Effect of papaverine on synaptic transmission in the guinea-pig ileum

1 The effect of papaverine, a well known smooth muscle relaxant, was investigated on neural transmission within the enteric nervous system. Segments of guinea-pig ileum were placed in a partitioned bath to enable drugs, including papaverine, to be applied to enteric nerve pathways without interfering with the recording of the smooth muscle contraction. Ascending excitatory enteric nerve pathways were activated by electrical field stimulation in the anal compartment (10 Hz for 2 s, 45 mA, 0.5 ms pulse duration) and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. 2 Tetrodotoxin (0.6 mu M) and hexamethonium (100 mu M) both abolished, or greatly reduced, the contractions when applied to either compartment indicating that nicotinic synapses are involved in this pathway. 3 Papaverine (0.3-30 mu M) applied independently to each compartment depressed in a concentration-dependent manner, the nerve-mediated contractions. The IC50 of this inhibitory effect was 3.53 mu M for the oral and 4.76 mu M for the anal compartments, respectively. Two other phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX 10-300 mu M) and theophylline (30-1000 mu M) added to the anal compartment also inhibited the nerve mediated contractions. Papaverine applied to the anal bath, after IBMX 100 mu M (or theophylline 300 mu M) further inhibited the nerve-mediated contractions, but was less effective than when applied alone. 4 Phentolamine (1 mu M), an alpha-adrenoceptor antagonist, reduced the inhibitory effect of papaverine, but not that of IBMX (100 mu M) or theophylline (300 mu M). A combination of phentolamine and IBMX (or theophylline) prevented the inhibitory effect of papaverine. 5 Tetrodotoxin, but not papaverine or hexamethonium, inhibited the contraction elicited by electrical stimulation just anal to the partition indicating that papaverine did not affect the generation or conduction of nerve action potentials. 6 Verapamil (1 mu M) and nifedipine (1 mu M), two smooth muscle relaxants which act by blocking L-type calcium channels. only inhibited the contractions when applied directly to the recording (oral) compartment. This indicates that L-type Ca2+ channels are probably not involved in synaptic transmission in these ascending pathways and thus that the PDE inhibitors do not inhibit synaptic transmission by acting on these channels, co-Conotoxin GVIA (10 nM), a potent inhibitor of the N-type Ca2+ channels. blocked the nerve-mediated contractions applied to either compartment. Whether the PDE inhibitors exert their inhibitory actions via those channels remains to be established. 7 The results indicate that the PDE inhibitors, papaverine, IBMX and theophylline inhibit excitatory enteric neural pathways by depressing synaptic transmission. The inhibitory effect of papaverine (but not IMBX or theophylline) involves, at least in part, the release of noradrenaline from sympathetic nerves acting on alpha-adrenoceptors on enteric neurones