Abstract
Pituitary adenylate cyclase-activating peptide (PACAP)1–27, PACAP1–38, and vasoactive intestinal peptide (VIP) initiated dose-dependent contractions of canine ileal circular muscle after intra-arterial injection in vivo or ex vivo. PACAP1–27- and VIP-induced contractions approached the tissue maximum; VIP was 100-fold less potent. PACAP1–38 was more potent than VIP. PACAP1–27contractions in vivo were unaffected by hexamethonium, reduced equally by atropine or atropine plus hexamethonium, and abolished by tetrodotoxin (TTX), suggesting that PACAP released acetylcholine and another excitatory neurotransmitter from postganglionic cholinergic enteric nerves. In myenteric plexus-free circular muscle strips, PACAP1–27 at 10−9 M and PACAP1–38 or VIP at 10−7 M increased [3H]acetylcholine release during nerve stimulation, suggesting the locus of one postganglionic site at which PACAP1–27 acts. All agonists inhibited nerve-mediated contractions in vivo with a potency rank order similar to that for excitation. Inhibition of nitric oxide (NO) synthetase or TTX decreased the duration and amplitude of PACAP1–27- but not PACAP1–38-induced inhibition. Inhibition of NO synthetase abolished VIP-induced inhibition, but TTX did not. Submaximal contractions to acetylcholine were amplified by PACAP1–27or VIP before TTX and inhibited after TTX. Thus, both PACAP molecules and VIP directly inhibit and indirectly excite smooth muscle contractions. PACAP1–27 and VIP also release NO. The functional potency differences between PACAP1–27 and VIP suggest PAC1 receptors mediate all responses, likely through the stimulation of adenylate cyclase.
Footnotes
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Send reprint requests to: Dr. E. E. Daniel, Department of Biomedical Sciences, 4N51, McMaster University Medical Center, 1200 Main St. W, Hamilton, Ontario, Canada L8N. E-mail:daniele{at}fhs.csu.mcmaster.ca
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↵1 This work was supported by the Medical Research Council of Canada.
- Abbreviations:
- EFS
- electrical field stimulation
- NANC
- noncholinergic nonadrenergic
- NPY
- neuropeptide Y
- l-NNA
- N-nitro-l-arginine
- NO
- nitric oxide
- TTX
- tetrodotoxin
- PACAP
- pituitary adenylate cyclase-activating peptide
- PYY
- peptide YY
- VIP
- vasoactive intestinal peptide
- Received June 12, 1998.
- Accepted February 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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