Effect of histamine and its methyl derivatives on cyclic AMP metabolism in gastric mucosa and its blockade by an H2 receptor antagonist.

In a cell-free system prepared from guinea pig gastric mucosa, histamine and Nalpha-methyl-histamine produced dose-dependent stimulation of cyclic AMP formation and 1,4-methylhistamine had a minimal stimulatory effect. N-methyl-N'-(2-[5-methylimidazole-4-yl-methylthio]-ethyl) -thiourea (metiamide), a new H2 receptor inhibitor, selectively blocked the stimulation of adenylate cyclase by histamine and its active methyl derivative but had no substantial effect on the basal adenylate cyclase activity or adenylate cyclase stimulated by sodium fluoride. Metiamide inhibited the histamine stimulation of adenylate cyclase at 1/100 the concentration of the histamine. Histamine, its methyl derivatives, and metiamide did not influence the activity of cyclic AMP phosphodiesterase from gastric mucosa. Therefore, histamine stimulates gastric mucosal adenylate cyclase via interaction with the H2 receptor without influencing cyclic AMP breakdown, and N-methylation of histamine on the side chain preserves or even increases its stimulating ability. On the other hand, N-methylation in the ring nearly abolishes the ability of histamine to interact with the H2 receptor.

Interaction of prostaglandins and histamine with enzymes of cyclic AMP metabolism from guinea pig gastric mucosa.

Prostaglandins (PGE1, PGE2, PGA1) and histamine have opposing effects on gastric HCl secretion, but we found that both stimulate adenylate cyclase activity in cell-free membrane preparations of guinea pig gastric fundic mucosa. The stimulatory effect of prostaglandins was found in this study to be specific and dose-dependent over a concentration range from 10(-7) to 10(-4) M. In similar preparations from antral regions of guinea pig gastric mucosa, the adenylate cyclase was stimulated only by PGE1, PGE2, and PGA1 and not by histamine. Maximum stimulating doses of PGE1, PGE2, or PGA1, and of histamine had an additive effect on the adenylate cyclase activity from fundic gastric mucosa. Metiamide, a histamine H2-receptor antagonist, inhibited the stimulation of fundic mucosa adenylate cyclase by histamine but did not interfere with the stimulation by prostaglandins. Cyclic AMP phosphodiesterase activity of guinea pig gastric mucosa was unaffected by PGE1 and PGE2 or by histamine, and was slightly depressed by PGA1. These results indicate that histamine and prostaglandins stimulate two different adenylate cyclase systems both present in guinea pig gastric mucosa tissue. Therefore, the known inhibitory effect of prostaglandins on gastric acid secretion is not related to the interference with the stimulation of the histamine H2-receptor-sensitive adenylate cyclase complex by histamine nor do prostaglandins accelerate cyclic AMP breakdown by cyclic AMP phosphodiesterase to reduce cyclic AMP levels.

Nitrogen metabolism in bears: urea metabolism in summer starvation and in winter sleep and role of urinary bladder in water and nitrogen conservation.

Three bears were studied under conditions of (1) no food but access to water for 2 weeks and (2) no food or water for 3 weeks. During starvation in summer, the bears could not inhibit the net production of urea but used lean body mass; when denied access to water as well, the bears became dehydrated and azotemic. Urea was continuously formed and degraded in the winter. Arginase activity in liver increased in winter sleep; hepatic steatosis and inflammatory reactions were also noted. The urinary bladder readsorbed labeled urea and D20 in winter; the rate of absorption of urea was equal to the rate of excretion of it into the bladder. The ability to preserve lean body mass during winter sleep apparently is a special mechanism associated with the induction of winter sleep. Bears cannot duplicate this feat during summertime starvation. In winter sleep, urea is formed and degraded but the nitrogen produced is conserved in some manner that maintains the total nitrogen pool constant. The urinary bladder plays a central role in maintaining the state of winter sleep by absorbing water and solute at a rate equal to their entry into the urinary bladder.

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).

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.

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.

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.

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.

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.

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.

Absence of Na+--H+ barrier function in mucosa of canine small bowel.

The study was designed to determine whether the special Na+--H+ barrier function of the gastric mucosa is present in the mucosa of the small bowel and whether a gastric mucosal barrier breaker (hexanoic acid) would accelerate the fluxes of sodium in duodenum-jejunum and ileum as in the stomach. The observations were made in healthy conscious dogs with Thiry-Vella fistulae of the small bowel or Heidenhain pouches of the gastric corpus. These barrier characteristics of the stomach were completely absent in the small intestine where bidirectional Na fluxes were 5--10 times greater than in the stomach and were not accelerated by hexanoic acid as they were in the stomach. A comparison was made between the rates of absorption of hexanoic acid, sodium hexanoate, and HCl from the pouches and fistulae. The lipid-soluble fatty acid was transported at all sites more rapidly than its water-soluble sodium salt. In the stomach and ileum the H+ of HCl and sodium hexanoate were absorbed at similar slow rates. The duodenal-jejunal mucosa, however, transported H+ at rates nearly identical to those of hexanoic acid. In our tests HCl was not neutralized in duodenal contents while large quantities were neutralized in the contents of ileum.

Duodenal-gastric reflux and slowed gastric emptying by electrical pacing of the canine duodenal pacesetter potential.

In 6 (10 to 12 kg) mongrel female dogs, silver electrodes for recording electrical activity and for pacing of pacesetter potentials (PP) were implanted on the stomach and duodenum and a catheter for intraluminal instillations was inserted into the duodenum. Beginning 2 weeks after operation, electrical recordings were made intermittently from the fasted, conscious dogs with no pacing and during pacing of the PP in the proximal and in the distal duodenum. A suspension of BaSO4 injected into the unpaced duodenum and observed cinefluoroscopically was swept quickly from the duodenum into the jejunum; little or none passed orad into the proximal duodenum, and BaSO4 rarely entered the stomach. Only 1 to 3% of a duodenal infusate of 154 mM NaCl with [14C] polyethylene glycol (2 ml per min) appeared in the stomach after 15 min. The results during proximal duodenal pacing were the same as with no pacing. However, distal duodenal pacing, which reversed the direction of propagation of the duodenal PP's, caused duodenal-gastric reflux of BaSO4 in every dog and forced about 30% of the duodenal infusate into the stomach during fasting and during gastric emptying of 400 ml of 154 mM NaCl; at the same time, the rate of emptying of the gastric instillate was slowed about 25%.