Bronchoconstrictors

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

Acetyl-P-methylcholine chloride [62-51-1/, commonly called methacholine chloride, is a parasympathornimetic bronchoconstrictor with clinical efficacy in bronchial asthma (45,46). 

Recent evidence from our laboratory shows that the supernatants of HHMC activated by anti-IgE can convert a synthetic substrate of big endothelin to endothelin 1. The latter observation is particularly important because endothelin 1 is a potent bronchoconstrictor in allergic subjects [30]. 

Bronchoconstrictor challenge tests are used to confirm the diagnosis of asthma. AHR to histamine or methacholine (the most commonly used stimuli) is identifiable in virtually all currently symptomatic... 

We and others have been able to develop mouse and rat models of allergic airways disease that exhibit shifts in DRC to bronchoconstrictor... 

Inhaled and intravenous histamine causes bronchoconstriction as one of the first recognized properties of histamine, which is inhibited by Hi antihistamines. As a manifestation of airway hyperresponsiveness, asthmatic individuals are more sensitive to the bronchoconstrictor effect of histamine than normal individuals. In addition, in vitro studies have shown increased histamine release in basophils and mast cells obtained from asthmatic subjects compared with... 

Both histamine and 5-HT have been demonstrated in extracts 5-HT is responsible for some of the bronchoconstrictor activity of cotton dust extracts. Brom-lysergic acid, a specific 5-HT inhibitor, partially reduces activity, suggesting the presence of an "unknown contractor." This does not appear to be acetylcholine or bradykinin. Thus, although histamine, 5-HT, and the "unknown contractor" can cause immediate contractor responses, delayed onset contractions may still be due to secondary release of histamine (105). 

Table VIII lists a variety of substances that are known chemotaxins. Chemotaxins attract white blood cells, primarily neutrophils, eosinophils and macrophages, to a specific site by causing directed movement. Once these cells arrive they phagocytize and degrade invading microorganisms, and/or release hydrolytic enzymes which can cause subsequent tissue injury. These cells also release bronchoconstrictors, which provides another mechanism worthy of consideration.

Bioassay of Bronchoconstrictor Substances in Extracts of Cotton Mill Dust and Cotton Bract... 

We have gained considerable knowledge in our laboratory of bronchoconstrictors in bract and dust. A comparison of rat bladder, colon, ileum and stomach sensitivity to 5-HT showed the stomach to be the most sensitive tissue to extracts as has been reported by others (62). 

Recent smooth muscle constrictor studies performed in our laboratory in collaboration with Dr. Marion Buck at Yale University have yielded interesting results. Various fractions were first tested in human volunteers for bronchoconstrictor activity and then bioassayed by the rat stomach strip isolated organ bath technique. The fractions demonstrating constrictor activity in man correlated precisely with the constrictor activity in the isolated organ bath. This effect was antagonized by methysergide (6 ). 

Jones et al. (49) also point to a possible connection between atopy and risk of byssinosis. Most but not all persons with extrinsic asthma exhibit atopy (50). From observations on 255 workers in four cottonseed crushing mills, Jones et al. (49) conclude that "Atopy and exposure to dust were found to have significant interaction large mean declines in FEVi and FEF25-75 occurred only in the workers exposed to 1 inter dust who were also atopic." They also state "These findings point to atopy as a risk factor in the bronchoconstrictor response to cotton dust aerosol, and, by inference, a risk in byssinosis. 

LTB4 is a potent bronchoconstrictor, as are several other leukotrienes. A 5-lip-oxygenase inhibitor, Zileuton, is approved for therapy of asthma (though it is not much used for this purpose) as is a leukotriene blocker, montelukast, marketed as Singulair. Singulair is widely used by asthmatics as a preventive for asthma attacks. Certain corticosteroids are employed for the same purpose. Neither montelukast nor the steroids are effective in terminating an established asthmatic attack. Beta agonists are employed for that purpose (see chapter 17). 

Norepinephrine opens the pupil of the eye acetylcholine narrows it. Note that an antagonist of acetylcholine at the muscarinic receptor, atropine, has the same outcome as norepinephrine (see above). Norepinephrine is a bronchodilator in contrast, acetylcholine is a bronchoconstrictor. Norepinephrine increases the heart rate, chronotropy, whereas acetylcholine slows the heart rate, bradycardy. Norepinephrine decreases the rate of intestinal movements, whereas acetylcholine increases them. In all these cases, the effects of these neurotransmitters are opposed. 

Pharmacology These agents are synthetic adrenocortical steroids with basic glucocorticoid actions and effects. Glucocorticoids may decrease number and activity of inflammatory cells, enhance effect of beta-adrenergic drugs on cyclic AMP production, inhibit bronchoconstrictor mechanisms, or produce direct smooth muscle relaxation. Inhaler use provides effective local steroid activity with minimal systemic effect. 

Methacholine is used to identify bronchial hyperreactivity in patients without clinically apparent asthma. For this indication, the drug is administered by inhalation, and patients who may be developing asthma usually produce an exaggerated airway contraction. Upon completion of the test, a rapid-acting bronchodilator (e.g., inhaled p-adrenoceptor agonist) can be given to counter the bronchoconstrictor effect of methacholine and relieve the patient s discomfort. 

Histamine stimulates bronchiolar smooth muscle contraction through activation of Hj-receptors. A much smaller bronchodilatory response is evoked by stimulation of Hz-receptors. Asthmatics are generally more sensitive to the bronchoconstrictor actions of histamine than are nonasthmatics. 

Bronchoconstrictor activity. Water extract of seed, administered by inhalation to human adults, was active k... 

Bradypnea. Abnormal slowness of breathing. Bronchoconstrictor. Constricting or narrowing the lumina of the air passages of the lungs. 

Bronchial muscle Bronchial and tracheal muscle are contracted by PGF s PGD and relaxed by PGE s. Asthmatic patients are sensitive to PGF and PGE PGE causes broncho dilatation. LTC LTD are bronchoconstrictors. 

Induction of labour PG s do not have any advantage over oxytocin for the induction of labour. The adverse effects of the prostaglandins are slightly higher than that produced by oxytocin. PGF has more gastrointestinal toxicity than PGE and is a bronchoconstrictor also. Oral PGE is superior to oral oxytocin. PGE PGF is used in place of oxytocin in renal failure patients. 

Apart from histamine, leukotiienes liberated during inflammation are more powerful bronchoconstrictor and longer acting. Leukotrienes also increase bronchial mucus secretion and increase vascular permeability. All the leukotrienes are derived from 5-lipoxygenase pathway of arachidonic acid and are synthesized by a variety of inflammatory cells in the airways e.g. eosinophils, mast cells, basophils and macrophages. The LTB, exert many... 

Inhibition of platelet activating factor (bronchoconstrictor and pro-inflammatory actions). 

There is limited evidence suggesting that celiprolol may have less adverse bronchoconstrictor effect in asthma and may even promote bronchodilation. Acebutolol is also a -selective antagonist. 

LTC4 and LTD4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis. There are four current approaches to antileukotriene drug development 5-LOX enzyme inhibitors, leukotriene-receptor antagonists, inhibitors of FLAP, and phospholipase A2 inhibitors. 

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