ovalbumin and 8-phenyltheophylline

1. The bronchoconstriction of airway-perfused lungs and contraction of superfused tracheal spirals from guinea-pigs in response to adenosine were examined. 2. In lungs from untreated animals, adenosine had little effect unless the perfusion pressure was raised with carbachol (1.1 microM), when it caused a fall in perfusion pressure. However, if removed from guinea-pigs sensitized with ovalbumin (5 mg and 10 mg i.p. 14 and 12 days before use), adenosine was bronchoconstrictor, exerting bronchodilator effects only at high (1 mg) doses. The constrictor response to adenosine (300 micrograms) was significantly greater than that in lungs from untreated or sham-injected animals. 3. In superfused trachea from untreated animals, adenosine exerted only relaxant responses. In tissues from ovalbumin-sensitized guinea-pigs adenosine produced contractile responses, with relaxation appearing only at high (1 mg) doses. 4. Thus sensitization by antigen challenge revealed a bronchoconstrictor response of isolated airway preparations to adenosine. This is related to the clinical situation where only asthmatic subjects respond to adenosine by bronchoconstriction and suggests that the sensitization may destabilize inflammatory cells for mediator release by adenosine. 5. The response to a second exposure to adenosine was consistently reduced (lungs) or converted to a relaxation (trachea) indicating tachyphylaxis and consistent with a mediator release mechanism. 6. The P1-purinoceptor antagonist, 8-phenyltheophylline (3.9 microM), antagonized the relaxant responses to higher doses of adenosine. However, it did not affect the contractile responses to lower doses of adenosine. Whether this is due to P,-purinoceptors not being involved in the contractile response, or whether preferential blockade of the relaxant response leaves the contraction unopposed and apparently unblocked, remains to be established.

Topics: Adenosine; Animals; Bronchoconstriction; Dose-Response Relationship, Drug; Guinea Pigs; Immunization; In Vitro Techniques; Lung; Ovalbumin; Perfusion; Theophylline; Trachea

Xanthines are effective in the treatment of asthma, but the mechanism of action remains unclear. Pulmonary effects of seven xanthines, exhibiting a range of potencies as cyclic nucleotide phosphodiesterase (PDE) inhibitors and as adenosine antagonists, were investigated in anesthetized and ventilated guinea pigs. The bronchodilator effects of xanthines, determined from reversal of bronchoconstriction induced by aerosols of histamine and carbachol, correlated with their relative potencies as cyclic AMP-PDE inhibitors. The hypotensive effects of xanthines at bronchodilator doses were also consistent with PDE inhibition. Prophylactic effects of xanthines against bronchoconstriction induced by an aerosol of ovalbumin in sensitized guinea pigs, or by aerosols of leukotriene D4 and platelet-activating factor (PAF) in normal guinea pigs, occurred by a mechanism unrelated to bronchodilation and could not be readily attributed to PDE inhibition or adenosine A1/A2 receptor antagonism. There was a close association between inhibition of the responses to antigen and leukotriene D4, suggesting a common mechanism of action, but these effects gave a different profile from inhibition of the response to PAF. In addition, PAF-induced hypotension was unaffected in animals in which PAF-induced bronchoconstriction was inhibited, suggesting a mechanism other than PAF receptor antagonism. These results indicate that the bronchodilator, antiallergic and anti-inflammatory effects of xanthines occur through multiple molecular mechanisms of action, including at least one unknown mechanism. Furthermore, 8-phenyltheophylline produces these prophylactic effects at a dose that does not produce the cardiovascular or emetic side effects associated with xanthines, thereby exhibiting unique characteristics of potential therapeutic importance.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adenosine; Administration, Inhalation; Aerosols; Animals; Blood Pressure; Bronchi; Bronchoconstriction; Bronchodilator Agents; Carbachol; Guinea Pigs; Heart Rate; Histamine; Lung; Male; Ovalbumin; Platelet Activating Factor; SRS-A; Theophylline; Xanthines