The autonomic control of intestinal electrolyte transport has been investigated in the in vitro, short-circuited rabbit ileum with varying doses of carbachol and with neuroeffector blocking agents. Low-dose carbachol (less than 10(-6) M) and high-dose carbachol (greater than 10(-4) M) had different effects on Na and Cl transport. Low-dose carbachol caused a transient increase in the potential difference and short-circult current, stimulated Cl secretion, and inhibited the residual flux (probably HCO3 secretion). This is a muscarinic response since it is inhibited by atropine (10(-6) M). After an initial increase of the potential difference and short-circuit current, high-dose carbachol reduced these electrical parameters, stimulated Na and Cl absorption, and abolished the residual flux. This is a nicotinic response since it is inhibited by hexamethonium (10(-5) M). This nicotinic response is identical to that reported by others with alpha-adrenergic agents and it was inhibited also by phentolamine (10(-7) M). We propose that high-dose carbachol stimulates nicotinic receptors on postganglionic sympathetic fibers present in our preparations causing a release of catecholamines and a resulting alpha-adrenergic response by the intestinal epithelial cell. The physiological significance of this response in the gut remains to be determined.
To study the effects of endogenous norepinephrine on intestinal ion transport, we tested the actions of an indirect sympathomimetic agent, tyramine, on electrolyte fluxes in the short-circuited rabbit ileum in vitro. Tyramine (10(-5) M) alone had no effect on short-circuit current or Na transport but increased Cl absorption. Tyramine decreased the short-circuit current, stimulated both Na and Cl absorption, and increased tissue conductance when its breakdown by endogenous monoamine oxidase enzymes was inhibited by pretreatment with pargyline (10(-4) M). Pargyline alone had no effect on short-circuit current and NaCl transport. The effect of norepinephrine on NaCl transport was inhibited by the alpha-adrenergic receptor antagonist, phentolamine (10(-7) M). This response was also prevented when animals were chemically sympathectomized with 6-hydroxydopamine. Although sympathectomy decreased measurable tissue norepinephrine by 80%, it did not alter basal short-circuit current, Na and Cl absorption, and the short-circuit current response to glucose-stimulated Na transport and to exogenous norepinephrine. Thus, a pool of norepinephrine in intestinal adrenergic neurons released by tyramine affects intestinal ion transport but does not alter basal ion transport. These data suggest close neuropharmacologic similarities between the adrenergic nervous system in the intestine and other organs.
Principles of autonomic nervous system control of intestinal ion transport need to include the newer concepts of the enteric nervous system (ENS). Based on studies of nervous control of the myenteric plexus, it is likely that ENS control of intestinal transport occurs through local mechanisms. In vitro transport studies and a limited number of radioreceptor-binding studies in mucosal cells support the notion that putative neurotransmitters alter transport by acting directly with mucosal receptors. In vivo and in vitro studies cannot alone uncover the indirect transport effects that neurotransmitters may have when they interact with enteric neurons. Studies focused on uptake and release of neurotransmitters suggest that norepinephrine (NE)-induced absorption may be modulated by local NE presynaptic neuronal mechanisms. Endogenous NE release may be enhanced by nicotinic and angiotensin II agents but decreased by muscarinic and alpha-adrenergic agents or prostaglandins. Presynaptic neuronal mechanisms that modulate endogenous acetylcholine (ACh) release and ACh-induced secretion are less well defined. Intestinal transport may be controlled by negative feedback, interneuronal, or transsynaptic presynaptic mechanisms. We propose that transport is controlled by a balance between the principal neurotransmitters NE and ACh. These neurotransmitters may be modulated by neuroactive peptides located either in neurons or in enteroendocrine cells. Efferent neurons may modulate release of neuropeptides from enteroendocrine cells into the luminal or antiluminal sides of mucosal cells. Intestinal transport also may be controlled by luminal factors that cause neuropeptide release from enteroendocrine cells or by specialized luminal receptors acting on sensory afferent neurons and intrinsic neuronal reflexes. Therefore, local modulation of intestinal transport by the ENS represents a finely tuned neuronal system with complex interrelations similar to many found in the central nervous system.
A B S T R A C T The effect of aspirin on normal and cholera toxin-stimulated electrolyte transport has been investigated in vitro, because this drug appears to inhibit cholera toxin-induced intestinal secretion in in vivo animal models. In the Ussing chamber, 10 mM aspirin decreased the control rabbit ileal potential difference and short-circuit current by 50% and increased conductance by 28%. Bidirectional electrolyte flux determinations showed that aspirin significantly increased both Na and Cl absorption and reduced the residual flux (which probably represents HCOs secretion) to zero. This effect of aspirin appears to be identical to that reported by others with catecholamines as determined with similar techniques. However, a-adrenergic blockers did not prevent the electrical effects of aspirin, suggesting that aspirin does not have its effect through release of tissue stores of catecholamines. In the presence of aspirin, cholera toxin increased the potential difference and short-circuit current, and decreased the conductance of rabbit ileum in a fashion qualitatively similar to control tissues. However, aspirin reversed cholera toxin-stimulated Na transport from secretion to absorption, inhibited cholera toxin, induced Cl secretion by 58%, and partially, but not significantly, inhibited HCOs secretion. Thus, the inhibitory effect of aspirin on cholera toxin-induced electrolyte secretion appears to be due to aspirin-stimulated Na and This work was presented in part at the American Gas-
Misoprostol, a synthetic analog of prostaglandin E1, inhibits gastric acid production and is cytoprotective at doses well tolerated by patients in preliminary trials. This multicenter double-blind study was performed in out-patients with endoscopically demonstrated duodenal ulcers, to compare the efficacy in ulcer healing and the safety of two dosages of misoprostol and placebo. Up to six antacid tablets daily were permitted for pain. 308 patients enrolled and were randomized to three treatment groups: placebo, misoprostol 50 micrograms and misoprostol 200 micrograms. After two weeks of treatment, the three groups had similar percentages of patients with complete ulcer healing. However, after four weeks, 76.6% of patients taking misoprostol 200 micrograms q.i.d. had complete healing, compared with 42.6% on misoprostol 50 micrograms q.i.d. and 51% on placebo (P less than 0.001, 200 micrograms versus placebo). Patients taking misoprostol 200 micrograms used less antacid than the others. Diarrhea, mild and self-limiting, was present in 13% of the 200 micrograms group versus 5% on placebo. We conclude that misoprostol 200 micrograms q.i.d. is effective, safe and well tolerated in the treatment of duodenal ulcers.
To determine how sulfation alters the biological properties of dihydroxy bile acids, we compared the effects of 3-sulfodeoxycholate (SDC) and deoxycholate (DC) in the rat and rabbit intestine. While 5 mM DC induced water and electrolyte secretion and inhibited glucose absorption in the rat, SDC enhanced jejunal and ileal water and solute absorption. SDC had no effect in the rabbit ileum. In the rat jejunum DC caused mucosal injury and enhanced mucosal permeability while SDC had no effect. In vitro in the rabbit ileum, 10 mM SDC enhanced net sodium flux and decreased net residual flux, while 0.5 mM DC reduced net sodium flux and induced Cl- secretion. Both bile acids increased short-circuit current and potential difference and decreased tissue conductance. During reversed-phase, high-performance liquid chromatography SDC was more polar than DC. Sulfation reduced the ability of DC to destroy large unilamellar liposomes by a factor of 10. Thus, sulfation abolishes the effects of DC on the intestine by enhancing the polarity of this molecule. The enhancement of intestinal solute and water absorption by SDC requires further study.
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