Involvement of thromboxane A2 in propranolol-induced bronchoconstriction after allergic bronchoconstriction in guinea pigs.

Abstract

Although it is well recognized that beta-blockers can induce bronchoconstriction only in patients with asthma, mechanisms of the bronchoconstriction are not well known. We hypothesize that bronchoconstriction induced by beta-blockers may result from inflammatory mediators released by allergic reactions. In this study, we developed a guinea pig model for propranolol-induced bronchoconstriction (PIB) after antigen inhalation and investigated the effect of specific thromboxane (TXA2) receptor antagonists, S-1452 and ONO NT-126, on PIB in passively sensitized and artificially ventilated guinea pigs to determine whether TXA2 is involved in PIB. Propranolol caused bronchoconstriction with 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. On the other hand, propranolol did not produce bronchoconstriction after antigen provocation in nonsensitized guinea pigs or after saline provocation in sensitized animals. Pretreatment of the animals with S-1452 in doses of 0.01 and 0.1 mg/kg and ONO NT-126 in doses of 1.0 and 10 micrograms/kg injected intravenously 15 min after antigen challenge as well as before antigen challenge reduced PIB in a dose-dependent manner. Bronchoconstriction caused by methacholine did not induce PIB. These results suggest that TXA2 has an important role in the pathophysiology of the PIB that develops after the allergic bronchoconstriction.

Involvement of PAF in postallergic propranolol-induced bronchoconstriction in guinea-pigs

“…It adds to the list of mediators that may be involved in the PIB. However, the contribution may be relatively small because the degree of inhibition of the PIB was smaller with the PAF antagonists used in this study than with TxA 2 antagonists examined in our previous study [5]. As PAF levels in bronchoalveolar lavage fluid (BALF) or bronchial tissues were not measured after the response, we do not know the detailed mechanism of the role played by PAF in the development of PIB in our animal model.…”

“…However, no correlation was found between the degree of bronchodilation provoked by terfenadine and the magnitude of the decrease in responsiveness to propranolol [23]. Our previous study [5] revealed that TxA 2 may also play an important role in the pathogenesis of this reaction. In addition, a recent preliminary study from our group [11] showed that a 5-lipoxygenase inhibitor, AL3264, inhibited the PIB developed after allergic reaction, leading us to examine the role of another lipid mediator, PAF, in the PIB.…”

“…Histamine was found to be involved in the PIB in asthmatic patients [10]. Our previous studies [5,11] showed that thromboxane A 2 and 5-lipoxygenase products are important in the PIB. These findings suggest that inflammatory mediators contribute to the development of PIB.…”

“…The reaction can be severe, prolonged, and difficult to reverse. We recently developed an animal model in which propranolol provokes bronchoconstriction within a few minutes when propranolol was inhaled 20 min after challenge with aerosolized antigen in passively sensitized and artificially ventilated guineapigs [5]. Propranolol inhalation did not cause bronchoconstriction 5 or 20 min after methacholine-induced bronchoconstriction in nonsensitized guinea-pigs, or 20 min after saline inhalation in passively sensitized animals [5].…”

“…We recently developed an animal model in which propranolol provokes bronchoconstriction within a few minutes when propranolol was inhaled 20 min after challenge with aerosolized antigen in passively sensitized and artificially ventilated guineapigs [5]. Propranolol inhalation did not cause bronchoconstriction 5 or 20 min after methacholine-induced bronchoconstriction in nonsensitized guinea-pigs, or 20 min after saline inhalation in passively sensitized animals [5]. In addition, a dual neurokinin-1 (NK 1 ) and neurokinin-2 (NK 2 ) antagonist, FK224, attenuated nonspecific bronchial hyperresponsiveness to methacholine induced by allergic reaction [6], but did not change the propranolol-induced bronchoconstriction (PIB) (unpublished data).…”