A B S T R A C T Vasoactive intestinal peptide (VIP), originally isolated from hog small intestinal mucosa, has been shown to cause small intestinal secretion. More recently, this peptide has been identified in the plasma and tumors of patients with the so-called "pancreatic cholera" syndrome. In order to explore the possible role of VIP in the pathogenesis of this syndrome, we examined the effects of this peptide and other hormones on the cyclic AMP levels, adenylate cyclase activity, and ion transport in in vitro preparations of ileal mucosa. In rabbit ileal mucosa, VIP (20 usg/ml) caused a prompt fivefold increase in cyclic AMP level, whereas nine other hormones, which have been postulated to cause intestinal secretion, failed to exert such an effect. Pentagastrin and glucagon also failed to increase cyclic AMP levels in canine ileal mucosa. An increase in mucosal cyclic AMP levels was observed at a VIP concentration of 0.1 4g/ml and appeared to be nearly maximal at 2.0 Ag/ml. VIP (100 sg/ml) stimulated adenylate cyclase activity in a membrane preparation from rabbit ileal mucosa. Secretin (6.0 X 10-M) failed to do so. When added to the serosal side of isolated rabbit ileal mucosa clamped in an Ussing chamber, VIP (2 ug/ml) increased short-circuit current (SCC) and caused net secretion of both C1 and Na. Net Cl secretion exceeded net Na secretion. These effects of VIP on mucosal cyclic AMP metabolism and ion transport are similar to those observed with cholera enterotoxin and certain prostaglandins. VIP was also tested with normal human Dr. Kimberg is the recipient of a Research Career Development Award, AM-19377.

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Effects of catecholamines on cyclic AMP (cAMP) levels and ion fluxes were examined in isolated rabbit ileal mucosa. The base-line cAMP level was unaffected by epinephrine (Epi), norepinephrine (Norepi), and isoproterenol. The theophylline-augmented cAMP level was decreased slightly be Epi in one series of experiments but not in another. Propranolol did not enhance this effect. The increase in cAMP level produced by cholera toxin was almost completely reversed by addition of Epi or Norepi. This reversal was prevented by phenoxybenzamine. Epi also partially reversed the increase in cAMP level produced by prostaglandin E1. Effects of Epi on ion fluxes were determined following addition of secretagogues. Epi significantly decreased theophylline-induced but not cAMP or cholera toxin-induced Cl secretion. A decrease in short-circuit current was nonetheless observed in the latter two instances. The observed discrepancies between alpha-adrenergic effects on cAMP levels and ion fluxes suggest the following possibilities: 1) ion transport-related cAMP is only a small fraction of total mucosal cAMP; 2) cAMP-induced active ion secretion is only slowly reversible, or 3) effects of alpha-adrenergic stimuli on ion transport are not due to inhibition of cAMP accumulation.

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