Proabsorptive Effect Research Articles

Neuropeptide Y and σ receptor agonists act through a common pathway to stimulate duodenal alkaline secretion in rats

Neuropeptide Y (NPY) has been shown to mimic the effects of some σ receptor agonists in the brain and to possess the same proabsorptive effect as these agonists in the isolated mouse jejunum. The aim of the present study was to investigate the effect of NPY on duodenal alkaline secretion in the rat and to define its mode of action. NPY (0.01 to 3 ωg/kg i.v.) induced a dose-related increase in duodenal bicarbonate secretion, the maximal effect being obtained at 1 ωg/kg. This response was significantly inhibited by the i.v. administration of haloperidol, BMY 14802, devazepide, hexamethonium, tetrodotoxin and by bilateral truncal vagotomy, but not by SCH 23390, sulpiride, prazosin or atropine, whereas i.c.v. devazepide had no effect. This pharmacological profile is identical to that reported for σ receptor agonists. The results suggest that NPY and σ ligands act through a common pathway to stimulate duodenal alkaline secretion in the rat.

Neuropeptide Y is a proabsorptive agent in the small intestine

In the mammalian intestine neuropeptide Y (NPY) is contained in sympathetic nerves and in enteric neurons originating from the myenteric and submucosal plexuses. This study investigated the role of NPY on small intestinal ionic transport using an isolated intestinal preparation. Rabbit ileal segments ( n = 12) were harvested and arterially perfused with a nonrecirculating oxygenated sanguinous solution. The intestinal lumen was perfused with an isotonic solution containing [ 14C]PEG. Net fluxes of H 2O, Na +, and Cl − were calculated for three 20-min periods: basal, drug infusion, and recovery. Two groups were studied: (1) NPY 50 p M/min ( n = 6) and (2) NPY 500 p M/min ( n = 6). NPY at 50 p M/min caused modest absorption and at 500 p M/min yielded a significant proabsorptive effect ( P < 0.05) for H 2O, Na +, and Cl − during the drug infusion period. There were no significant changes in vascular perfusion pressure in either group. These data demonstrate a significant proabsorptive effect of NPY on water and electrolyte transport in the isolated perfused ileum. This proabsorptive effect occurs at a constant arterial blood flow and without alteration in perfusion pressure, supporting a direct effect of NPY on intestinal ionic transport.

Neural blockade in basal and postreceptor-stimulated intestinal transport

Postreceptor protein stimulation significantly alters the transport state of the ex vivo small intestine. This study investigated the effects of neural blockade on basal and stimulated ionic transport. Rabbit ileal segments ( n = 46) were arterially perfused with an oxygenated sanguinous buffered electrolyte solution. The lumen was perfused with an isotonic solution containing [ 14C]-polyethylene glycol as a nonabsorbable marker. Net fluxes of H 2O, Na +, and Cl − were calculated. Tetrodotoxin (TTX) was used to block enteric neural transmission. Forskolin (FOR) was used to activate adenylate cyclase, and phorbol 12,13-dibutyrate (PDB) served to activate protein kinase C. Two groups were studied. Group A preparations had no TTX pretreatment, while group B preparations were pretreated with TTX. In the Group A preparations, TTX at 10 −6 M and PDB at 10 −5 M caused significant proabsorptive effects with a ΔF H 2O of +20 ± 7 and +15 ± 2 μl/min, respectively ( P < 0.05), while FOR stimulated significant secretion with a ΔF H 2O of −14 ± 3 μl/min ( P < 0.05). In the Group B TTX-pretreated preparations, FOR did not cause secretion and PDB maintained an absorptive state. These results indicate that neural blockade with TTX reverses basal secretion in the ex vivo intestine, suggesting that an intact enteric nervous system maintains the secretory status of the intestine. FOR-induced adenylate cyclase-activated secretion does not occur in the presence of TTX, implying that intact neural transmission is required for the FOR effect. PDB-induced protein kinase C-activated absorption occurs despite neural blockade, suggesting that the PDB-induced proabsorptive effect is mediated without neural intermediaries.

Naloxone-insensitive transport effects of loperamide in guinea-pig gallbladder epithelium

The effects of the antidiarrheal drug, loperamide, on HCO3 and Na transport across guinea-pig gallbladder epithelium were investigated using Ussing-chamber methods. Under basal conditions, mucosal loperamide (10(-4) mol/l) moderately lowered both the absorptive (JHCO3ms) and the secretory HCO3 flux (JHCO3sm) (pH-stat method), most likely by changing paracellular HCO3 flow. Exposure to serosal prostaglandin E1 (10(-6) mol/l) abolished Na absorption and turned HCO3 secretion electrogenic. The associated short-circuit current (Isc) was inhibited by loperamide in a concentration-dependent manner; mucosal addition (threshold at 3 x 10(-6) mol/l) of the drug was more effective. Inhibition of Isc was related to a decrease in JHCO3sm, but exceeded the drop in JHCO3net. The effects on JHCO3sm and Isc were mimicked by [Met5]enkephalin. Naloxone (10(-6) mol/l) was unable to influence the effects of loperamide and [Met5]enkephalin on Isc. There were no pro-absorptive effects of loperamide on unidirectional Na fluxes. We conclude that antisecretory properties of loperamide are solely due to inhibition of electrogenic HCO3 secretion, an effect unrelated to opiate receptor binding.

Luminal adrenergic agents modulate intestinal transport

Intestinal transport is controlled by luminal solutes, neural pathways, and paracrine or humoral agents. The current study investigated the effect of luminally administered adrenergic agents on the intestinal transport of water and electrolytes. Dogs with 25-cm jejunal Thiry-Vella loops were studied. The loops were luminally perfused with an isotonic solution containing [ 14C]PEG, and the fluxes of H 2O, Na +, and Cl − were calculated. Each experiment consisted of three 1-hr periods: basal, luminal agent infusion, and recovery. Luminal adrenergic agents did not alter heart rate. Norepinephrine ( α 1 > α 2 and β adrenergic agonist) and phenylephrine ( α 1 adrenergic agonist) caused significant absorption of water and sodium. Clonidine ( α 2 adrenergic agonist) and isoproterenol (β adrenergic agonist) caused significant secretion of water, sodium, and chloride. Luminally administered adrenergic agents can influence small intestinal water and electrolyte transport. Alpha 1 agonists have a proabsorptive effect, while α 2 and β agonists have a secretory effect. Luminally administered proabsorptive adrenergic agents may prove useful in pathologic secretory states such as diabetic diarrhea, small bowel transplantation, or diarrhea-associated endocrinopathies.

Effect of somatostatin analog (SMS 201-995) on in vivo intestinal fluid transport in rats. A limited systemic effect.

Somatostatin analog, SMS 201-995, effectively inhibits the release of hormones from gastrointestinal endocrine tumors and reduces hormonally mediated diarrheas. Its clinical efficacy in nonhormonally mediated diarrhea is limited, despite a potent antisecretory and proabsorptive effect in vitro. The effect of serosal addition of SMS 201-995 on in vitro short-circuit current responses in rat intestine is dependent upon chloride and more marked in colon and ileum than jejunum. In contrast, in vivo loop studies demonstrated that systemic administration of SMS 201-995 for five consecutive days produced a paradoxical decrease in basal colonic fluid absorption with no effect in jejunum or ileum. Furthermore, systemically administered SMS 201-995 did not alter cholera toxin-stimulated intestinal secretion. We conclude that despite a previously identified intestinal antisecretory and proabsorptive effect of SMS 201-995 in vitro, this effect is not seen in vivo and may explain the limited use of SMS 201-995 as an antidiarrhoeal agent in nonhormonally mediated diarrhoea.