Search PubMedSearch

Biomedical subjects

E H Livingston

Publications and source records attributed to E H Livingston.

At least 19 recordsLinked to original sources

Bicarbonate diffusion through mucus.

The mucus layer overlying duodenal epithelium maintains a pH gradient against high luminal acid concentrations. Despite these adverse conditions, epithelial surface pH remains close to neutrality. The exact nature of the gradient-forming barrier remains unknown. The barrier consists of mucus into which HCO3- is secreted. Quantification of the ability of HCO3- to establish and maintain the gradient depends on accurate measurement of this ion's diffusion coefficient through mucus. We describe new experimental and mathematical methods for diffusion measurement and report diffusion coefficients for HCO3- diffusion through saline, 5% mucin solutions, and rat duodenal mucus. The diffusion coefficients were 20.2 +/- 0.10, 3.02 +/- 0.31, and 1.81 +/- 0.12 x 10(-6) cm2/s, respectively. Modeling of the mucobicarbonate layer with this latter value suggests that for conditions of high luminal acid strength the neutralization of acid by HCO3- occurs just above the epithelial surface. Under these conditions the model predicts that fluid convection toward the lumen could be important in maintaining the pH gradient. In support of this hypothesis we were able to demonstrate a net luminal fluid flux of 5 microliters.min-1.cm-2 after perfusion of 0.15 N HCl in the rat duodenum.

Animals

Central vagal activation by TRH induces gastric hyperemia: role of CGRP in capsaicin-sensitive afferents in rats.

The role of calcitonin gene-related peptide (CGRP) in the vagal cholinergic-mediated increase in gastric mucosal blood flow (GMBF) induced by the stable thyrotropin-releasing hormone (TRH) analogue RX-77368 injected intracisternally (ic, 30 ng) was investigated in urethan-anesthetized rats using the hydrogen gas clearance technique. alpha-CGRP (14 micrograms.kg-1.h-1) or bethanechol (150 micrograms.kg-1.h-1) infused close intra-arterially to the stomach or RX-77368 injected intracisternally increased GMBF by 76, 102, and 131%, respectively, 30 min after administration. The CGRP antagonist, human CGRP-(8-37) [hCGRP-(8-37)], injected intravenously (15 micrograms/kg bolus and 3 micrograms.kg-1.h-1) inhibited by 100, 97, and 73% the gastric hyperemic response to alpha-CGRP, TRH analogue, and bethanechol, respectively, whereas the substance P antagonist CP-96,345 (3 mg/kg iv) had no effect. In capsaicin-pretreated rats, hCGRP-(8-37) no longer blocked the increase in GMBF induced by intracisternal RX-77368. These results suggest that the gastric hyperemic response to central vagal activation induced by intracisternal TRH analogue at 30 ng is mediated by local effector function of capsaicin-sensitive afferent fibers releasing CGRP.

Animals

Gastric hyperemia accompanying acid secretion is not mediated by sensory nerves.

It is not known how the signal to increase gastric mucosal blood flow is passed from the gastric parietal cell layer to the resistance vessels in the submucosa. We tested the hypothesis that mucosal hyperemia accompanying stimulated gastric acid secretion is mediated by capsaicin-sensitive sensory nerves. Rats were denervated by systemic capsaicin treatment (125 mg/kg, subcutaneously, 10-14 days prior to experimentation). Acid secretion was stimulated by intravenous pentagastrin (4, 12, and 36 micrograms/kg/hr) and was measured by a continuous perfusion method. Mucosal blood flow was measured by the hydrogen gas clearance method. Sensory denervation did not affect basal blood pressure, gastric acid secretion, or mucosal blood flow. In control rats, increases in gastric mucosal blood flow and acid secretion were dose-related. With denervation, not only was there no inhibition of the blood flow response to acid secretion, but the dose-dependent rise in acid secretion was accompanied by increased mucosal blood flow that was out of proportion to the acid secretory response. The capsaicin-sensitive afferent fibers do not transmit the signal to increase gastric mucosal blood flow in response to stimulated acid secretion. It appears that sensory nerves modulate but do not mediate the mucosal hyperemic response to acid secretion.

Analysis of Variance

Heterogeneous distribution of gastric mucosal blood flow with restraint stress in the rat.

Cold water immersion restraint (CWIR) is associated with gastric hypercontractility and gastric corpus erosions in the rat. Because the gastric blood flow response to CWIR has not been well defined, we performed the following study. Rats were implanted with force transducers, subjected to CWIR for 2 hr, and then blood flow was determined by the iodo[14C]antipyrine autoradiographic (IAP) technique. When compared to control animals, the CWIR-treated animals displayed foci of gastric corpus hyperemia with a marked and significant increase in blood flow in all layers of the gastric corpus. There was approximately a 100% increase in the mucosa and a 50% increase in the muscularis externa. The hyperemia was not uniform, but rather alternated every 2.1 +/- 0.2 mm with regions of low blood flow. Blood flow in the antrum and duodenum was unaffected by CWIR. We conclude that CWIR is associated with alternating regions of high and low blood flow only in the gastric corpus. Reduction of corpus mucosal blood flow might be due to the powerful gastric contractions associated with CWIR.

Animals

The stomach as a system and the pathogenesis of experimental ulcer.

The stomach is prone to ulceration because of the hostile environment that exists within its lumen. The most important etiologic factor remains a topic of debate. We have considered the stomach as a system to lend insight into which pathophysiologic mechanisms might be most important. Systems are described by their content, hierarchy, entropy and interactions. The states of health, disease and death (i.e. ulceration) are represented by progressively increasing levels of entropy. It is argued that many of the purported causes of ulcer disease, such as acid back-diffusion or alcohol related necrosis, represent alterations in the system that affect small groups of cells that are low in the hierarchy and cause the tissue to enter the diseased state. We hypothesize that because blood flow is high within the hierarchy it represents the major homeostatic mechanism. If blood flow responds appropriately the system may return to the healthy state. If it does not the death of the system results in ulceration. Experimental evidence to support these contentions is presented.

Animals

Treatment of pancreatic carcinoma.

Pancreatic carcinoma remains a significant cause of cancer death worldwide. In spite of more effective diagnostic techniques, most patients still have advanced and incurable disease when the diagnosis is made. Treatments differ depending on the extent of the disease at presentation, but accurate staging preoperatively is difficult. The Whipple procedure is now done with an operative mortality of 5% or less. More effective means of nonoperative palliation are being developed. Adjuvant therapy is still largely ineffective.

Cause of Death

Spectrum of injury produced in the duodenum by perfusion with luminal acid in the rat.

The dose and time dependence of duodenal mucosal injury by luminal acid perfusion was studied. Saline, 0.01, 0.05, 0.15, and 0.3N HCl, were perfused through the proximal duodena of rats for 5, 15, or 30 minutes and then harvested for histological examination. In a second set of studies, after a 30-minute perfusion, duodena were harvested either immediately or 2, 4, 8, or 24 hours after the perfusion to study the recovery from injury. Acid disappearance (acid delivered minus acid recovered) was measured in all groups. Duodena were examined grossly, then fixed, stained, and scored histologically. Whereas no gross mucosal injury was noted, there was graded histological injury proportional to acid concentration. Injury occurred early in the perfusion and changed little with increased perfusion durations. The initial injury lead to an acid disappearance rate that was proportional to acid concentration and, therefore, the degree of injury. After the initial injury occurred, the rate of acid neutralization was unchanged by increased duration of acid perfusion. This acid neutralization protected against further injury despite the continued presence of acid. Recovery from injury was complete with physiological (0.01 and 0.05N HCl) but not pharmacological (0.15 and 0.3N HCl) concentrations of acid. It is concluded that acid-induced duodenal injury occurs within 5 minutes of exposure, is proportional to the acid concentration, and results in acid neutralization that protects against extension of the injury with continued acid exposure.

Animals

Effect of elevated intracranial pressure on gastric acid secretion, mucosal blood flow and mucosal injury.

Head injury is frequently accompanied by an increase in intracranial pressure and gastric lesion formation. We used a model of controlled intracranial pressure to investigate the effect of elevated intracranial pressure on gastric acid secretion and mucosal blood flow and on the susceptibility of the gastric mucosa to lesion formation. With increasing intracranial pressure, there was a corresponding increase in gastric acid output but no significant change in gastric mucosal blood flow. This imbalance between acid secretion and blood flow could be a factor in the pathogenesis of the gastric lesions seen with head injury. Susceptibility to gastric mucosal injury then was studied in a model that is independent of the acid secretory state--exogenous intragastric HCl plus ethanol. Elevated intracranial pressure did render the gastric mucosa more susceptible to injury in this model, but there was no impairment of the increased gastric mucosal blood flow response to the increased acid back-diffusion. In this situation, factors other than altered overall blood flow appear to be responsible for the increased lesion formation.

Animals

Surgical treatment of pancreatic cancer. The United States experience.

About 28,000 new cases of pancreatic cancer are diagnosed yearly in the United States. The diagnosis is now made up to two months more quickly than just a few years ago, but this has had no impact on survival. In most institutions, 20-25% of patients have resectable lesions. The standard operation is still the Whipple pancreaticoduodenectomy, but many surgeons now use the pylorus preserving modification of that procedure. The operative mortality rate has fallen to less than 5%. The five-year survival rate after a resection for attempted cure is about 9%. Palliation requires cholecysto(docho)jejunostomy and gastrojejunostomy, which is often done prophylactically. The operative mortality rate in patients undergoing palliation is less than 10% (recent UCLA experience), and the average survival is seven months.

Adenocarcinoma

Sensory neurons signal for an increase in rat gastric mucosal blood flow in the face of pending acid injury.

Disruption of the gastric mucosal barrier is quickly followed by an increase in gastric mucosal blood flow, which is thought to be a defensive reaction to prevent further injury. This study examined how this increase in blood flow is brought about. When the stomach of urethane-anesthetized rats was perfused with 0.15N HCl, disruption of the gastric mucosal barrier with 15% ethanol increased the disappearance of acid from the gastric lumen and enhanced gastric mucosal blood flow. This increase in blood flow was blocked by local arterial infusion of tetrodotoxin (60 ng/min) to the stomach and by chemical ablation of capsaicin-sensitive sensory neurons. Inhibition of the blood flow increase was associated with exaggeration of gross and histological injury to the mucosa. IV injection of atropine (0.2 mg/kg) or pyrilamine (2 mg/kg) did not affect blood flow increase in response to barrier disruption, whereas morphine injection (2 mg/kg) inhibited it. The current findings show that the increase in gastric mucosal blood flow that follows disruption of the gastric mucosal barrier in the presence of acid is mediated by sensory neurons that seem to monitor acid back-diffusion and in turn signal for a protective increase in blood flow.

Animals

Elevated intracranial pressure stimulates gastric contractility in the rat.

The gastric contractile response to elevated intracranial pressure (ICP) was studied in conscious rats. Elevation of intracranial pressure to 20 mm Hg was associated with a marked increase in the amplitude of gastric contractions (70-90% over baseline) without any change in contractile frequency (5.2 +/- .5 contractions per min). The increase in contractility continued for 45 min following release of the pressure. Vagotomy completely blocked the increase in gastric contractility seen with elevation in ICP. We conclude that acute elevation of intracranial pressure in rats results in increased force of gastric contractions. The forceful contractions persist despite release of the pressure and the increased contractile force is vagally mediated.

Animals

Resuscitation. Revival should be the first priority.

During resuscitation, it is important to distinguish between those maneuvers directed at patient revival and those directed at examination and measurement. Revival should always be the top priority. The steps for revival are easily remembered as ABCDEF: Airway, Breathing, Circulation, Decompression, Elimination, and Fluids. Once these steps have been completed, vital functions can be assessed and measurements to aid in diagnosis can be taken.

Blood Circulation

Role of peptidergic sensory neurons in gastric mucosal blood flow and protection.

The present findings have revealed a new aspect of how mechanisms of gastric mucosal resistance to injury are called into effect and are coordinated by the nervous system. Capsaicin-sensitive sensory neurons in the stomach play a physiological role in monitoring acid influx into the superficial mucosa. Once activated, they strengthen gastric mucosal defense against deep injury, with a key process in this respect being an increase in blood flow through the gastric mucosa. This concept opens up completely new perspectives in the physiology and pathophysiology of the gastric mucosa if we consider that the long-term integrity of the gastric mucosa may be under the subtle control of acid-sensitive sensory neurons and that, vice versa, improper functioning of these neutral control mechanisms may predispose to gastric ulcer disease. The present observations also indicate that some of the peptides contained in gastric sensory nerve endings might fulfill a transmitter or mediator role in controlling gastric mucosal blood flow and integrity. Whereas substance P and neurokinin A are unlikely to play a role in the regulation of gastric mucosal blood flow, there is severalfold evidence that CGRP is very important in this respect. This peptide, which in the rat gastric mucosa originates exclusively from spinal sensory neurons, is released upon stimulation of sensory nerve endings and is extremely potent in facilitating gastric mucosal blood flow and in protecting the mucosa from injurious factors. Selective ablation of spinal sensory neurons containing CGRP weakens the resistance of the gastric mucosa against acid injury, which is most likely due to inhibition of protective vasodilator reflexes. We now aim at providing direct pharmacological evidence that antagonism of endogenously released CGRP results in similar pathophysiological consequences as ablation of capsaicin-sensitive sensory neurons.

Animals

Sensory neurons mediate protective vasodilatation in rat gastric mucosa.

Sensory nerve stimulation by intragastric capsaicin (160 microM) prevents ethanol injury to the gastric mucosa and facilitates gastric mucosal blood flow (GMBF). The present study examined whether the capsaicin-induced increase in GMBF accounts for mucosal protection. Gastric perfusion of capsaicin (160 microM) in urethan-anesthetized rats did not change blood pressure but significantly enhanced GMBF as measured by hydrogen gas clearance. The same increase in GMBF was seen when capsaicin was administered together with an injurious concentration of ethanol (25%). GMBF was facilitated by capsaicin in a dose-related manner (10-640 microM), and the dose-dependent vasodilatation was significantly correlated with a dose-dependent reduction of gross damage to the mucosa. Histology showed that capsaicin prevented deep but not superficial mucosal damage. The vasodilator and protective effects of capsaicin resulted from stimulation of sensory neurons and propagation of nerve activity, since they were blocked after ablation of capsaicin-sensitive neurons or local intra-arterial infusion of tetrodotoxin. This and the finding of a limited access of intragastric capsaicin to the gastric wall indicates that the vasodilator and protective effects of capsaicin are mediated by a neural reflex. It is concluded that facilitation of GMBF is the major mechanism of sensory nerve-mediated prevention of gastric mucosal injury.

Animals

Strong gastric contractions cause mucosal ischemia.

Contractions of a segment of bowel result in alterations of its blood flow. However, the precise temporal and spacial relationships between contractions and mucosal blood flow are unknown. Rats were fitted with strain gauge force transducers and implanted with silver wire electrodes into the muscularis externa of the stomach. In vivo microscopic observation of motility and of the gastric mucosal blood flow was performed during electrical field-stimulated contractions. Contractions originated in the midcorpus, were 0.237 +/- 0.018 cm wide, traveled along the corpus at 0.133 +/- 0.024 cm/s, and had a duration of 5.9 +/- 0.1 s. Antral contractions were 0.174 +/- 0.032 cm wide, traveled at 0.070 +/- 0.009 cm/s, and had a duration of 5.6 +/- 0.7 s. During the contraction, capillary flow velocity in the corpus decreased from a basal value of 410 +/- 105 to 206 +/- 104 microns/s at the peak of a contraction. Five seconds after the contraction was released hyperemia was observed with the flow velocity increasing to 570 +/- 102 microns/s. In the antrum, flow stopped completely during the contraction irrespective of the initial flow velocity and no hyperemia occurred with release of the contraction; rather, flow velocity slowly returned to baseline values. In both regions the flow reductions were in phase with the contractions as measured by the force transducers. These studies provide direct evidence that strong gastric contractions can effectively reduce or stop gastric mucosal blood flow.

Animals

Bombesin microinjected into the dorsal vagal complex inhibits TRH-stimulated gastric contractility in rats.

The effects of centrally injected bombesin on central and peripheral stimulated gastric contractility were investigated in fasted urethane-anesthetized rats. Miniature strain gauge force transducers were acutely implanted on the corpus of the stomach and gastric contractility was analyzed by computer. Intracisternal injection of the stable thyrotropin-releasing hormone (TRH)-analog RX 77368 (77 pmol) induced a stimulation of gastric contractility for 40 min. Intracisternal injection of bombesin (62-620 pmol) followed 30 min later by that of RX 77368 resulted in a dose-related inhibition of the TRH-analog-induced gastric contractility. Intracisternal injection of bombesin (620 pmol) did not modify gastric contractility stimulated by intravenous carbachol. Stimulation of gastric contractility induced by TRH-analog microinjected into the dorsal vagal complex (DVC) was dose-related suppressed by concomitant injections of bombesin (6.2-620 pmol). Neither bombesin alone (6.2 pmol) nor vehicle modified basal gastric contractility. These results demonstrate that bombesin acts within the brain to inhibit vagally stimulated gastric contractility and that the DVC is a sensitive site for bombesin inhibitory action. These findings suggest a possible interaction between TRH and bombesin in the central vagal regulation of gastric contractility.

Animals

Role of oxyradicals in cold water immersion restraint-induced gastric mucosal injury in the rat.

Cold water immersion restraint of the rat results in focal gastric mucosal erosions. The lesions are associated with powerful, prolonged-duration gastric contractions. Phasic gastric contractions may attenuate gastric mucosal blood flow, resulting in ischemia followed by reperfusion. Therefore, the conditions of cold-water-immersion restraint might lead to mucosal injury by an oxyradical-mediated mechanism. To test this hypothesis, we studied the effect of oxyradical inhibition on cold water immersion restraint-induced lesions. In separate groups of rats subjected to cold water immersion restraint (6-10 animals per group), oxyradical inhibition was achieved by chronic feeding of a sodium tungstate diet, oral administration of allopurinol, or intraperitoneal administration of dimethylsulfoxide. None of these regimens significantly attenuated the number of lesions per stomach, the total lesion area, or the percent of corpus mucosa containing lesions. We conclude that oxyradicals do not play a role in the pathogenesis of cold water immersion restraint-induced lesions.

Allopurinol