Morphological changes caused by exposure of rabbit oesophageal mucosa to hydrochloric acid and sodium taurocholate

The present authors have studied the light and electron microscopic changes in rabbit oesophageal mucosa which has been exposed to solutions of hydrochloric acid and sodium taurocholate (ST). In an in vivo model the oesophagus was perfused with saline, acid (0.1-40 mmol/l of H+) or taurocholate (0.1-1.0 mmol/l at pH 2.0 or 1.0 mmol/l at neutral pH). At the end of each perfusion experiment the oesophagus was removed and assessed by the naked eye, light and electron microscopy. Some desquamation of superficial stratum corneum cells occurred in all specimens perfused for 5 h. Injury was more evident to the stratum spinosum and basal cell layers. Damage was more severe in the bile salt plus acid perfused specimens, varying between margination of nuclear chromatin in the basal cells to complete necrosis and separation of the overlying layers. Taurocholate in neutral solution did not damage the oesophageal epithelium. Electron microscopy revealed that damage to cells in the basal layers and stratum granulosum occurred within 30 min of exposure to acidified taurocholate, this damage increasing with time. It is concluded that taurocholate is able to damage oesophageal mucosa, that the damage first occurs in the deeper layers of the oesophageal mucosa and that the damage may occur in the absence of gross or light microscopic changes in the mucosa.     

Acidification of arterial blood enhances gastric mucosal injury induced by bile salts in dogs

The influence of intraarterial infusion of hydrochloric acid on gastric mucosal injury induced by topical bile salts was assessed in a canine ex vivo model. Exposure of the gastric mucosa to 5.0 mM sodium taurocholate in acid bathing solution alone resulted in a slight but not significant reduction in intramural pH of gastric mucosa and mild mucosal damage. When hydrochloric acid (0.1 N) was infused directly into the artery perfusing the stomach of the dogs, the intramural pH of gastric mucosa markedly decreased. The mucosal acidification was associated with severe ulcers in all test dogs that received intraarterial infusion of hydrochloric acid. The deleterious effect of intraarterial infusion of hydrochloric acid was not due to ischemia since the gastric blood flow remained relatively unchanged. The severe mucosal ulcerations were perhaps caused by the decrease in the ability of gastric blood to buffer the incoming luminal acid induced by topical bile salts. These results suggest that (1) the pH of arterial blood perfusing the stomach may also be an important determinant in the ability of the gastric mucosa to protect itself against acid injury, and (2) better management of systemic acid-base balance may contribute to a lower incidence of stress ulcers in critically ill patients.     

Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?

Pretreatment with the mild irritant 1 mmol acidified taurocholate protects the gastric mucosa from the injury induced by the subsequent application of 5 mmol acidified taurocholate, a phenomenon referred to as "adaptive cytoprotection." How this occurs remains an enigma. The purpose of this study was to investigate the role of sensory neurons and mucus secretion in this phenomenon. Prior to injury with 5 mmol acidified taurocholate (pH 1.2), the stomachs of six groups of rats were subjected to the following protocol. Two groups were topically pretreated with either saline or the mild irritant 1 mmol acidified taurocholate. Two other groups received the topical anesthetic 1% lidocaine prior to pretreatment with either saline or 1 mmol acidified taurocholate. The last two groups got the mucolytic agent 10% N-acetylcysteine (NAC) after pretreatment with either saline or 1 mmol acidified taurocholate. Injury was assessed by measuring net transmucosal ion fluxes, luminal appearance of deoxyribonucleic acid (DNA), and gross and histologic injury. Pretreatment with the mild irritant 1 mmol acidified taurocholate significantly decreased bile acid-induced luminal ion fluxes and DNA accumulation, suggesting mucosal protection (corroborated by gross and histologic injury analysis). This effect was negated by lidocaine but not by NAC. Thus, it appears that sensory neurons, and not increased mucus secretion, play a critical role in adaptive cytoprotection.     

Selective lipoxygenase inhibitor reduces bile acid-induced gastric mucosal injury.

Leukotriene receptor blockade attenuates topical bile acid-induced gastric mucosal injury, suggesting that peptidyl-leukotrienes may be mediators of this injury. The purpose of this study was to test the hypothesis that a selective 5-lipoxygenase inhibitor protects against bile acid-induced gastric epithelial injury in the rat. Prior to injury with 10 and 20 mM acidified taurocholate (pH 1.2), rat stomachs were pretreated with either vehicle or WY50295K (selective 5-lipoxygenase inhibitor, 20 mg/kg). Injury was assessed by measuring net transmucosal hydrogen ion flux, luminal appearance of DNA, and gross mucosal injury. Topical 5-lipoxygenase inhibitor significantly reduced luminal H+ ion loss, surface epithelial cell loss (as measured by luminal accumulation of DNA), and gross mucosal injury in bile acid-injured stomachs compared to controls. This study lends further support to the hypothesis that leukotrienes may be mediators of bile acid-induced gastric mucosal injury.     

Protection of gastric mucosa against acute ulceration by intravenous infusion of sodium bicarbonate.

The influence of intravenous infusion of sodium bicarbonate on gastric mucosal injury induced by topical sodium taurocholate and hemorrhagic shock was assessed in a canine ex vivo model. As expected, exposure of the gastric mucosa to sodium taurocholate and acid resulted in excessive back diffusion of hydrogen ions (H+) and mild mucosal damage. This mucosal injury was enhanced by hemorrhagic shock in the control dogs. The degree of mucosal injury was significantly less in the test dogs that received intravenous infusions of sodium bicarbonate. The protection afforded by intravenous bicarbonate was not due to a reduction in the amount of H+ entering the tissue, since the net H+ loss from the lumen was not significantly different between the control and the test dogs. The protection effect of intravenous infusion of sodium bicarbonate is probably secondary to an enhancement of mucosal tolerance to H+. These results support the hypothesis that the enhancement of mucosal injury during hemorrhagic shock may be a result of a decrease in the ability of the gastric mucosa to buffer the influxing H+.     

Effect of verapamil on insulin-stimulated choleresis

Insulin is one of several neurohumoral substances known to have a choleretic effect in vivo and in the isolated perfused rat liver. Infusion of insulin in the perfused rat liver preparation results in stimulation of bile acid-independent bile flow evidenced by increased bile flow, decreased bile acid concentration, and stable bile acid output. The mechanism of insulin-stimulated choleresis is unknown but may involve calcium as an intracellular second messenger. The present studies were performed to assess the role of membrane calcium channels in mediating choleresis and insulin-stimulated bile acid-independent bile flow in the in situ perfused rat liver. We have shown that verapamil, a specific calcium channel blocker, has no effect on bile flow, bile acid concentration, or bile acid output during bile acid-stimulated choleresis at a taurocholate infusion rate of 40 or 80 nmole/g liver/min. Insulin caused a significant increase in bile flow (18-30%) and a decrease in bile acid concentration (13-21%) without affecting bile acid output at a taurocholate infusion rate of 40 or 80 nmole/g liver/min. Verapamil failed to inhibit insulin-stimulated choleresis at a taurocholate infusion rate of 80 nmole/g liver/min. Although we observed an insulin-stimulated increase in bile flow and a decrease in bile acid concentration in the presence of verapamil at a taurocholate infusion rate of 40 nmole/g liver/min, these changes failed to reach statistical significance. We conclude that verapamil has no effect on choleresis or insulin-stimulated bile flow in the perfused rat liver and that the mechanism by which insulin promotes bile acid-independent bile flow is not mediated by verapamil-sensitive calcium channels.     

Leukotriene receptor blockade reduces bile acid-induced superficial gastric mucosal injury.

Leukotriene C4 and D4 are putative mediators of the severe gastric mucosal injury caused by a variety of topical irritants. The purpose of this present study was (1) to investigate the effect of pretreatment with topical leukotriene C4 and D4 on the more superficial injury caused by low concentrations of bile acid and (2) to determine the effect of leukotriene receptor blockade, alone and during leukotriene pretreatment, on this injury. Prior to injury with topical 5 mM acidified taurocholate (pH 1.2) rat stomachs were pretreated with either normal saline, leukotriene C4 or D4, SKF-104353 (a leukotriene receptor antagonist), SKF-104353/LTC4, or SKF-104353/LTD4. Injury was assessed by measuring hydrogen ion flux and DNA efflux, a marker of gastric mucosal cell exfoliation. Both LTC4 and LTD4 significantly increased bile acid-induced luminal hydrogen ion loss and DNA efflux. Leukotriene receptor blockade not only blocked this effect, but also significantly decreased the injury from bile acid alone. Thus, both LTC4 and LTD4 exacerbate the superficial gastric mucosal injury caused by physiologic concentrations of bile acids. Leukotriene receptor blockade with SKF-104353 completely blocks these effects and reduces injury from bile acid alone.     

Acute gastric mucosal ulcerogenesis is dependent on the concentration of bile salt.

Studies on animals implicating reflux of bile salts in formation of "stress ulcer" often are suspect because of the inordinately high intragastric concentrations of bile salts used to induce experimental acute gastric mucosal damage. We studied reflux of bile salt in 11 patients after operation. Nine refluxed bile salts in a mean intragastric concentration of 1.87 +/- 0.24 mM. (range, 0.34 to 4.88 mM.). In the present study, therefore, the ulcerogenic potential of physiologic concentrations of bile salts was evaluated. With use of vascularized, chambered canine gastric mucosa, groups of animals were studied during three consecutive periods. Group A = topical acid test alone (ATS) during periods 1, 2, and 3; Group B = (1) ATS, (2) ATS, (3) ATS + vasopressin (VP = 0.1 U per Kg.-min. via the splenic artery); Group C = (1) ATS, (2) ATS + topical 1 mM. sodium taurocholate (TC), (3) ATS + 1 TC + VP; Group D = (1) ATS, (2) ATS + 2 TC, (3) ATS + 2 TC + VP; Group E = (1) ATS (2) ATS + 5 TC, (3) ATS + 5 TC + VP. Parameters evaluated were (1) net fluxes H+, Na+; (2) electrical potential difference (PD); (3) clearance of aminopyrine, a measure of mucosal blood flow (MBF); and (4) formation of lesions, graded zero to six by an independent observer who used photographs. In nonischemic mucosa, bile salts produced no ulcers, a significant concentration-dependent increase in H+ "back diffusion" and fall in PD, and a noncentration-dependent increase in MBF. In ischemic mucosa, the combination of topical acid, topical bile salts, and mucosal ischemia was acutely ulcerogenic. The severity of mucosal injury was dependent on the concentration of bile salt (y = 0.108 + 1.53x, r = 0.90, p less than 0.01). These data indicate that acute mucosal damage occurs in the presence of physiologic concentrations of bile salt, i.e., those routinely found in the gastric contents of postoperative patients.     

Adaptive cytoprotection of gastric surface epithelial cells against injury by physiologic concentrations of bile acid

The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.     

Cimetidine protects against stress-induced gastric injury augmented by mucosal barrier breakers.

An experimental rat model utilizing cold-restraint stress was employed to test the ability of an H2-receptor antagonist, cimetidine, to control gastric mucosal injury associated with stress augmented by the gastric mucosal barrier breakers, aspirin and taurocholate. Both aspirin and taurocholate, when combined with stress, caused a significant increase in gastric mucosal injury over that seen in animals receiving either stress alone or only gastric mucosal barrier breakers without stress. Pretreatment with cimetidine caused a significant reduction in gastric mucosal injury in stressed animals receiving gastric mucosal barrier breakers. This reduction was to the level of lesions seen in nonstressed animals.     

Bile absorption occurs during disruption of the esophageal mucosal barrier

The role of bile salt absorption in bile-induced disruption of the esophageal mucosal barrier was determined using the continuously perfused rabbit esophagus model. Mucosal barrier disruption was determined by measuring net flux of hydrogen ion, potassium, and glucose. Bile salt absorption was measured by determining net flux of radiolabeled bile salt solution using liquid scintillation counting. Bile salt-containing solutions were prepared with varying concentrations of two bile salts, taurocholate and deoxycholate. The pH of the bile salt exposure also was varied to vary the extent of mucosal injury. The results show that changes in bile salt concentration and in pH of exposure were associated with significant differences in both extent of mucosal barrier disruption and bile salt absorption. Bile salt absorption was associated by direct linear correlation with each index of mucosal barrier function studied. These findings suggest that bile salt absorption plays a role in bile-induced disruption of the esophageal mucosal barrier.     

Experimental studies of biliary excretion of piperacillin.

The nonrecirculating isolated perfused rat liver was used to study biliary antibiotic excretion by the liver in a steady-state, controlled environment in which bile flow, bile salt output, and antibiotic delivery were maintained under constant conditions. The effects of piperacillin, ampicillin, and gentamicin on bile flow and bile salt output were analyzed; none altered bile salt output, and only high concentrations of piperacillin (100 micrograms/mL) increased bile flow. The ratio of antibiotic concentration in bile and perfusate depended on the type of antibiotic and perfusate concentration. Piperacillin infusions at perfusate concentrations of 50 or 100 micrograms/mL (in the presence of 60 microM taurocholate) yielded bile to perfusate ratios of 112 +/- 10 versus 49 +/- 3, respectively. Using similar perfusate, the concentration ratios for ampicillin (20 micrograms/mL) and gentamicin (10 micrograms/mL) were only 3.4 +/- 0.5 and 0.5 +/- 0.1, respectively. By altering the perfusate to contain either 60 microM or 240 microM taurocholate, we found variance in bile salt output from 27 +/- 1 to 115 +/- 2 mumol/h, yet this alteration had little effect on the output of ampicillin (perfusate concentration of 20 micrograms/mL), 73 +/- 7 versus 74 +/- 12 micrograms/h, or piperacillin (perfusate concentration 100 micrograms/mL), 10 +/- 1 versus 11 +/- 2 mg/h. Thus, it appears ampicillin and piperacillin are excreted into bile at high concentrations by bile salt-independent pathways. Partial biliary obstruction (6 cm H2O) results in significant decreases in bile volume. Infusion of 50 micrograms/mL of piperacillin resulted in increased biliary flow that approached nonobstructed values. Obstruction resulted in significant decreases in bile piperacillin concentration. Whether the choleretic effect of high concentrations of piperacillin has any clinical significance in nonobstructed or obstructed conditions remains to be established.     

H+ back diffusion interferes with intrinsic reactive regulation of esophageal mucosal blood flow

The esophageal mucosa maintains a barrier that is relatively impermeable to glucose, H+, and other small molecules. Injury of the mucosa causes disruption of this barrier, manifest initially by increased permeability to small molecules. In the stomach the mucosa is protected from gross ulceration in the presence of bile-induced H+ back diffusion (JH+) by increases in mucosal blood flow (Qm). Qm to the esophagus during injury has never been studied. We explored the possibility that esophageal Qm would increase as a compensatory reaction to early barrier disruption. Rabbits (2 to 4 kg) were anesthetized and the in situ esophagus was luminally perfused for two 1-hour periods with subulcerogenic concentrations of bile salts, pepsin, or trypsin in the presence (pH 2) or absence (pH 7) of acid. Qm was measured with 15 mu radioactive microspheres in nine experimental groups with a total of 62 rabbits. Changes in Qm were compared with changes in permeability of the esophageal barrier to glucose, Na+, and H+. When the mucosal barrier was broken by bile salts or trypsin at a neutral pH, no acid back diffusion occurred and barrier disruption was accompanied by dramatic increases in esophageal mucosal blood flow. In contrast, barrier disruption by bile salts, pepsin, or acid during pH 2 perfusions failed to elicit increases in Qm when significant JH+ (50 microEq/hr) occurred. These results demonstrate a loss in reactive regulation of esophageal Qm in the presence of significant JH+ that may contribute to the injury seen in acid reflux esophagitis.     

The effect of acid perfusion on mucosal blood flow and intramural pH of rabbit duodenum

To evaluate the role of blood flow for acid tolerance of the duodenal mucosa, we perfused the duodenums of anesthetized rabbits with different concentrations of hydrochloric acid (HCl). Acid perfusion stimulated blood flow to the duodenal wall in a concentration-dependent fashion up to 80 mmol/L HCl (0 mmol/L; 0.44 +/- 0.05, 10 mmol/L; 0.84 +/- 0.14, 50 mmol/L; 1.44 +/- 0.11, 80 mmol/L; 2.03 +/- 0.12, 100 mmol/L; 1.82 +/- 0.07 ml/gm/min X +/- SEM). The pH in the lamina propria of the mucosa, which was measured with antimony microelectrodes was not changed in experiments during perfusion with 50 and with 80 mmol/L HCl in normotension. Acidosis in the lamina propria could be demonstrated only when the duodenum was perfused with 100 and with 80 mmol/L HCl combined with hemorrhagic hypotension. Damage to the mucosa, which developed after 30 and 60 minutes of acid perfusion, also showed a H+-dependent pattern. Reduction of blood flow by hemorrhagic hypotension aggravated the morphologic damage. We conclude that luminal acid stimulates blood flow in the duodenum. The decrease in blood flow induced by hypotension results in a greater susceptibility to mucosal damage.     

Effect of Hepatic Artery Flow on Bile Secretory Function After Cold Ischemia

These studies evaluated the influence of hepatic arterial flow on biliary secretion after cold ischemia. Preparation of livers for transplantation or hepatic support impairs biliary secretion. The earliest indication of cold preservation injury during reperfusion is circulatory function. Arterial flow at this time may be critical for bile secretion. Porcine livers were isolated, maintained at 4 degrees for 2 h and connected in an extracorporeal circuit to an anesthetized normal pig. The extracorporeal livers were perfused either by both the hepatic artery and portal vein (dual) or by the portal vein alone (single). Incremental doses of sodium taurocholate were infused into the portal vein of both the dual and single perfused livers, and the bile secretion was compared. Most endogenous bile acids are lost during hepatic isolation. After supplementation, the biliary secretion of phosphatidyl choline and cholesterol was significantly better in the dual than single vessel-perfused livers; however, no difference was seen in bilirubin output. Single perfused livers were completely unable to increase biliary cholesterol in response to bile acid. The dependence of bile cholesterol secretion on arterial flow indicates the importance of this flow to the detoxification of compounds dependent on phosphatidyl choline transport during early transplantation.     

Experimental and clinical studies on the effects of supplemental administration of bile salts after relief of biliary obstruction

Changes of hepatic bile production and hepatocellular function such as bile acid and bilirubin excretion, BSP transfer rate constant, hepatic clearance of bile acid and ultrastructure of bile secretory apparatus after relief of biliary obstruction were investigated in both experimental rat model and clinical cases. The results were as follows: Increase in bile acid excretion after total bile fistula was significantly delayed in the jaundiced rats as compared with that of the control rats. In the jaundiced rats, bile salt-induced choleretic effect was significantly augmented and sodium taurocholate infusion caused a marked decrease in bilirubin excretion. Biliary transport of BSP was significantly decreased after biliary decompression, but showed remarkable restoration by simultaneous injection of sodium taurocholate. Hepatic clearance of 14C-taurocholic acid was disturbed in a group with long-term obstruction. The most remarkable morphological alterations were found in the bile canaliculus in the rat with relieved obstruction. Studies on clinical cases showed correlation between bile acid clearance and bilirubin excretion. In conclusion, effective elimination of plasma bilirubin after biliary decompression might be achieved by supplemental administration of bile salts, provided that bile acid clearance remains intact.     

Taurodeoxycholate modulates the effects of pepsin and trypsin in experimental esophagitis

Pepsin and trypsin cause erosive, hemorrhagic lesions in our rabbit model of experimental esophagitis. Since the gastroduodenal contents of patients with reflux esophagitis may also contain bile salts, we used our model to determine the effect that a bile salt, taurodeoxycholate (TDC), would have on the esophageal mucosa when combined with either pepsin in an acid perfusate (pH 2) or trypsin in an alkaline perfusate (pH 7.5). Indexes of esophageal injury included gross appearance of the mucosa, microscopic examination, and mucosal barrier integrity as determined by permeability to hydrogen ion. We found that when 5 mM TDC was combined with pepsin (0.3 mg/ml), the gross and microscopic changes of esophagitis, as well as net hydrogen ion flux, were diminished when compared with those observed with pepsin exposure alone. When increasing concentrations of TDC (2 to 10 mM) were added to pepsin, the morphologic degree of injury as well as hydrogen ion flux decreased in a dose-dependent manner. In contrast, when 5 mM TDC was combined with trypsin (1000 U/ml) in the alkaline perfusate, the gross and microscopic changes of esophagitis and the net of hydrogen ion flux were increased when compared with either bile salt or trypsin alone. These effects were also dose dependent. These data demonstrate that bile salts present in the gastroduodenal contents of patients with reflux esophagitis have the capacity to modulate the effects of pepsin and trypsin on the esophageal mucosa.     

Mediators of bile acid-induced alterations in gastric mucosal blood flow

The topical application of acidified (pH 1.2) bile acids to acid-peptic-secreting gastric mucosa increases mucosal blood flow, an important protective event because, when it is blunted, gross mucosal injury occurs. The mediators of this response are unknown. The current study examined the potential roles of luminal pH, luminal bile acid concentration, and, indirectly, endogenous prostaglandin generation in groups of dogs prepared with ex vivo chambered wedges of proximal gastric wall. Parameters evaluated included H+ fluxes, mucosal blood flow using radiolabeled microspheres, and the severity of gross mucosal injury induced at high and low intraluminal pH (7 and 1.2), at differing concentrations of bile acid (0, 2.5, 5.0 mM), in the presence of indomethacin pretreatment with or without concomitant close intra-arterial infusion of prostacyclin. The results indicate that topical bile acids increase mucosal blood flow in proportion to their capacity to induce H+ loss. This response is blunted (but not ablated) by indomethacin, resulting in gross mucosal injury, effects that are reversed by prostacyclin infusion. Thus, in large part, endogenous prostaglandins are its likely mediators.     

Do leukotrienes mediate bile acid-induced gastric mucosal injury?

Leukotrienes C4 and D4 are potent vasoconstrictors and have been proposed as mediators of the severe gastric mucosal injury caused by a variety of necrotizing agents. The purpose of this study was to investigate the role of leukotrienes on the less severe gastric mucosal injury caused by low concentrations of bile acid. Prior to injury with 5 mM acidified taurocholate (pH 1.2), rat stomachs were pretreated with either normal saline, leukotrienes C4 or D4 (10(-6), 10(-8), and 10(-9) M), or SKF-104353 (a leukotriene D4 receptor antagonist 10(-7) M). Injury was assessed by measuring net transmucosal hydrogen ion flux, luminal appearance of DNA, and histologic injury. Topical pretreatment with LTC4 and LTD4 significantly increased bile acid-induced luminal hydrogen ion loss and DNA accumulation in a dose-dependent manner. Leukotriene receptor blockade with SKF-104353 significantly decreased these parameters. Thus, both LTC4 and LTD4 exacerbate the gastric mucosal injury caused by the application of low concentrations of bile acid while leukotriene receptor blockade reduces this injury (corroborated by histologic injury analysis). This study suggests that leukotrienes may be mediators of bile acid-induced gastric mucosal injury.     

Uptake and excretion of vecuronium bromide and pancuronium bromide in the isolated perfused rat liver

Using the isolated perfused rat liver preparation, the disappearance from the perfusate and the excretion in the bile of vecuronium bromide and pancuronium bromide and their metabolites were followed for 2 h after the addition of 1 mg of either drug to the perfusate. In addition, the rate of change of the hepatic content of these two compounds was calculated by serially subtracting the amount of the compound and the metabolites in the bile and in the perfusate from the dose of drug added to the perfusate. It was found that, whereas the concentration of pancuronium in the perfusate declined slowly and monoexponentially, vercuronium concentration in the perfusate declined rapidly in a biexponential manner. No metabolites of either drug were detected in the perfusate. Approximately 40% of the injected dose of vecuronium was excreted in the bile as unchanged vecuronium and another 30% as the 3-hydroxy metabolite. No other metabolites of vecuronium were found in the bile. In total only about 7% of pancuronium (unchanged) was collected in the bile by the end of the experiment. It is concluded that, in comparison to pancuronium, the rat liver takes up large amounts of vecuronium rapidly, half of which is eliminated as unchanged vecuronium and half as the 3-hydroxy derivative. A small amount of vecuronium or its 3-hydroxy metabolite is returned to the perfusate from the liver. Some possible mechanisms underlying these differences are discussed.