β₂‐Adrenoceptor blockade is the basis of guinea‐pig bronchial hyper‐responsiveness to leukotriene C₄ and other agonists

Abstract

1 Four P-adrenoceptor antagonists, namely (-)-propranolol, (+)-propranolol, ICI-118551 and (±)-practolol, were investigated for their effects on leukotriene C4 (LTC4)-induced bronchoconstriction in the anaesthetized guinea-pig. (-)-Propranolol was also investigated for its effects on acetylcholine and histamine bronchospasm in the anaesthetized guinea-pig, and on LTC4-induced contractions of guinea-pig isolated trachea and lung parenchyma. 2 The various 1-adrenoceptor antagonists potentiated, dose-dependently, the bronchoconstriction induced by threshold doses of LTC4 and the intensity of the potentiation correlated with the 12-blocking capacity possessed by the drugs.3 (-)-Propranolol potentiated the bronchospasm induced by threshold doses of acetylcholine and histamine but to a lesser degree than the LTC4-induced bronchospasm. 4 The airway hyper-responsiveness induced by (-)-propranolol was unaffected by pretreatment with mepyramine, cyproheptadine, phenoxybenzamine, atropine or indomethacin. 5 The airway hyper-responsiveness induced by (-)-propranolol persisted even in adrenalectomized or reserpine-treated guinea-pigs, although adrenalectomy induced some increase in airway responsiveness. 6 (-)-Propranolol had no effect on LTC4, histamine and acetylcholine-induced contractions of isolated trachea and lung parenchyma.7 The results show that the airway hyper-responsiveness induced by P-adrenoceptor antagonists generally correlates with their P2-blocking activity. The possibility remains that some other unknown mechanism(s) may also be implicated.

Catecholamine and β-Adrenoceptor Influences on Airway Reactivity to Antigen in Guinea Pigs

“…It must be acknowledged that distinct dif ferences in patterns of responsiveness in upper airways in conscious versus anesthetized animals probably exist. The contributing mediators of bronchoconstriction in this mod el, predominantly histamine and leukotrienes from mast cell activation, have been well described [23.34], However, there has been disagreement concerning the mechanism by which the (3-adrenoceptor antagonists induce potentiation of bronchoconstriction elicited by a variety o f spasmogens, including histamine and lcukotrinc C4 [13,14,35,36]. Hirshman el al.…”

“…Several laboratories have demonstrated an enhanced air way responsiveness to antigen, as well as other spasmogens, with treatment with a (3-adrenoceptor antagonist [13,24], It has been suggested that this increase in response was due to a decrease in the adrenergic tone generated by circulating catecholamines acting at |3: -adrenoceptors [14,25], Other studies have shown an increase in airway reactivity to se lected spasmogens in animals which had been adrenalecto mized [14]. To our knowledge, circulating plasma catecho lamine levels have not been measured in hyperresponsive guinea pigs.…”

“…Demonstration of a protec tive effect of disodium cromoglycate on propranolol-in duced bronchospasm in asthmatics suggests an effect which may involve the cholinergic system and may suggest that cromoglycate has protective effects that are independent of its mast-cell-stabilizing activity [II], Administration of antigen to sensitized animals results in significant acute bronchoconstriction mediated predomin antly by extrusion of mast cell contents [12]. A propranololinduced potentiation of the airway response to histamine, 5-hydroxytryptamine, leukotricnes CA, D4 and antigen has been demonstrated [13][14][15][16], In some species, histamine, bradykinin and leukotrienes liberate catecholamines into the circulation [17][18][19][20][21], Using an elegant blood-bathed or gan technique. Piper and Collier [22] indirectly demon strated significant catecholamine-mediated relaxations of tissues perfused with extracorporeal blood from guinea pigs undergoing antigen-induced anaphylaxis.…”

Food Restriction–Mediated Adrenal Influences on Antigen–Induced Bronchoconstriction and Airway Eosinophil Influx in the Guinea Pig

“…It has been suggested that this increase in responsiveness is due to a decrease in the adrenergic tone generated by circulating catecholamines acting at β2–adrenoceptors [29, 30]. Other studies have shown an increase in airway reactivity to selected spasmogens [31]or antigen [17, 19]in adrenalectomized animals. This enhanced reactivity correlates with a reduced level of circulating catecholamines [17, 19].…”

Involvement of Platelet-Activating Factor (PAF) in Septic Shock and Priming as Indicated by the Effect of Hetrazepinoic PAF Antagonists

“…The failure of c~administered propranolol to potentiate the lethal effect of endotoxin suggests that during the time interval between the administration of endotoxin and of propranolol, endotoxin may prime the generation of shock mediators such as thromboxanes, cytokines, leukotrienes, peptides, and PAF. Propranolol synergizes with a number of mediators (18). The ability of the selective PAF antagonist WEB 2170 to antagonize the propranolol-precipitated lethal effect of endotoxin (15,16) indicates that PAF may play a key role in the release of mediators and their interaction in vivo.…”