Abstract
Vasoactive intestinal polypeptide (VIP) has long been proposed as an inhibitory neurotransmitter in the internal anal sphincter (IAS) but direct evidence for this hypothesis is limited. The present study examined the role of VIP in inhibitory neuromuscular transmission (NMT) in the mouse IAS by comparing contractile and membrane potential responses to electrical field stimulation (EFS) of nerves in wild type (WT) and VIP−/− mice. EFS with short trains of stimuli (4s) gave rise to frequency (0.1–20 Hz) dependent relaxation and hyperpolarization in WT and VIP−/−mice. Peak EFS‐induced responses were not different between mice under control conditions and in the presence of the P2Y1 receptor antagonist MRS2500 (1 μM) while they were abolished with combined MRS2500 plus the nNOS inhibitor L‐NNA (100 μM) indicating that VIP is not required for nitrergic NMT. With longer trains of EFS (5Hz, 30–60s; 20 Hz 10–30s) a more slowly developing nitrergic and purinergic‐independent response was observed in WT but not VIP−/−mice suggesting that this component is due to VIP. In WT mice this component was blocked by the VIP receptor antagonist VIP6‐28 (10 μM) further supporting this hypothesis. In conclusion, these data provide evidence that the third inhibitory neural component in the mouse IAS is due to VIP. This pathway requires higher levels of EFS and persists well beyond the period of nerve stimulation. Grant support: DK078736.
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