INDIRECT MUSCARINIC RECEPTOR ACTIVATION BY PENTAMIDINE ON AIRWAY SMOOTH-MUSCLE

1 Pentamidine is routinely used to reduce the incidence of Pneumocysti s carinii pneumonia in patients infected with human immunodeficiency v irus, but it has been described as inducing pulmonary adverse effects, such as cough and bronchospasm 2 In this paper we have investigated t he effects of pentamidine on guinea-pig isolated main bronchi and huma n isolated bronchi. Pentamidine induced a concentration-dependent cont raction in both preparations with pD(2) values of 9.64+/-0.07 (n=8) an d 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 bro nchi respectively. Atropine (0.01 to 0.1 mu M) and the muscarinic M(3) receptor antagonist, hexahydro-siladiphenidol (0.1 and 1 mu M) inhibi ted pentamidine-induced concentration-responses in both preparations i n a non-competitive manner, whereas only high concentrations of the M( 1) receptor antagonist pirenzipine (1 mu M) inhibited pentamidine conc entration-response curves. 3 The cholinesterase inhibitor, tacrine (1 mu M), potentiated the effect of pentamidine; in contrast, morphine in hibited pentamidine-induced responses. 4 The bronchoconstrictor effect of pentamidine on guinea-pig and human isolated bronchi was not modif ied by the H-1 histamine receptor antagonist, mepyramine, by indometha cin or by the neurokinin NK1 and NK2 receptor antagonists, CP-96,345 a nd SR 48969 respectively, suggesting that neither histamine receptor s timulation, arachidonic acid derivative formation, nor tachykinin rele ase are involved in pentamidine-induced contraction of human and guine a-pig airways. 5 Our overall results suggest that pentamidine induces contraction of guinea-pig and human isolated bronchi through prejuncti onal cholinergic nerve stimulation.