Bleeding in portal hypertensive gastropathy evaluated in terms of gastric mucosal microcirculation and coagulation-fibrinolysis system

Gastric intramucosal bleeding in portal hypertensive gastropathy was investigated in terms of gastric mucosal microcirculation, coagulation-fibrinolysis factors, and local fibrinolysis in patients with liver cirrhosis. The gastric mucosa was examined by endoscopy, and the patients were classified into two groups with or without bleeding. Gastric mucosal blood flow was measured simultaneously with coagulation-fibrinolysis factors or local fibrinolysis in both groups. As gastric mucosal blood flow, the gastric mucosal blood volume (IHb) and the oxygenated hemoglobin concentration (ISO2) were determined by the organ reflection spectrum method. Coagulation-fibrinolysis factors were measured in the blood. For evaluation of local fibrinolysis, gastric biopsy specimens were placed on a standard fibrin plate, and the fibrinolysis area was measured. Compared with the non-bleeding group, the bleeding group showed increased IHb and decreased ISO2 (p < 0.05), suggesting marked congestion of blood flow. Gastric intramucosal bleeding was frequently observed in patients with marked congestion of blood flow and markedly abnormal values of coagulation-fibrinolysis factors. Gastric local fibrinolysis was also significantly enhanced in the bleeding group (p < 0.05). In addition, local fibrinolysis was correlated positively with the gastric mucosal blood volume (r = 0.68, p < 0.05) and negatively with the oxygenated hemoglobin concentration (r = -0.58, p < 0.05). These results suggest the following mechanism of gastric mucosal bleeding in liver cirrhosis and portal hypertension. Congestion of gastric mucosal blood flow is present in liver cirrhosis and portal hypertension. An increase in the microvascular pressure and hypoxia cause release of tissue plasminogen activators from gastric mucosal cells and vascular endothelial cells. As a result, gastric local fibrinolysis is enhanced, causing gastric mucosal bleeding.     

Involvement of free radicals and histamine in the potentiating action of cigarette smoke exposure on ethanol-induced gastric mucosal damage in rats

Cigarette smoking has been associated with peptic ulcer diseases. We studied the effects of cigarette smoke exposure on ethanol-induced gastric mucosal damage and its relationship with vascular integrity and the possible role of free radicals and histamine. Male Sprague-Dawley rats were exposed to cigarette smoke followed by ethanol administration (70% v/v). Smoke exposure alone dose-dependently reduced basal blood flow and increased xanthine oxidase (XO) activity but superoxide dismutase (SOD) activity remained unaffected in gastric mucosa. Cigarette smoking followed by ethanol administration significantly potentiated mucosal lesion formation along with augmentation of the mucosal blood flow, vascular permeability and myeloperoxidase (MPO) activity. The potentiating effect of smoking on ethanol-induced gastric mucosal lesion and MPO activity was abolished by pretreatment with allopurinol, terfenadine or ranitidine. Terfenadine and ranitidine also reduced the increased mucosal blood flow and vascular permeability induced by smoking and ethanol combined. These findings suggested that cigarette smoke adversely affected the defense mechanisms of the gastric mucosa by reducing the mucosal blood flow which in turn led to ischemia and increased XO activity. Activation of XO together with histamine H1 and H2 receptors stimulation could lead to neutrophil aggregation and vascular damage. However, the potentiating action of cigarette smoke on ethanol ulceration is unlikely through reduction of SOD activity in gastric mucosa.     

Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study

To evaluate rectal mucosal hemodynamics in patients with chronic hepatitis, we employed reflectance spectrophotometry and examined the results in relation to the presence and severity of chronic hepatitis. Twenty-six patients with histologically diagnosed chronic hepatitis and 21 controls were examined for rectal vascular findings by endoscopy. Indices (I) of rectal mucosal oxygen saturation (ISO2) and rectal mucosal hemoglobin (IHb) concentration were measured. To minimize the effects of systemic anemia, the IHb was divided by blood Hb concentration, giving the rectal index for Hb (RHb). The relationship between rectal mucosal hemodynamics and the histological grade of chronic hepatitis was studied. Rectal vascular lesions were observed in three patients with chronic hepatitis (11.5%). The RHb in patients with chronic hepatitis was significantly higher than that in the controls (5.74 +/- 0.71 and 4.82 +/- 1.12, respectively; P < 0.01). There was no significant difference in ISO2 levels (44.23 +/- 5.84 and 41.94 +/- 4.91, respectively). No significant correlation was observed between rectal mucosal hemodynamics and the histological severity of chronic hepatitis, although rectal mucosal hemodynamics changed in patients with chronic hepatitis. Early vascular changes were observed in the rectal mucosa of patients with chronic hepatitis.     

Influence of nitroglycerin on portal pressure and gastric mucosal hemodynamics in patients with cirrhosis

We studied 30 patients with cirrhosis to determine the effect of nitroglycerin on portal and gastric mucosal hemodynamics. Systemic hemodynamics, portal venous pressure (PVP), the hemoglobin index (IHB), and the oxygen saturation index (ISO2) of the gastric mucosa were measured before and after a continuous infusion of nitroglycerin. The patients were divided into two groups according to the presence or absence of major portal-systemic collateral routes on portograms. Nitroglycerin caused a reduction in PVP in all patients. Although there was no significant difference in systemic hemodynamic changes between the two groups, the reduction in PVP in patients with major portal-systemic collaterals was significantly higher than in those without major collaterals. A nitroglycerin infusion, at a dose of 1.0 micrograms/kg per min for 10 min, produced a reduction in both IHB (-16%, P < 0.001) and ISO2 (-13%, P < 0.001) in the gastric mucosa, indicating gastric mucosal ischemia secondary to splanchnic vasoconstriction. These findings suggest that the continuous infusion of nitroglycerin reduces PVP in cirrhotic patients, particularly in those with major portal-systemic collaterals, and reduces the congestion of the gastric mucosa in patients with portal hypertension.     

Modulatory role of 5-HT3 receptors in gastric function and ethanol-induced mucosal damage in rat stomachs

The involvement of 5-hydroxytryptamine (5-HT) in gastric function and mucosal damage has been defined. 5-HT also potentiates lesion formation in animals. The current study investigated further whether these actions are mediated through 5-HT3 receptors in rats. Ondansetron, a 5-HT3 receptor antagonist, was given subcutaneously, 2 or 4 mg/kg, 30 min before the gastric parameters were measured. The higher dose of ondansetron, 4 mg/kg, significantly increased gastric mucosal blood flow (GMBF) and also basal acid and Na+ secretion. However, it did not affect pepsin output. 5-HT time dependently reduced GMBF and pepsin secretion, but not that of acid and Na+. These actions were not altered by ondansetron pretreatment. The drug, however, dose dependently reduced ethanol-induced gastric mucosal lesions in the 5-HT-treated animals. These findings indicate that 5-HT3 receptors regulate not only basal GMBF, but also acid and Na+ secretion in stomachs. However, the depressive action of 5-HT on GMBF and pepsin secretion is most likely not mediated through 5-HT3 receptors. Ondansetron also modulates the toxicities of ethanol in the stomach and this action is likely to be mediated through the preservation of GMBF.     

Mixed tumors of the pineal area. Diagnosis and therapy consisting of secreting germ cell tumor

This study examined the effects of early burn wound excision on gastric blood flow and on morphologic changes in mucosal vessels. Wistar rats were given a 30% total body surface area burn and divided into four groups, consisting of control animals (group 1), animals with burn injury without and with fluid resuscitation (groups 2 and 3, respectively), and animals with both fluid resuscitation and early wound excision (group 4). Gastric mucosal blood flow (GMBF) was measured by the hydrogen gas clearance method up to 24 h post-burn. Morphologic changes in mucosal vessels were examined by scanning electron microscopy (SEM) at 3 and 24 h post-burn. The GMBF sharply decreased in the acute period after the burn. In group 4, however, it recovered to the initial value by 6 h post-burn and there was no significant change throughout the experiment. Morphologically, although the mucosal capillaries revealed some changes such as irregularity in diameter in groups 2-4 at 3 h, most of mucosal capillaries retained their original appearance in group 4 at 24 h post-burn. These result suggest that early excision does not aggravate the state of gastric ischemia.     

Direct effect of endotoxin on the gastric mucosal microcirculation and electrical gradient

The effects of intra-arterial infusion of E. coli endotoxin at 1.0 mg. per minute on the gastric total and mucosal blood flows, electrical potential difference, and ionic fluxes across the gastric mucosa were studied in an exteriorized, chambered preparation of canine fundic stomach. Gamma-labelled microsphere technique was used in addition to venous drainage and plasma aminopyrine clearance for the measurement of total and mucosal blood flow, respectively. In spite of normal systemic blood pressure throughout the experiment, E. coli endotoxin infusion caused a significant decrease in total gastric blood flow and in the fractional distribution of flow to the mucosae. There was no significant arteriovenous shunting of microspheres. Significant reduction in potential difference and hydrogen-ion back diffusion also was noted after endotoxin infusion, possibly as a consequence of reduced mucosal blood flow. The results indicate that significant gastric mucosal ischemia can occur and may represent a mechanism in the development of gastric erosions in endotoxemia, even in the absence of systemic hypotension.     

Character of changes in the microcirculatory bed of the mesentery of the small intestine in experimental acute myocardial infarct

On the first day of the development of acute coronary insufficiency there appears a spastic state of all the vascular system of the small intestine mesentery and a deceleration of the blood flow. On the third day after ligation of the coronary artery branch against the background of spasmed arterioles the alternation of sites of constricted and dilated capillaries, postcapillaries and venules was observed, i.e., there was a well pronounced spasticatonical state of the microcirculation bed vessels. On the fifth and seventh day the characteristic features were dilatation and decreased tonus of the venous part of the microcirculatory bed, redistribution of blood and more considerable disorders in microcirculation with aggregation and diapedesis of erythrocytes.     

Potassium channels participate in gastric mucosal protection in rats with partial portal vein ligation

Glybenclamide, an adenosine triphosphate-dependent potassium (K+(ATP)) channel blocker, lowered portal pressure and attenuated the hyperdynamic splanchnic circulation in rats with partial portal vein ligation (PPVL). The purpose of this report was to confirm these observations and to test the hypothesis that glybenclamide could reduce acidified ethanol-induced gastric mucosal injury in rats with PPVL. Gastric mucosal blood flow (hydrogen gas clearance), systemic blood pressure, and portal pressure were monitored in rats with PPVL or sham operation (SO). Intravenous glybenclamide (20 mg/kg) or vehicle was administered, followed by intragastric acidified ethanol (0.15 N HCl and 15% ethanol). The area of gastric mucosal lesions was assessed by image analysis. In contrast to published findings, there was no significant elevation of portal pressure after glybenclamide administration in rats with PPVL. Glybenclamide did not alter the gastric mucosal hyperemia in these rats. Glybenclamide significantly increased mucosal injury. The data are consistent with the hypothesis that K+(ATP) channels play a role in protecting the gastric mucosa in rats with PPVL.     

Gastric mucosal blood flow response to stress in streptozotocin diabetic rats: regulatory role of nitric oxide

To investigate cytoprotection against mucosal injuries of the stomach in patients with diabetes, we investigated gastric mucosal blood flow (GMBF), its response to a burn stress, and the involvement of nitric oxide (NO) in streptozotocin (STZ) diabetic rats. GMBF was measured by laser-Doppler velocimetry (LDV) and by the hydrogen gas clearance technique (HGC). The steady-state GMBF of STZ rats decreased according to the duration of diabetes, and insulin treatment blocked this decrease. Burn stress caused a rapid decrease in the GMBF. Reduction of the GMBF and gastric mucosal leakage of Evans blue (EB) after the burn stress were greater in the STZ rats than in the controls, but insulin treatment completely blocked this increase in EB leakage in the STZ rats. There was a significant negative correlation between the percent GMBF 3 h after the burn stress and EB leakage at the same time point. In the controls and the insulin-treated STZ rats, N-nitro-L-arginine (L-NNA), an NO synthase inhibitor, enhanced the decrease in postburn GMBF and EB leakage, but was without effect in the STZ rats. These results suggest that NO may be involved in the regulation of GMBF, and that persistent hyperglycemia may impair this regulation. These findings suggest that patients with diabetes have reduced cytoprotection against a variety of gastric mucosal injuries.     

Telomere length, telomerase activity and telomerase RNA expression during mouse mammary tumor progression

The effects of intraportal administration of prostaglandin E1 (PGE1) on portal venous flow, hepatic arterial flow, peripheral tissue blood flow, and systemic arterial flow before and after 60 min total liver ischemia followed by 70% partial hepatectomy in rats were investigated. Total liver ischemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 at a dose of 0.5 microg/kg/min was infused intraportally for 15 min before inducing hepatic ischemia (preischemic period) and for 60 min after ischemia (postischemic reperfusion period) in the treatment group. Normal saline was infused in the control group. Seventy percent partial hepatectomy was performed during ischemia. Serum biochemical analysis and liver tissue histology were carried out 1, 3, and 24 h, and 1 and 24 h after reperfusion respectively. One-week survival of the PGE1 group was improved to 70% compared to that of the control group of 30%. Postischemia reperfusion values of portal and peripheral tissue blood flows in the PGE1 group were 6.33 +/- 0.600 ml/min and 27.2 +/- 23.5 (arbitrary), and were significantly different from those of the control group of 4.34 +/- 0.400 ml/min and 23.5 +/- 5.54 (arbitrary), respectively. There was no significant difference in hepatic arterial flow between the two groups. Serum alkaline phosphatase decreased significantly in the prostaglandin group. Histological examination revealed a significant portal venous congestion in the control group 1 and 24 h after reperfusion. The extent of the sinusoidal congestion was also severe in the control group 24 h after reperfusion. It was concluded that PGE1 has a protective effect against liver damage when the liver was injured by warm ischemia and reperfusion followed by partial resection.     

Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction

OBJECTIVE: Investigation of leukocyte sequestration in alveolar capillaries and of microhemodynamic changes after pulmonary ischemia/reperfusion injury. METHODS: The kinetics of leukocyte passage and the hemodynamics in pulmonary microcirculation were investigated in 16 rabbits by intravital microscopy. Mean red blood cell velocity and the number of sticking leukocytes were measured in pulmonary arterioles, venules, and capillaries after 1 hour of tourniquet ischemia and 10 minutes and 1 hour after reperfusion. RESULTS: The decrease of red blood cell velocity after reperfusion was associated with a largely increased heterogeneity of blood flow. Immediately after the onset of blood flow, sequestered leukocytes were found in all microvascular segments. An increased number of leukocytes was present in arterioles, venules, and alveolar capillaries 10 minutes and 1 hour after reperfusion. Concomitantly, width of alveolar septa was increased while arterial oxygen tension was reduced, indicating the development of interstitial pulmonary edema. CONCLUSION: Leukocytes are sequestered after pulmonary ischemia and reperfusion not only in alveolar capillaries but also in arterioles and venules, and they may contribute to the development of reperfusion edema.     

Effects of afferent and efferent celiac nerves on acute gastric lesions: due to changes in blood flow?

Since ablation of afferent nerves prior to stress results in increased severity of acute gastric mucosal lesions, afferent nerves are thought to mediate protective mechanisms in the stomach. These mechanisms are known to include vasodilation of gastric mucosal vessels; vasodilation is thought to allow the gastric mucosa to respond to injurious substances. However, it is not known whether other aspects of mucosal health, independent of those caused by increased blood blow, are affected by afferent blockade. This study compared gastric blood flow and acute gastric mucosal lesions during stress in rats with either chemical sympathectomy or afferent blockade. The purpose of the study was to compare the lesion index and blood flow in each treatment group. The lesion index was highest in rats with afferent blockade and lowest after sympathectomy. Gastric blood flow was partially preserved after sympathectomy, but was not greatly increased, suggesting that some of the effects observed after afferent blockade are unrelated to changes in blood flow.     

Role of beta-adrenoceptors in gastric mucosal integrity and gastroprotection induced by epidermal growth factor

The central and peripheral adrenergic systems are involved in the regulation of gastric secretion but little is known about the role of alpha- and beta-adrenoceptors in gastroprotection. In this study, acute gastric lesions were produced by an intragastric (i.g.) application of 100% ethanol and gastric blood flow (GBF) was determined by H2-gas clearance technique in rats with or without i.g. or intraperitoneal (i.p.) administration of alpha- or beta-adrenoceptor agonists or antagonists. Phenylephrine, alpha1-adrenergic agonist, and clonidine, alpha2-agonist, significantly augmented the ethanol-induced lesions while decreasing the GBF and these effects were reversed by the blockade of alpha1-adrenoceptors with prazosin and alpha2-adrenoceptors with yohimbine. In contrast, isoproterenol (ISO) (0.01-10 mg/kg i.g.), beta-adrenoceptor agonist, reduced dose-dependently ethanol-induced mucosal injury and this effect was accompanied by an elevation of the GBF similarly as after epidermal growth factor (EGF) (100 microg/kg x h s.c.) or after classic protective agent, 16,16-dimethyl-PGE2 (PGE2) (10 microg/kg i.g.). The pretreatment with beta-antagonist, propranolol, diminished the protective and hyperemic effects of ISO and EGF but failed to affect those induced by PGE2. Suppression of nitric oxide (NO) synthase activity by L-NAME or sensory denervation with capsaicin attenuated significantly the ISO- and EGF-induced gastroprotection and elevation of GBF, whereas the inhibition of PG biosynthesis by indomethacin remained without any significant effect. Adrenal medullectomy or chemical sympathectomy by 6-hydroxydopamine by itself failed to influence significantly the ethanol-induced damage but completely abolished the protective and hyperemic effects of EGF being without any influence on those induced by PGE2. ISO combined with EGF, restored the protective and hyperemic effects of this peptide in medullectomized rats. We conclude that (1) local activation of beta-adrenoceptors by ISO affords protection and elevation of GBF, both these effects being mediated by arginine-NO pathway and sensory nerves and (2) sympathetic system and adrenal medulla contribute to the protective and hyperemic activity of EGF.     

Capsaicin-induced gastric mucosal hyperemia and protection: the role of calcitonin gene-related peptide

BACKGROUND: Topical capsaicin augments gastric mucosal blood flow and is cytoprotective. This phenomenon is blocked by nitric oxide (NO) synthase and cyclooxygenase inhibition. Capsaicin-sensitive neurons store and release calcitonin gene-related peptide (CGRP). The purpose of this investigation was to study the effects of a CGRP antagonist on capsaicin-induced hyperemia and protection and to determine the role of NO and the cytoprotective prostaglandin PGE2 in this process. METHODS: The glandular stomachs in male Sprague-Dawley rats (280 to 350 gm) were chambered with the blood supply intact. Animals were divided into four groups. Normal saline solution (group 1) or the CGRP antagonists hCGRP8-37 (groups 2 through 4, 0.047 mg/ml) were continuously infused intraarterially via a retrograde splenic artery catheter at a rate of 0.034 ml/min after rats were given an intravenous bolus of either NSS (groups 1 and 2), L-arginine (group 3), or D-arginine (group 4) (200 mg/kg). The gastric mucosa was then topically exposed to normal saline solution (pH 7.4), followed by 160 mumol/L capsaicin and then 100 mmol/L acidified taurocholate (pH 1.2), each for 15 minutes. Gastric mucosal blood flow (ml/min/100 gm tissue) was continuously measured (laser Doppler) and mucosal injury was assessed. Luminal PGE2 production was measured during the bile acid injury period by radioimmunoassay. RESULTS: The CGRP antagonist hCGRP8-37 significantly inhibits capsaicin-induced hyperemia and its associated mucosal cytoprotection and also significantly decreases luminal mucosal PGE2 production. Pretreatment with L-arginine, but not D-arginine, reverses these effects of CGRP antagonism. CONCLUSIONS: CGRP is a mediator of capsaicin-induced hyperemia and protection. This effect may be dependent on both NO and PGE2 production.     

Neurophysiological evaluation with multimodality evoked potentials in craniostenosis and craniofacial stenosis

OBJECTIVE: To observe the changes of gastric mucosal hemodynamics and discuss the possible regulatory factors of prehepatic portal hypertensive rat. METHOD: Prehepatic portal hypertensive (PHT) rat model was produced by various degree of portal vein constriction, and gastric mucosal hemodynamics was measured by radioactive microsphere technique. Statistical analysis was performed by ANOVA, the student t test, and linear correlation. RESULT: The gastric mucosal blood flow was significantly reduced in PHT rats, whereas the blood flow in submucosa, muscular layer prominently increased. The resistance of mucosal vasculature was elevated in PHT rats, however, that of submucosa and muscular layer was decreased remarkably. There was a negative correlation between the gastric mucosal blood flow and portal pressure. CONCLUSION: The gastric mucosa of prehepatic portal hypertensive rat model is poorly perfused prominently. It may be due to the increased mucosal vascular resistance and elevated portal pressure.     

Intercostal pedicle flap for thoracic oesophageal perforations

Since exogenously applied tachykinins (substance P and neurokinin A) prevent the neurogenic hyperaemia which is elicited by acid back-diffusion in the rat stomach, we investigated whether endogenous tachykinins would act in a similar manner. Acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCI, increased gastric mucosal blood flow (GMBF) by 60-100% as determined by hydrogen clearance in urethane-anaesthetized rats. This response remained unchanged after pretreatment with the tachykinin NK1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK2 receptor antagonist MEN 10,627 (200 nmol/kg). When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333. We conclude that endogenously released tachykinins, acting via NK2 receptors, limit the gastric hyperaemic response to acid.     

Role of polymorphonuclear leucocytes and oxygen-derived free radicals in the formation of gastric lesions induced by HCl/ethanol, and a possible mechanism of protection by anti-ulcer polysaccharide

This study examined the role of oxygen-derived free radicals in the pathogenesis of gastric mucosal lesions induced by HCl/ethanol. Superoxide dismutase, and catalase, and their combination reduced gastric lesion formation in mice. Gastric lesions were also reduced in mice treated with cyclophosphamide or anti-neutrophils, but not in mice treated with allopurinol or desulphated-carrageenan. Cobra venom factor did not reduce lesion formation. These results suggested that oxygen-free radicals may contribute to the formation of gastric mucosal lesions induced by HCl/ethanol, and that oxygen radicals were generated from neutrophils but not from xanthine oxidase. Anti-ulcer pectic polysaccharide, bupleuran 2IIc, which was recently isolated from the roots of Bupleurum falcatum L., showed potent inhibition of HCl/ethanol-induced gastric lesions in mice. Bupleuran 2IIc seemed to scavenge hydroxyl radical effectively. It was suggested that this anti-ulcer polysaccharide may provide protection to the gastric mucosa by scavenging oxygen-free radicals.