Water and enzyme secretion are tightly coupled in pancreatic secretion stimulated by food or CCK-58 but not by CCK-8

Abstract

Pancreatic secretion of protein, water, chloride, and bicarbonate under basal conditions and in response to intravenous and intraduodenal stimuli were studied in awake rats fully recovered from surgery. During the basal phase of pancreatic secretion, protein output and water output were weakly correlated or uncorrelated, consistent with separate regulation and distinct cellular origin of enzyme (acinar cells) and water (duct cells), referred to as the two-component paradigm of pancreatic secretion. When pancreatic secretion was stimulated physiologically, water and protein output abruptly became strongly and significantly correlated, suggesting that protein secretion and water secretion are tightly coupled or that protein secretion is dependent on water secretion. The apparent function of this coupling is to resist or prevent increases in protein concentration as protein output increases. This pattern of secretion was reproduced by intravenous infusion of the CCK-58 form of cholecystokinin, which strongly stimulates pancreatic water and chloride secretion, but not by CCK-8, which only weakly stimulates water and chloride secretion in a non-dose-dependent manner. The remarkably tight association of water and protein secretion in food-stimulated and CCK-58-stimulated pancreatic secretion is consistent with a single cell type as the origin of both water and enzyme secretion, i.e., the acinar cell, and is not consistent with the two-component paradigm of pancreatic secretion. Because CCK-58 is the only detectable endocrine form of cholecystokinin in the rat and its bioactivity pattern is markedly and qualitatively different from CCK-8, actions previously recorded for CCK-8 should be reexamined.

CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

“…In contrast, in vivo studies showed differential effects of the two molecular forms on pancreatic physiology and pathology. CCK-58, but not CCK-8, strongly stimulates pancreatic fluid secretion in rats (46,62), and CCK-8, but not CCK-58, induces pancreatitis Gates were closed at 90 min before the onset of the dark phase. Directly before lights off, animals were injected with CCK-8 or CCK-58 (0.6, 1.8, and 5.2 nmol/kg ip) or vehicle (saline containing 0.1% BSA) and placed back in their home cage.…”

“…Ϫ1 over a 3-h period strongly stimulated pancreatic fluid secretion in a dose-dependent fashion in an in vivo rat model (46,62). CCK-58 induces a more sustained pancreatic protein secretion than CCK-8, as shown by the return to basal values at the end of the 3-h infusion period with CCK-8, whereas protein output remained significantly elevated compared with basal in CCK-58-treated rats (46,62).…”

“…CCK-58 induces a more sustained pancreatic protein secretion than CCK-8, as shown by the return to basal values at the end of the 3-h infusion period with CCK-8, whereas protein output remained significantly elevated compared with basal in CCK-58-treated rats (46,62). In addition, intravenous infusion of CCK-58 at 2 or 4 nmol·kg Ϫ1 ·h Ϫ1 for 6 h in a conscious rat model did not induce pancreatitis at a dose at which CCK-8 induced several parameters indicative of pancreatitis, including interstitial edema, inflammatory cell infiltration, intracellular vacuolization, increased pancreatic myeloperoxidase activity, and elevated serum amylase levels (61).…”

The Pancreas Misled: Signals to Pancreatitis

“…The calcium signals are tightly linked to the physiological release of inactive zymogens from the apex of the acinar cell [13] into the pancreatic duct and duodenum, where the zymogens are activated. The vast majority of studies have been carried out using cholecystokinin-8, widely thought to be the physiological secretory hormone; however, recent evidence calls this view into question, suggesting that other forms of this peptide, such as cholecystokinin-58, may in fact be more relevant [14,15] . For example, cholecystokinin-58 is the only detectable form of cholecystokinin in the rat [14] , where water and enzyme secretion are tightly coupled in pancreatic secretion stimulated by cholecystokinin-58 but not cholecystokinin-8 [15] .…”

“…The vast majority of studies have been carried out using cholecystokinin-8, widely thought to be the physiological secretory hormone; however, recent evidence calls this view into question, suggesting that other forms of this peptide, such as cholecystokinin-58, may in fact be more relevant [14,15] . For example, cholecystokinin-58 is the only detectable form of cholecystokinin in the rat [14] , where water and enzyme secretion are tightly coupled in pancreatic secretion stimulated by cholecystokinin-58 but not cholecystokinin-8 [15] . To resolve controversy arising from these recent in vivo observations, comparative studies of the actions of cholecystokinin-58 and cholecystokinin-8 on isolated pancreatic cells are required.…”