The finding by Stoff that activation of adenylate cyclase stimulated secretion by the gland led to the search of a hormone. Hormones involved in volume regulation were tested to no avail. Hormones found in vertebrate gastrointestinal tract were tested because the rectal gland was part of that tract. Of the hormones of the secretin family, vasoactive intestinal peptide (VIP) activated the gland. Other hormones or neurotransmitters such as growth hormone-releasing peptide (GHRH), peptide histidine isoleucine (PHI), and pituitary adenylate cyclase-activating peptide (PACAP) also activated the gland but not a well as VIP. VIP did not activate the rectal gland of Scyliorhinus canicula, or Raja erinacea where the activating agents were scyliorhinin II and gastric inhibitory peptide (GIP) and glucagon. VIP was found to activate the rectal gland adenylate cyclase and a receptor for VIP was cloned and expressed in frog oocytes by Bewley. VIP levels did not change in response to the volume loading unlike the gland secretion indicating a disconnection between the response to a salt load and the effect of VIP. This observation suggested that there was a missing link between a salt load and the effect of VIP on shark rectal gland secretion.