may be useful in the therapy of asthma. In guinea pigs sensitized to ovalbumin (OA), the effects of three PDE inhibitors were compared: siguazodan (PDE III selective, IC50 = 0.7 microM), rolipram (PDE IV selective, IC50 = 0.8 microM) and zardaverine (dual PDE III/IV, IC50S = 2.5 microM and 1.1 microM, respectively) against histamine-, leukotriene (LT) D4- and OA-induced bronchospasm in vitro and in vivo. Rolipram or zardaverine (0.1-10 microM), but not siguazodan, inhibited OA-induced contraction of the isolated trachea in a concentration-dependent manner. Rolipram or siguazodan alone (10 microM) were ineffective against histamine- or LTD4-induced contractions. Zardaverine alone (10 microM) or the combination of rolipram and siguazodan (10 microM each) markedly antagonized the contractions elicited by both spasmogens. In anesthesized, ventilated guinea pigs, the i.v. ID50S against OA-induced bronchospasm were: rolipram = 0.2 mg/kg, siguazodan > 10 mg/kg and zardaverine = 2.4 mg/kg. When administered at doses up to 7.5 mg/kg, i.v., rolipram or siguazodan were markedly less effective (i.e., < or = 50% inhibition) than zardaverine (ID50S = 2.4 and 1.7 mg/kg, respectively) at blocking exogenous histamine- or LTD4-induced bronchospasm. However, when administered in combination with siguazodan (5.4 mg/kg, i.v.), rolipram (0.4-5.4 mg/kg) abolished histamine- and LTD4-induced bronchoconstriction. In conscious guinea pigs, zardaverine (5 mg/kg, intragastrically (i.g.) or the combination of rolipram and siguazodan (5 mg/kg each) were substantially more effective than rolipram or siguazodan alone at inhibiting aerosol histamine- or LTD4-induced bronchospasm. In the same animals, rolipram or zardaverine (5 mg/kg, i.g.) but not siguazodan (5 mg/kg, i.g.) markedly inhibited aerosol OA-induced bronchoconstriction. The OA-induced pulmonary eosinophil infiltration in these animals was attenuated by all treatments with zardaverine producing the greatest degree of inhibition. These results indicate that 1) PDE IV inhibitors but not PDE III inhibitors are effective at blocking antigen-induced bronchospasm, 2) compounds that selectively inhibit either PDE III or PDE IV are poor inhibitors of bronchoconstriction elicited by exogenously administered spasmogens, and 3) the combined inhibition of both PDE III and PDE IV isozymes a

Topics: Animals; Antigens; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Drug Synergism; Eosinophils; Guanidines; Guinea Pigs; Histamine Antagonists; In Vitro Techniques; Isoenzymes; Leukotriene D4; Male; Phosphodiesterase Inhibitors; Plethysmography, Whole Body; Pulmonary Eosinophilia; Pyridazines; Pyrrolidinones; Rolipram; Trachea