Bronchoconstrictor activity

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). 

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 ). 

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

Of adult asthmatics 2-20% have aspirin hypersensitivity (9). The mechanism is related to a deficiency in bronch-odilator prostaglandins prostaglandin inhibition may make arachidonic acid produce more leukotrienes with bronchoconstrictor activity. Oral challenge in asthmatic patients is an effective but potentially dangerous method for establishing the presence of aspirin hypersensitivity (63). 

Amin et al. have observed that vasicinone, an auto-oxidation product of vasicine from extracts of A. vasica leaves, causes definite bronchodilation in the presence of histamine-induced bronchospasm, slight hypotension and a positive cardiac inotropic action with increased coronary flow. The investigators attribute the bronchodilator effect of vasaka leaves to the small amount of vasicinone produced by auto-oxidation of vasicine (cited after 124). Mehta et al. (136) have isolated 1-vasicinone from A. vasica and demonstrated that it is not an artifact as it has bronchodilator activity in contrast to the bronchoconstrictor activity of 1-vasicine. 

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]. 

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. 

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. 

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

Fig. 1.4 The bronchoconstrictor effects of adenosine, NECA, CPA, CGS 21680 and 2-C1-IB-MECA in actively sensitised, Brown Norway rats 3 h post intratracheal instillation of vehicle (saline, 0.2 ml) or ovalbumin (OA, 0.3 mg kg-1). The agonists were given i.v. and to avoid tachyphylaxis, only one response was generated per animal. Results are expressed as means s.e. means (n = 4—5). P < 0.01, P < 0.001 that the value is significantly different from the equivalent value in the vehicle-challenged group (from Hannon et al. 2002b, with permission)...

Hannon JP, Tigani B, Williams I, Wolber C, Howes C, Mazzoni L, Fozard JR (2002b) Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitised Brown Norway rats. Br J Pharmacol 135 685-696... 

Drugs that preferentially block the [ receptors have been developed to eliminate the unwanted bronchoconstrictor effect (p2) of propranolol seen among asthmatic patients. Cardioselective p-blockers, such as acebutolol [a se BYOO toe lole], atenolol [a TEN oh lole], and metoprolol [me TOE proe lole], antagonize receptors at closes 50 to 100 times less than those required to block p2 receptors. This cardioselectivity is thus most pronounced at low doses and is lost at high drug doses. [Note Acebutolol has some intrinsic agonist activity.]... 

Neurokinin A and B are both decapeptides discovered by Kimura et al. (142) from the porcine spinal cord. Both have very similar amino acid composition and sequence homology to the undecapeptide substance P, and they also have similar biological activities as substance P. They are potent bronchoconstrictors, constrict smooth muscle, and activate the micturition reflex. 

Vasicinone (185) exhibited bronchodilator, - - - weak cardiac stimulant," and potent antianaphylactic activities, whereas vasicine (184) displayed bronchoconstrictor > and cardiac depressant activities. The structure-bronchodilator activity relationship was discussed. Vasicine (184) also had marked respiratory and uterine stimulant activities and a moderate hypotensive activity.Vasicinone (185) was devoid of these activities. ... 

The activation of NOS or the products thereof modulates airway constrictor responses as well. Atropine-sensitive, electrical field stimulation-induced bronchoconstrictor responses in the guinea-pig are enhanced by NOS inhibitors (Belvisi etal., 1991). Nitrogen oxides also modulate the effects of non-cholinergic bronchoconstrictors. H stimulation of Hi receptors in the guinea-pig lung leads... 

Delineation of the role of a specific mediator in the bronchomotor response to a proinflammatory stimulus is usually obtained by the ability of a specific receptor antagonist to block the response. This process of identification is dependent on the antagonist s being applied in doses sufficient to block the receptor for the endogenously released mediator and selective for the receptor of the mediator at the applied doses. Specific antagonists have been developed or are currently being developed for many of the inflammatory cell-derived mediators possessing bronchoconstrictor or proinflammatory activity. 

Leukotriene Antagonists. The leukotrienes are metabolites of arachidonic acid generated de novo after inflammatory cell activation [69,75] and are potent bronchoconstrictors and proinflammatory agents (vide supra). The biological effects of the cysteinyl-leukotrienes (viz. C4, D4, and E4) and of leukotriene B4 are mediated via cysLTi and BLT receptors, respectively [69,76]. The development of potent, selective cysLT receptor antagonists, such as montelukast, pranlukast,... 

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