Bronchoconstrictive effects

Sheppard (1988) examined the chemical mechanisms that underlie the bronchoconstrictive effect of sulfur dioxide. Sulfur dioxide dissolves in water to form bisulfite ion, sulfite ion, and hydrogen ion. The bisulfite ion is a nucleophile that can disrupt disulfite bonds. It has been postulated that bisulfite... 

Adenosine binds to adenosine receptors (AD-Rs) (subtypes Ah A2A, A2b and A3). Ap and Ap R activation gives Gai-mediated inhibition of adenylyl cyclase (resulting in decreased cAMP) and Gai/Gao-mediated activation of a K+ channel (with a de-excitatory hyperpolarizing effect). A2A and A2B activation gives Gas-mediated stimulation of adenylate cyclase (resulting in elevated cAMP). Adenosine acting via particular receptors variously has cardioprotective, neuroprotective, sedative, anticonvulsant, soporific, vasodilatory and bronchoconstrictive effects. The plant-derived methylxanthines theophylline and caffeine are adenosine A1 and A2 receptor antagonists (Table 5.1). 

The bronchoconstrictive effects of PAF in animal models (primarily guinea pig) appear to be mediated primarily by the activation of platelets and release of a secondary bronchoconstrictive substance (Vargaftig et al., 1982). A direct effect of PAF on guinea pig and human parenchymal tissue has also been reported, however (Stimler and O Flaherty, 1983 Stimler et al., 1983). One or both of these mechanisms of bronchoconstriction may occur in man. 

Introduction of alkyl substitutuents at C15 or C e of the 15-hydroxy series and at Cje or C17 of the 16-hydroxy series has provided compounds of high potency. However, bronchoconstrictive effects often have been noted and high activity has not been demonstrable for the 15-hydroxy series in our pilocarpine dog assay. 

The bronchoconstrictive effects of the beta blockers can be opposed by beta2 agonist bronchodilators such a salbutamol, but as the manufacturers point out, large doses may be needed and they suggest that ipratropium and intravenous aminophylline may also be needed. ... 

The more recently discovered leukotrienes result from arachidonic acid via the 5-hydroperoxide and the 5,6-epoxide (Leukotriene A4, LTA4). The leukotrienes contain a conjugated triene unit within a total of three (from 20 3, n—9), four (from 20 4, n—6), or five (from 20 5, n—3) double bonds. This total unsaturation is indicated by the numerical subscript. While the 8,11,14-triene unit provides the necessary unsaturation for prostaglandins and thromboxanes the 5,8,11-triene unit is required for leukotrienes. The various LTB, LTC, LTD and LTE compounds show a range of pharmacological activities of which the most widely studied is their relation to asthma arising from their bronchoconstricting effect. 

Elevation of cycHc AMP levels is also known to inhibit the release of inflammatory and contractile mediators from mast cells (42). The good clinical efficacy of P2" goiAsts may be related to this action because some members of this class of dmgs inhibit mediator release at the same concentrations at which they relax smooth muscle (43). In contrast to their effectiveness against immediate bronchoconstriction, P2" gonists do not inhibit the late asthmatic... 

C22H23NNa202, (17), both inhibit the effect of sensory nerve activation, thereby interfering with bronchoconstriction (101). 

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. 

Induces dyskinesia/vasodilatation, schizophrenia/4- coordination Vaso constriction/cell proliferation/aldosterone secretion Vaso constriction/cell proliferation/bronchoconstriction 4-memory, sedation/vasodilatation/4 GI motility A blood pressure/4- GI secretion Vagal effects/A blood pressure/tachycardia... 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Respiratory Effects. Pulmonary edema has been reported in humans who died of acute methyl parathion (Wofatox) intoxication (Fazekas 1971). Edema was foimd in a man who died 2 horn s after intoxication and in others who died as long as 9 days after exposure. Bronchoconstriction and h er-secretion of bronchial glands are primary muscarinic effects of methyl parathion. Pulmonary edema is not considered to be a primary effect of methyl parathion it is considered to be secondary to the neurologic effects of this compound on the heart and vascular smooth muscle. 

Findlay, S.R., Barden, J.M., Easley, C.B. and Glass, M. (1992). Effect of the oral leukotriene antagonist ICI 204,219 on the antgen-induced bronchoconstriction in subjects with asthma. J. Allergy Clin. Immunol. 89, 1040-1045. 

Inhaled short-acting fl2-agonists are the most effective agents for reversing acute airway obstruction caused by bronchoconstriction. 

Bronchoconstrictive and hyperglycemic effects can be minimized with / -selective /f-blockers. 

Ipratropium bromide and tiotropium bromide are competitive inhibitors of muscarinic receptors they produce bronchodilation only in cholinergic-mediated bronchoconstriction. Anticholinergics are effective bronchodila-tors but are not as potent as /J2-agonists. They attenuate, but do not block, allergen- or exercise-induced asthma in a dose-dependent fashion. 

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