Indirect muscarinic receptor activation by pentamidine on airway smooth muscle

1 Pentamidine is routinely used to reduce the incidence of Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus, but it has been described as inducing pulmonary adverse effects, such as cough and bronchospasm 2 In this paper we have investigated the effects of pentamidine on guinea-pig isolated main bronchi and human isolated bronchi. Pentamidine induced a concentration-dependent contraction in both preparations with pD(2) values of 9.64+/-0.07 (n=8) and 9.73+/-0.06 (n=8) and a maximal effect (E(max)) of 40+/-4% and 34+/-5% of the response to acetylcholine (1 mM) in guinea-pig and human bronchi respectively. Atropine (0.01 to 0.1 mu M) and the muscarinic M(3) receptor antagonist, hexahydro-siladiphenidol (0.1 and 1 mu M) inhibited pentamidine-induced concentration-responses in both preparations in a non-competitive manner, whereas only high concentrations of the M(1) receptor antagonist pirenzipine (1 mu M) inhibited pentamidine concentration-response curves. 3 The cholinesterase inhibitor, tacrine (1 mu M), potentiated the effect of pentamidine; in contrast, morphine inhibited pentamidine-induced responses. 4 The bronchoconstrictor effect of pentamidine on guinea-pig and human isolated bronchi was not modified by the H-1 histamine receptor antagonist, mepyramine, by indomethacin or by the neurokinin NK1 and NK2 receptor antagonists, CP-96,345 and SR 48969 respectively, suggesting that neither histamine receptor stimulation, arachidonic acid derivative formation, nor tachykinin release are involved in pentamidine-induced contraction of human and guinea-pig airways. 5 Our overall results suggest that pentamidine induces contraction of guinea-pig and human isolated bronchi through prejunctional cholinergic nerve stimulation.