Biomedical subjects
D Fromm
Publications and source records attributed to D Fromm.
Effects of p-chloromercuribenzene sulfonic acid on Na and Cl transport by isolated gastric mucosa.
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Mechanism of the inhibitory action of electric current on H+ secretion by frog gastric mucosa.
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Effects of histamine receptor antagonists on ion transport by isolated ileum of the rabbit.
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Gastric mucosal "barrier".
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Anastomotic dehiscence after low anterior resection of the rectum.
Thirty-two patients who had anastomoses to the extraperitoneal rectum underwent radiographic contrast studies about two weeks after operation in order to determine the incidence of anastomotic dehiscence. No extravasation occurred in the sixteen anastomoses in which the middle hemorrhoidal arteries were intact, but partial disruption occurred in four of seventeen (24%) anastomoses in which the middle hemorrhoidal arteries were sacrificed. Since not all patients with anastomotic dehiscence after low anterior resection are symptomatic, the incidence of anastomotic breakdown will be under-estimated unless x-ray studies are performed. More data are required for a better understanding of the technical features of operation which will reduce the incidence of leakage from anastomoses to the extraperitoneal rectum.
Gastric mucosal defense mechanisms: effects of salicylate and histamine.
Some of the recent concepts about the gastric mucosal defense mechanisms against damage by luminal acid and the effects of histamine and salicylate on these mechanisms are reviewed. The mucosal barrier to acid appears to consist of at least two physiologic components: a permeability mechanism and a metabolic mechanism related to cellular bicarbonate production as a result of acid secretion. In the absence of salicylate, histamine appears to exert some protection by affecting both mechanisms, but in the presence of salicylate, histamine's protective effect is limited to altering mucosal permeability. The actions of salicylate on the gastric mucosa are complex, related in part to the concentration of salicylate and the pH of the luminal fluid. The damaging effects of salicylate appear to be related more to the concentration of acid in the lumen than to the lipid solubility of the drug. Salicylate increases permeability regardless of pH; the increase is initially selective for cations and subsequently becomes nonselective, involving both cations and anions. Although both low and high concentrations of salicylate increase mucosal permeability to hydrogen ions, only high concentrations of salicylate affect cellular bicarbonate production.
Relationship between ulceration and intramural pH of gastric mucosa during hemorrhagic shock.
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Effect of the acid secretory state on intramural pH of rabbit gastric mucosa.
Intramural pH of the gastric mucosa was measured using a microelectrode technique in rabbit gastric pouches under different secretory conditions and luminal acidity. Exposure of spontaneously secreting or metiamide-treated fundic pouches to a relatively high concentration of luminal acid. HCl 120 mM, for 60 min, led to a marked net loss of luminal H+ which was associated with a significant decrease in the intramural pH (7.28 +/- 0.09 to 6.88 +/- 0.10 and 7.23 +/- 0.07 to 6.99 +/- 0.09, respectively). A linear relationship was observed between the rates of net disappearance of luminal acid and the intramural pH. All 10 spontaneously secreting and five metiamide-treated pouches had superficial mucosal erosions. In contrast, when fundic pouches were exposed to luminal acid in histamine-treated animals, the net loss of luminal H+ was negligible and the intramural pH remained at its base-line level (7.25 +/- 0.07). Histamine stimulation without acid in the lumen caused a small but insignificant increase in the intramural pH (7.27 +/- 0.03 to 7.39 +/- 0.05). Only three of the eight histamine-treated fundic pouches had lesions. In the antral pouches the intramural pH changes in response to exposure to luminal acid were smaller and histamine treatment did not influence the intramural pH. None of the antral pouches had lesions. The results suggest that acidification of the tissue by the diffusion of luminal acid may be an important factor in the pathogenesis of acute gastric ulceration. The acid secretory state of the gastric mucosa can significantly influence the acid-base balance in the mucosa and thus modify its response to acid diffusing from the lumen. Histamine stimulation protected the gastric mucosa by improving its buffering capacity and/or otherwise decreasing the diffusion of H+ from the lumen into the mucosa.
Salicylate and gastric mucosal damage.
The mechanism(s) of salicylate-induced damage of the gastric mucosa is complex. The presence of acid in the lumen is essential for the occurrence of such injury. Although the absorption of salicylate is greater in the presence of acid, salicylate can selectively increase cation permeability both in the absence and presence of acid. Recent studies suggest that this permits increased diffusion of luminal acid into the tissue, which leads to major permeability changes of the mucosa. Salicylate also affects metabolic processes of the gastric mucosa, which appear to be independent of the increased diffusion of acid into the tissue also caused by salicylate. The release of histamine, which has been shown to occur in vivo as a result of mucosal damage, does not appear to intensify existing mucosal injury in an isolated system.
Effects of compounds chemically related to salicylate on isolated antral mucosa of rabbits.
This study examines some of the gastric mucosal effects of compounds structurally related to salicylate (which consists of a hydroxyl and a carboxyl group attached to a benzene ring) in order to determine the importance of the various ligands of the salicylate molecule. The presence of carboxyl group increases mucosal permeability to acid. This increase in cation flow initially is associated with a decrease in anion permeability. These ion selective effects subsequently give way to a nonspecific increase in permeability. The presence of a carboxyl group also is associated with a more than 80% decrease in short circuit current. A similar decrease in short circuit current occurs when the mucosa is exposed to a pyridine molecule with an attached carboxyl group (pyridine-3-carboxylic acid), but in a relatively low concentration, this agent also decreases the back diffusion of acid. The above noted changes in mucosal permeability and short circuit current do not appear to be attributable to the benzene or phenolic ligands of the salicylate molecule. It is concluded that the presence of a sufficient concentration of an exposed carboxyl group on the mucosal side of the tissue causes an increase in the permeability of the mucosa to acid. The presence of a carboxyl group also appears to alter active ion transport, but this effect cannot be attributed to enhanced diffusion of acid into the tissue. The data implicate the carboxyl group of salicylate as being key to its damaging effects on the stomach.
Effects of lysolecithin on isolated gastric mucosa.
The effects of lysolecithin, a normal constituent of duodenal juice, on gastric mucosa were measured under isolated conditions. In a relatively low concentration (0.5 mg/ml), lysolecithin, added to the luminal side, caused liberation of organic acids without altering the spontaneous rate of mineral (i.e., HCl) acid secretion by fundic mucosa. The low concentration of lysolecithin also did not appear to affect other active ion transport processes or permeability of either fundic or antral mucosa. However, at a higher concentration (1 mg/ml) lysolecithin inhibited spontaneous mineral acid secretion by fundus, altered active transport of other ions, and increased mucosal permeability of both fundic and antral mucosa. The results suggest that intraluminal lysolecithin in concentrations found in vivo may contribute to gastric mucosal damage.
Secretory state of gastric mucosa and resistance to injury by exogenous acid.
The capacity of the stomach to resist the effects of highly acid solutions was assessed by comparing the effects of such solutions on spontaneously secreting, stimulated, and inhibited gastric mucosae of rabbits in vivo and frogs in vitro. Exposure of unstimulated resting mucosa to HC1, 120 mM, for 60 minutes produced superficial erosions in all rabbits, whereas such lesions were observed in only one of ten animals stimulated with histamine. Metiamide obviated the protective effect of histamine against ulcerations even though it did not reduce H+ secretion to zero. Exposure of inhibited isolated frog fundic mucosa to HC1 resulted in significant deterioration of electrical parameters, suggesting impairment of active transport processes and increased tissue permeability. These data are consistent with the hypothesis that actively secreting gastric mucosae from two species resist injury to exogenous acid more effectively than do resting or inhibited tissues, perhaps in part as a result of a greater alkaline tide.
Role of sulfhydryl groups in acid transport by stomach.
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Effects of salicylate and bile salt on ion transport by isolated gastric mucosa of the rabbit.
The effects of luminal addition of salicylate and taurocholate on ion transport by fundic mucosa were examined in vitro using isotopic and pH stat techniques. Salicylate, 3 mM, did not alter, but 20 mM caused a 40% decrease in, the acid secretory rate. Taurocholate, 20 mM, caused a transient, apparent cessation of acid secretion followed by stimulation. Salicylate, 3 or 20 mM, increased Na+ but not Cl- permeability at luminal pH 7. At luminal pH 4, however, salicylate increased Cl- in addition to Na+ and H+ permeability. Taurocholate, 10 or 20 mM, increased both cation and anion permeability at pH 7 and 4. Addition of salicylate or taurocholate results in stimulation of net Na+ transport. While salicylate and taurocholate increase cation permeability at pH 7, they have differing effects on acid secretion and anion permeability. The data suggest that salicylate and taurocholate alter cation permeability by different mechanisms and are consistent with the concept that enhanced diffusion of H+ into the tissue causes a nonspecific alteration in the permeability pathway.
Histamine effects on H+ permeability by isolated gastric mucosa.
This study examines the effects of histamine on mucosal permeability to acid by isolated stomach of rabbits. Histamine (9 X 10(-5) M) decreased antral luminal acid loss which could not be accounted for by active H+ secretion or appearance of organic acid. Histamine also increased antral electrical resistance and decreased the unidirectional luminal to serosal flux (Jls) of (14)c-erythritol. Histamine, theophylline, and N(6),O(2)-dibutyryl adenosine 3',5'-monophosphate did not significantly alter secretion by fundus in the presence of salicylate (5 X 10(-3)M). However, after removal of salicylate, these agents stimulated acid secretion. Histamine decreased luminal acid loss by both antrum and fundus treated with salicylate, increased the electrical resistance of these tissues, and decreased Jls erythritol of fundic mucosa. Burimamide (1 X 10(-3) M) inhibited the permeability effects of histamine on antrum and fundus. The data indicate that histamine decreases spontaneous antral mucosal permeability as well as salicylate-induced increase in mucosal permeability of both antrum and fundus. The effects of burimamide suggest that antrum contains H2 receptor sites urelated to acid secretion and that fundus contains H2 receptor sites which also govern permeability but are independent of those related to acid secretion.
Ion selective effects of salicylate on antral mucosa.
The effects of luminal salicylate, 5mM, were measured on rates of ion transport by isolated antral mucosa. At neutral luminal pH, salicylate increases Na and decreases Cl permeability. Salicylate does not alter net Na transport but decreases net Cl secretion. At luminal pH 4, the effects of salicylate can be arbitrarily divided into two phases. The intitial phase is associated with an increase in Na and marked decrease in Cl permeability. Subsequently, a greater increase in Na permeability and a marked increase in Cl permeability occurs. Active Na transport persists in the presence of salicylate at pH 4. Indirect evidence also suggests that Cl secretion persists under these conditions, buy at a reduced rate. The rate of luminal acid acid loss also increases in the presence of salicylate. A 4-fold increase in salicylate concentration or decrease in luminal pH from 4 to 3 did not appear to intensify the effects observed for 5 mM salicylate at pH 4. The increase in cation and decrease in anion permeability observed at pH 7 and initially at pH 4 are compatible with an influence of a negative charge of the salicylate anion. The subsequent changes observed in the presence of acid also are compatible with the concept that as the mucosa becomes overwhelmed with acid, a nonspecific increase in permeability occurs. However, the effect of salicylate on active Cl transport is largely independent of acid diffusing into the mucosa.
Transport of H plus and other electrolytes across isolated gastric mucosa of the rabbit.
The relationship of transmural and cellular phenomena to the rate of spontaneous luminal HH+ secretion by short-circuited gastric mucosa bathed in HCO3- and CO2-free Ringer solution was studied by the pH-stat technique. The bulk of luminal acidification can be accounted for by the appearance of H+ and not by organic acids. Acid secretion requires the presence of O2 and exogenous substrate but is not limited by endogenous CO2 production. The rate of H+ secretion is matched by the serosal appearance of alkali. The greater appearance of CO2 on the serosal side of the mucosa is consistent with hydroxylation of CO2 and greater permeability of the serosal border to HCO3-. Luminal changes in H+ concentrations affect H+ secretion but serosal changes do not, suggesting that the gradient produced by H+ secretion is at the luminal border. Steady-state isotopic Na+ and Cl- fluxes indicate net secretion of both ions, but net K+ transport is negligible.