Histamine leukocytosis. II. Source of histamine leukocytosis.

Leukocytes were labelled by intravenous injection of tritiated thymidine (3H-thymidine) in dogs to discover the source of the increased number of neutrophils in the circulating blood after injection of histamine in beeswax. Dogs with normal hemograms were given 1.0 mCi/kg of 3H-thymidine alone, and in different sequences, with histamine in beeswax. When 3H-thymidine was given during maintained histamine leukocytosis, labelled granulocytes appeared in and disappeared from the blood earlier than in control tests and the number of labelled cells was greater in the histamine-treated animals. Administration of histamine in beeswax 3 days after injection of 3H-thymidine also induced the premature appearance and disappearance of labelled neutrophils in the circulating blood. It was concluded that leukocytosis induced by the chronic action of histamine is due to 1) stimulated proliferation and differentiation of neutrophil precursor cells in the bone marrow and 2) the release of mature leukocytes from the bone marrow.

Histamine leukocytosis. I. Effect of histamine on peripheral leukocyte counts.

The effect of chronic administration of histamine on the number of cells in peripheral blood of dogs, rabbits and guinea pigs was tested by single and consecutive intramuscular injections of histamine in a beeswax-sesame oil mixture. Leukocytosis due to increased numbers of neutrophils occurred in all animals after single injections of histamine in beeswax, although erythrocytes and hematocrit values were unaffected in all species. When injection of histamine was repeated on consecutive days, the extent of leukocytosis subsided in some cases; however, the simultaneous administration of aminoguanidine restored leukocytosis. Single or daily injections of the beeswax-sesame oil mixture without histamine had none of these effects in any animals tested. Although simultaneous injections of histamine and H1 receptor antagonists did not alter histamine effects, the combined administrations of histamine and H2 receptor blocking agents suppressed histamine-induced leukocytosis.

Partial supination versus Gz protection.

Visual and loss of consciousness endpoints during 2 G/s onset G forces sustained for 5 s in 14 and for 10 s in 27 untrained pilots indicated high tolerances when upright, and increases of greater than 3 G when supinated to 60 degrees. Protection against visual symptoms of only 1.1 G when tilted 60 degrees and especially none when experienced subjects were tilted 45 degrees from vertical were unexpected results in 1942. Subsequent findings by others of slight decreases in tolerance at 30 degrees are contrary to hydrostatic basis of G tolerance. Presumably factors other than heart to brain distance (e.g., increased intracranial and intraocular pressures) affect G tolerance when subjects are supinated 30 degrees. We conclude that the apparent increased incidence of G-LOC since the incorporation of 30 degrees seat in F-16 and other fighters in mid-1970's supports the current relevance of these data and suggests that all aircrew should follow the lead of veteran test pilots who sit upright in preparation for and during high G maneuvers (10).

Histamine--whither now?

This review presents, from the author's viewpoint, avenues of histamine research likely to produce new information. One potentially useful approach may be to attempt to relate histamine's function to its occurrence in different body tissues such as the pituitary and hypothalamus, the gastrointestinal mucosa, and the bone marrow and white blood cells. Prospects also seem bright for quantitative studies of histamine metabolites in blood and urine and possible changes in the relative amounts of these metabolites in a variety of diseases.

Pyloric and duodenal motor contributions to duodenogastric reflux.

The motor mechanisms of duodenogastric reflux were identified in 4 healthy, conscious dogs using electromyographic and fluoroscopic recordings of stomach, duodenum and upper jejunum. A barium suspension was injected via a pre-placed cannula in the orad jejunum, during the interdigestive period. Under normal conditions, reflux was uncommon. It was produced by duodenal segmental contractions occurring when the pylorus was open, or forced open by the duodenal contractions. Reflux was more common during retrograde electrical pacing of the duodenal pacesetter potential. It was then also produced by duodenal segmental contractions associated with an open, or opening, pylorus. During intravenous administration of apomorphine, reflux occurring early in the vomiting complex, was again produced by duodenal segmental contractions associated with an open, or opening, pylorus. The major apomorphine reflux event, however, occurred later when an emetic antiperistaltic contraction, originating in the duodenum or orad jejunum swept the contents before it into the stomach.

The effect of celiac and superior mesenteric ganglionectomy on the canine gastric mucosal barrier.

The role of the sympathetic nervous system in gastric function remains poorly understood. This study was designed to evaluate the effect of celiac and superior mesenteric ganglionectomy on gastric mucosal barrier function. Four dogs with Pavlov-type pouches were studied. In the preganglionectomy phase, the pouch gastric mucosa was challenged with progressively higher concentrations of known damaging agents, ethanol and taurocholic acid. Mucosal integrity was studied by measuring ionic fluxes (H+, Na+, K+, Cl-) and transmucosal electrical potential difference (PD). Celiac and superior mesenteric ganglionectomy was then performed and after adequate recovery, the postganglionectomy phase of the study was done challenging the mucosa with the same damaging agents at the same concentrations used in the preganglionectomy study. The major alterations which occurred postganglionectomy were primarily motility-related and little evidence of altered gastric mucosal barrier permeability was detected. Specifically, all four animals developed an intractable diarrhea postganglionectomy which resulted in a 20% weight loss over 4-6 weeks. In contrast, there was no significant difference in H+ loss from and Na+/K+ gain to the pouches when the pre- and postganglionectomy fluxes were compared. Similarly, after challenge with damaging agents, PD changes in the pre- and postganglionectomy were not significantly different.

Gastric bicarbonate appearance with ethanol ingestion. Mechanism and significance.

Increasing quantities of HCO3- appeared in the stomach and in gastric pouches of conscious dogs with gastric infusion of increasing concentrations of ethanol. HCO3- appearance was closely correlated with gains of K+ and of glucose to the contents and with reductions in transmucosal potential differences, each of which is associated with increased mucosal permeability. We concluded that increased diffusion of HCO3- through a more permeable mucosa accounted for the appearance of HCO3- with the lower concentrations of ethanol we used (5-20%) and that bulk movement of the interstitial fluid into the contents added to HCO3- entry with the most damaging, desquamating, concentration (40%). With the gastric contents at 100 mM HCl, an unstirred layer of mucus gel over the mucosa would need to be of greater depth than previous estimates to produce mucosal surface neutrality at the rates of HCO3- appearance we observed. However, faster rates of HCO3- production combined with an unstirred layer could provide significant protection to the gastric mucosa.

The protective effect of sucralfate on the gastric mucosa of rats.

Fasted, anesthetized female rats were used to test the effects of sucralfate (Sc) on the response of the gastric mucosa to ethanol (EtOH) in NaCl or taurocholic acid (TcA) in HCl. The trachea was cannulated and the esophagus and pylorus were ligated. Tubes placed into the stomach permitted instillation of test solutions and determinations of transmucosal potential difference (PD). All periods were 15 min. Each test began with a baseline 150 mM HCl period followed by two treatment periods; in the first, 5600 mg Sc in NaCl or NaCl alone was placed in the stomach; in the second, neutral EtOH or acidified TcA solution was added. In the final two posttreatment test periods, the pH of the gastric contents of the animals treated with Sc was higher, the disappearance of H+ was less, and the index of mucosal damage was reduced. The results demonstrate that Sc has a protective effect on the gastric mucosa of rats. Pretreatment with Sc also reduced the net Cl-loss from the contents and produced an unexplained significant reduction in PD. Sc formed a white coating over the glandular mucosa. This coating may a play a role in its protective action.

Defense mechanisms of the gastric mucosa.

The chemical and physical architecture of the apical membranes of the surface epithelial cells and of the tight junctions which bind the cells together, are such that water and water soluble substances are very slowly admitted. This impermeability is the most important factor in the defense of the gastric mucosa against damaging agents. The barrier provided by this impermeability can be measured by determining the rate of passage of substances from gastric contents to blood. Damage to the barrier will be reflected in an increase in this rate. The common ions, H+, Na+, K+, Cl- and HCO3- and water provide suitable yardsticks for the estimate. The rate of entry of H+ is the most important for it is the common agent producing serious damage to mucosal cells. The state of the barrier is not static. It can be lowered or raised. Barrier breakers are fat soluble, e.g. ethanol, bile, aspirin. They enter the apical membranes of the surface epithelial cells and in doing so permit H+ and other ions to penetrate at accelerated rates. Exposure to a damaging agent can, however, produce an increase in the resistance of the mucosa to subsequent exposures. Increased resistance of the mucosa can be accomplished also by pretreatment with prostaglandins or epidermal growth factor. Both inhibit acid secretion and this is an important element in limiting mucosal damage. Prostaglandins and some barrier breakers also increase the production of HCO3- and of mucus by the mucosa. Both may aid in disposal of damaging agents. Increases in mucosal circulation can also contribute by ridding the submucosa of damaging substances. Protective factors can also increase the impermeability of the membrane but how this is accomplished is unknown.

Chronic bile exposure increases resistance of canine gastric mucosa to bile.

Because four successive weekly exposures of the gastric mucosa of intact dogs to bile did not alter the appearance or the barrier function of the mucosa during subsequent challenges with bile, the effects of chronic continuous exposure to bile were tested. This was accomplished by diversion of the flow of bile from the duodenum into the stomach by cholecystogastrostomy and diversion of the common bile duct. After four weeks, on endoscopic examination the mucosa was dark red but covered in some areas by a creamy coloured, strongly adherent pseudomembrane. Histologically the mucosa was normal. Ion fluxes, when an acid test solution was used, were close to normal. Differences between control dogs and those with chronic bile diversion became very evident, however, when the mucosa was exposed to increasing concentrations of bile. The control dogs displayed increases in net fluxes of H+, Na+, Cl- and K+ as the concentration of the bile was increased but the dogs with chronic bile diversion did not. Also the changes in PD and fluxes in K+ were less in the dogs with bile diversion. In the intact control dogs bile placed in the stomach always produced bleeding and hemorrhagic erosion; in the dogs with chronic bile diversion added bile in the stomach never caused bleeding and the mucosa appeared normal on endoscopic and histological examination. We conclude that the resistance of the gastric mucosa to the barrier breaking action of bile was increased in the dogs with chronic gastric bile diversion.

Motilin-independent ectopic fronts of the interdigestive myoelectric complex in dogs.

We have studied in four conscious dogs the relationship between circulating concentrations of motilin and the activity front (phase III) of the interdigestive myoelectric complex. During fasting, cyclic peaks of motilin secretion were concomitant in every instance with the initiation of activity fronts that began in the stomach or duodenum. When somatostatin was administered at doses of 5, 2.5, or 0.625 microgram x kg-1 x h-1 for 3 h, motilin concentrations were stabilized at lowered levels and no activity fronts occurred in the duodenum. Somatostatin also inhibited the stimulatory effects of exogenous motilin on the entire small intestine. During somatostatin infusion, however, ectopic fronts began in the jejunum and were propagated to the cecum despite low motilin concentration. After a 100-g meat meal, the cyclic increase of motilin was interrupted and no activity fronts were observed in the duodenum, but ectopic fronts started lower in the small intestine. Our study supports the hypothesis that motilin induces activity fronts in the canine duodenum, but it shows that ectopic fronts are not controlled by motilin.

Prostaglandins and gastric ulcer.

Interest in the prostaglandins as possible gastric-mucosal cytoprotective agents was first aroused by the oberved antagonism between these compounds and ulcerogenic anti-inflammatory drugs. It has now been shown that several PGs can depress gastric acid secretion and reduce HCl-induced lesions in experimental animals. The clinical implications appear to be well worth exploration.

Effects of celiac and superior mesenteric ganglionectomy on interdigestive myoelectric complex in dogs.

The interdigestive myoelectrical activity of the stomach and small bowel has been studied before and after celiac and superior mesenteric ganglionectomy in four healthy, well-trained conscious dogs. The interdigestive myoelectric complex was present before and after the gangliomectomy in all dogs, but variability in the duration of its cycles was increased by ganglionectomy. The percentage of time that action potential activity was present during the interdigestive period in the stomach and orad half of the small bowel was also increased in all animals after the ganglionectomy. The duration of phase III, the activity front, was unaltered by the operation, but the timing of the other phases became more variable after ganglionectomy. The time required for migration of the complex from duodenum to terminal ileum was more variable after ganglionectomy in the three animals in which it could be measured, and in two of them the migration time was shorter. An abnormal electrical pattern occurred in all animals after ganglionectomy. Its duration ranged from 0.5--5 min. Electrically, it appeared to represent an elongated, nonmigrating activity front.

Increased resistance of the gastric mucosal barrier to barrier breakers in the rat.

The effects of two exposures of the gastric mucosa to either 10 mM taurocholic acid (TcA) or 20% ethanol, both in 150 mM HCl, on transmucosal potential difference (PD) and net fluxes of H+, Na+, and K+ ions have been tested in the rat. The interval between exposures was 30 min. The results demonstrated that the first exposure of the gastric mucosa, either to TcA or to ethanol, reduced the net fluxes of H+, Na+, K+ and the change in transmucosal PD induced by the second exposure, indicating an increased resistance of the mucosa to the barrier breaking effects of TcA or ethanol.

Physiological and morphological characteristics of progressive disruption of the canine gastric mucosal barrier.

The investigation had two major goals: to define the progression of physiological changes associated with disruption of the gastric mucosal barrier to sodium and hydrogen and to identify the morphological correlates of the physiological alterations. Fluxes of ions and water were determined before and after treatment of oxyntic mucosa with graded concentrations of butyric acid using dogs with gastric pouches. Three phases of barrier disruption were characterized: I, acceleration of normal Na+/H+ exchange; II, neutralization of H+; III, exudation of interstitial fluid. Parallel studies assessed morphological damage associated with these phases. In Phase I, cellular bulging into the lumen and dilation of intercellular spaces were evident. Some cellular erosion and extreme intercellular dilation were prominent in Phase II. Phase III was represented by necrotic changes and desquamation. It is concluded that disruption of transport mechanisms occurs sequentially and is closely correlated with morphological signs of progressive damage.