Marie G Dr Mckenniff

Characterisation of receptors mediating the contractile effects of prostanoids in guinea-pig and human airways

Receptors mediating the contractile effects of prostanoids in the airways of guinea-pig and man have been compared using a range of selective agonists and antagonists. In guinea-pig and human lung parenchymal strips, contractile responses to all prostanoid agonists were blocked by EP092 and AH23848 (antagonists of thromboxane-sensitive receptors) but were unaffected by the EP1 receptor antagonist, AH6809. In guinea-pig tracheal rings responses to the thromboxane mimetic U46619 were antagonised by EP092 and AH23848. AH6809 was ineffective, but did antagonise responses to 16,16-dimethylPGE2 and PGF2 alpha in this tissue. In the human bronchiolar ring responses to U46619 were poorly antagonised by AH23848, EP092 and AH6809. The results suggest that prostanoid contractile agonists act through thromboxane receptors in guinea-pig and human lung parenchymal strips and through thromboxane and EP1 receptors in guinea-pig trachea. A novel prostanoid receptor type, or subtype, mediating contractile effects may be present in human bronchioles.

BAY u3405, a potent and selective thromboxane A2 receptor antagonist on airway smooth muscle in vitro

1 BAY u3405 (3(R)‐[[(4‐fluorophenyl) sulphonyl]amino]‐1,2,3,4‐tetrahydro‐9H‐carbazole‐9‐propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA2‐mimetic U46619‐induced contractions of human, guinea‐pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10−9–10−4 m). 3 The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)‐enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea‐pig and human airway smooth muscle. 4 BAY u3405 also competitively antagonized contractions of guinea‐pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9α, 11β‐PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2α and 16, 16‐dimethyl‐PGE2. 5 A high concentration (10−6 m) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP1, EP2, FP or IP). 6 BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.

The thromboxane receptors of rat and guinea-pig lung.

The thromboxane (TXA2) receptors on rat and guinea-pig lung strips were compared using TXA2 agonists and TXA2 receptor antagonists. On rat lung strip several TXA2 mimetics were full agonists whilst the primary prostanoids lacked agonist activity. On guinea-pig lung strip the same agonists displayed markedly different efficacies. Both preparations contained homogeneous populations of TXA2 receptors as evidenced by BAY u3405 giving comparable pA2 values against four TXA2 mimetics. However, the observed pA2s of nine different TXA2 receptor antagonists, determined against U46619, did not correlate between the two preparations. These results point to the existence of TXA2 receptor subtypes.