Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.