To determine if vasoactive intestinal peptide (VIP) restores neural activity from tetrodotoxin (TTX) blockade, we studied the effects of VIP and related agents on carbachol (Cch)-induced Cl- secretion in control-isolated guinea pig distal colon and in that treated with TTX. The short circuit current (Isc) increased dose-dependently after serosal applications of Cch (10-6 - 2 × 10-5 M) and VIP (5 ×10-9 - 10-7 M). But no additive or synergistic increase in Isc was observed. Cch- and VIP-induced Isc was completely abolished by a serosal application of TTX (10-6 M). However, a serosal application, not mucosal, of VIP (10-7 M) and 8-bromo-cAMP (10-3 M) restored the Cch-stimulated, TTX-inhibited Isc by 113% and 75.8%, respectively. Furthermore, mucosal and serosal applications of forskolin (adenylate cyclase activator) restored the Isc by 43.9% and 65.3%, respectively. The restored Isc was completely abolished by atropine (muscarinic receptor antagonist). These results suggest that VIP may restore the cholinergic activity by increasing the level of intracellular cAMP, and that cholinergic neuron is very likely to be responsible forthe regulation of Cl- secretion at neuroepithelial junctions. The exact mechanism of VIP's effect on the TTX-inhibited epithelial Cl- secretion, and its possible usefulness in the treatment of TTX-induced pathophysiological conditions, remain to be determined.
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