CONDITIONAL INVOLVEMENT OF MUSCARINIC M(1) RECEPTORS IN VAGALLY MEDIATED CONTRACTION OF GUINEA-PIG BRONCHI

The involvement of ganglionic muscarinic M(1) receptors in vagally ind uced bronchoconstriction in guinea-pig airways is controversial. There fore, we studied the effects of the M(1)-selective muscarinic receptor antagonist pirenzepine on vagus nerve (VNS, preganglionic) and electr ical field stimulation (EFS, postganglionic)-induced contractions of t he guinea-pig main bronchus under various experimental conditions. Usi ng identical stimulation parameters for VNS and EFS (8V, 30 Hz, 0.5 ms , 5s every min), the amplitude of the VNS-induced twitch contractions was 30.4% of the EFS-induced responses, and pirenzepine showed 2.3-fol d selectivity (pIC(50)-values 6.45 and 6.09, respectively) to inhibit vagally induced contractions. With the stimulation frequency for EFS l owered to match contraction levels obtained using VNS, pirenzepine was equipotent to inhibit both types of response at M(1) receptor-selecti ve concentrations, suggesting that M(1) receptors are not involved. By contrast, when the stimulation episode was prolonged until plateau co ntraction (10-20 s), in the presence of the nicotinic antagonist hexam ethonium (5 mu M), the M(2) receptor antagonist AQ-RA 741 (0.1 mu M) a nd the beta-adrenoceptor antagonist timolol (1 mu M), and again using matched VNS- and EFS-induced contraction levels, pirenzepine inhibited nerve stimulation-evoked responses in a biphasic manner, yielding pIC (50)-values of 8.12 (indicative of M(1) receptor blockade) and 6.43 (i ndicative of M(3) receptor blockade) for the first and second phase, r espectively, while postganglionic stimulation showed a purely monophas ic inhibition (pIC(50) = 6.32). These results show that facilitatory m uscarinic M(1) receptors are involved in vagally mediated contraction of guinea-pig bronchi, under conditions of elevated neurotransmission and partial nicotinic receptor blockade.