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Biomedical subjects

P H Guth

Publications and source records attributed to P H Guth.

At least 19 recordsLinked to original sources
PubMed1992

Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: evidence for a role for superoxide anion.

Controversy exists as to the role of oxygen-derived free radicals in tissue injury and the no-reflow phenomenon in reperfusion injury after ischemia. In this study using an experimental rat model, left hepatic lobar ischemia followed by reperfusion resulted in an increase of serum glutamic pyruvic transaminase at 30 min with concomitant histological evidence of hepatocellular necrosis at 24 hr. In the in vivo liver microcirculation, reperfusion after ischemia resulted in an initial transient return of blood flow, but stasis of blood flow later developed in the liver sinusoids. Thus a no-reflow phenomenon in the microcirculation was demonstrated. Intravenous administration of a long-acting form of superoxide dismutase (half-life 6 hr, dose 4 or 8 mg/kg) significantly decreased the hepatocellular necrosis and reduced the microcirculatory stasis in the liver sinusoids. These studies established the important contribution of the no-reflow phenomenon in ischemia-reperfusion injury to the liver and the participation of superoxide anions in mediating the no-reflow phenomenon.

Animals↗
PubMed1992

Na+/H+ exchange regulates intracellular pH of rat gastric surface cells in vivo.

Intracellular pH (pHi) and viability of gastric surface cells of the rat stomach in response to luminal acidification, and the role of Na+/H+ exchange in maintaining pHi homeostasis were studied in vivo using a fluorescent microscopic technique. pHi was measured during superfusion with buffers of pH 1.2-7.4. When the pH of the superfusate was 7.4, baseline pHi was unchanged. Superfusion with pH 3 buffer rapidly decreased pHi to 6.7, with subsequent recovery to baseline pHi within 15 min despite continuing acid exposure. Superfusion with buffers of pH 1.7 and 1.2 decreased pHi continuously to below 6.2 with no recovery observed. Despite the relentless decline in pHi during superfusion with pH-1.2 and -1.7 solutions, over 75% of the surface cells were still viable, as measured by exclusion of the vital dye propidium iodide. We then examined the role of Na+/H+ exchange in the regulation of pHi. Superfusion with amiloride did not affect recovery of pHi from intracellular acidification induced by a NH4Cl prepulse. Exposure to the potent, lipophilic Na+/H+ exchange inhibitor 5-(N,N-hexamethylene)-amiloride (HMA), either in the superfusate or by close arterial perfusion, decreased baseline pHi from 7.1 to 6.8. Close arterial perfusion of HMA additionally attenuated the recovery of pHi to baseline during superfusion with pH 3 buffer. We conclude that luminal protons permeate into the cytoplasm of gastric surface cells, where they are eliminated by an Na+/H+ exchanger, most probably localized to the basolateral membrane.

Amiloride↗
PubMed1992

Nitric oxide-mediated gastric hyperemia decreases ethanol-induced gastric mucosal injury in uremic rats.

We investigated whether the recently described endothelium-derived nitric oxide-mediated gastric hyperemia in the uremic rat protects the gastric mucosa against ethanol injury. Uremia was induced by subtotal nephrectomy. Basal gastric mucosal blood flow, measured by a hydrogen gas clearance technique, was significantly higher in uremic than control rats. Continuous intragastric perfusion with 40% ethanol produced significantly less gross and histological lesions in uremic than in control rats. The administration of 3 mg/kg of NW-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide biosynthesis, decreased resting gastric mucosal blood flow to control levels in uremic rats, but had no effect on basal gastric blood flow in control rats. This pretreatment with the inhibitor of nitric oxide biosynthesis increased 40% ethanol-induced gastric mucosal lesions in uremic rats to the same level as that observed in control rats, but had no effect on lesions in control rats. In conclusion, this study suggests that in the uremic rat, gastric hyperemia, mediated by increased endothelium-derived nitric oxide, attenuates ethanol-induced gastric mucosal injury.

Animals↗
PubMed1992

Superior mesenteric artery is more important than inferior mesenteric artery in maintaining colonic mucosal perfusion and integrity in rats.

Mucosal hemodynamics (by reflectance spectrophotometry) and mucosal damage (by histologic examination) following acute colonic ischemia were evaluated in different anatomic locations in the colon of anesthetized rats. The reflectance spectrophotometer provides an index of mucosal hemoglobin concentration (IHB) and an index of oxygen saturation of hemoglobin (ISO2). The patterns of ischemia without congestion (decreases IHB, decreases ISO2) during superior mesenteric artery occlusion, and ischemia with congestion (increases IHB, decreases ISO2) during portal vein occlusion, previously demonstrated in the stomach and duodenum, are also applicable to the colon. The significant linear correlations between changes (as percent of baseline) in IHB, ISO2, and hydrogen gas clearance suggest that changes in these indices are adequate indicators of changes in colonic mucosal perfusion. Superior mesenteric artery ligation produced significant reductions in both indices, and an increase in damage in the mucosa of the cecum, transverse colon, splenic flexure, and left colon, but not the rectum. Inferior mesenteric artery ligation produced only slight reduction in these indices and minimal damage only in the mucosa of the splenic flexure. These results support the hypothesis that the superior mesenteric artery is more important than the inferior mesenteric artery in maintaining colonic perfusion and colonic mucosal integrity in the rat.

Animals↗
PubMed1992

Uremia increases gastric mucosal permeability and acid back-diffusion injury in the rat.

The possibility that chronic uremia renders the gastric mucosa more susceptible to acid injury was investigated. A rat model of chronic renal failure was induced by subtotal nephrectomy. [H+] back-diffusion across the mucosa, following intragastric perfusion of 0.15N HCl or 15% ethanol in 0.15N HCl, was significantly greater in uremic than in sham-operated rats. Gastric mucous gel thickness and transmural potential difference were significantly lower in rats with renal insufficiency. Furthermore, a significantly greater acidification rate of the surface epithelial cells was found in uremic rats than in sham-operated rats during superfusion with pH 1.7 buffer. Intragastric administration of acidified ethanol or aspirin solutions markedly increased gastric mucosal blood flow (68% and 89% respectively) in the sham-operated group producing mild injury, in contrast to uremic rats, where a lesser increase in mucosal blood flow (7% and 14% respectively) was associated with more pronounced mucosal injury. It was concluded that enhanced susceptibility to acid injury in uremia is due to a reduction of function of pre-epithelial, epithelial, and postepithelial elements of the gastric mucosal barrier.

Animals↗
PubMed1992

Neutrophil accumulation in ischemic reperfused rat liver: evidence for a role for superoxide free radicals.

Oxygen-derived free radicals and leukocytes have been implicated in the pathogenesis of ischemia-reperfusion injury. This study aimed at determining, by using biochemical and histochemical techniques, whether an accumulation of neutrophils occurs in the ischemic reperfused rat liver and whether superoxide free radicals play a role in mediating this neutrophil accumulation. Hepatic ischemia was induced by occluding blood supply to the left and median lobes, and reperfusion was reinstituted by releasing the occlusion. Myeloperoxidase activity of the liver was measured with a tetramethylbenzidine-H2O2 assay after removal of glutathione (by dialysis) and in the presence of 3-aminotriazole (catalase inhibitor). A modification of Graham and Karnovsky's method was used to stain neutrophils in liver frozen sections, and the number of neutrophils was counted. Results showed that ischemia-reperfusion of the liver produced a 4.4-fold increase in myeloperoxidase activity (from 0.073 +/- 0.009 to 0.320 +/- 0.017 units/mg liver, means +/- SE), which was proportional to the number of neutrophils (3.1-fold increase from 18 +/- 7 to 57 +/- 4 cells/mm2) in the liver tissue. Pretreatment with long-acting superoxide dismutase significantly attenuated the elevated myeloperoxidase activity and the number of neutrophils. These results indicate that reperfusion after a period of ischemia induces an accumulation of neutrophils in the liver, and superoxide anion free radicals are important mediators in the mechanism of this neutrophil accumulation.

Animals↗
PubMed1992

Regional differences in gut blood flow and mucosal damage in response to ischemia and reperfusion.

Ischemia and reperfusion of the small intestine and colon in rats were produced by reversible occlusion (for 30 min and 1 or 3 h) of the superior mesenteric artery and the aorta above the inferior mesenteric artery. Despite a greater reduction of mucosal perfusion in the colon than in the small intestine with 30 min of ischemia, the depth of mucosal damage was significantly smaller in the former than in the latter. Thirty minutes of ischemia followed by 1 h of reperfusion induced an increase in polymorphonuclear leukocyte infiltration in both locations. Exacerbation of mucosal injury occurred only in the small intestine, suggesting that reperfusion injury is independent of polymorphonuclear leukocyte infiltration. Reperfusion after 1 or 3 h of ischemia did not exacerbate mucosal damage in either location. Allopurinol significantly diminished the exacerbation of injury after reperfusion in the small intestine. The protective effect of allopurinol, however, was neither associated with an improvement in perfusion nor a reduction in polymorphonuclear leukocyte infiltration. These data indicate that there is a window (30 min) of reperfusion injury in the small intestine, but there is no evidence of reperfusion injury in the colon.

Allopurinol↗
PubMed1992

Effect of phorone and allopurinol on ischemia-reperfusion injury in gastrointestinal mucosa of the rat.

We studied the effect of inhibition of oxyradical formation and of endogenous glutathione (GSH) depletion on lesion formation in the gastrointestinal tract in a modified rat hemorrhagic shock model (1 h hypotension and 1 h reperfusion). Allopurinol, an inhibitor of xanthine oxidase, did not protect against lesion formation. This suggests that oxygen radicals generated from xanthine oxidase may not be the major cause of injury under these conditions of prolonged 'ischemia'-reperfusion. Phorone (diisopropylideneacetone), a GSH depletor, decreased mucosal GSH levels in the corpus, duodenum and small intestine, and also significantly reduced lesion formation histologically in the corpus, antrum, duodenum and small intestine. However, there was no significant differences in mucosal blood flow (as estimated by changes in mucosal hemoglobin concentrations and oxygen saturation of mucosal hemoglobin) in the corpus, antrum, duodenum and small intestine between phorone-pretreated and control rats. We conclude that phorone decreased mucosal GSH concentrations and exerted a protective effect against hemorrhagic shock-induced gastrointestinal mucosal lesions. The protective effect appears to be independent of mucosal blood flow.

Allopurinol↗
PubMed1992

Calcitonin gene-related peptide mediates the gastric hyperemic response to acid back-diffusion.

Disruption of the gastric mucosal barrier with resultant increased acid back-diffusion leads to a marked increase in gastric mucosal blood flow (GMBF). This increase in GMBF is blocked by ablation of capsaicin-sensitive sensory neurons. The gastric arterioles are densely innervated by afferent neurons containing vasodilator peptides, calcitonin gene-related peptide (CGRP) being the most potent of these. We investigated (a) whether CGRP is the vasodilator mediator released by acid stimulation of capsaicin-sensitive sensory neurons and (b) whether the resultant hyperemia protects against the acid-induced mucosal injury. When the stomach was perfused with 0.15N HCl plus 15% ethanol, GMBF significantly increased by 70%. This hyperemic response was completely blocked by intra-arterial infusion of human CGRP8-37 (500 pmol/min), a CGRP-receptor antagonist, close to the stomach. With the blockade of the hyperemic response to acid back-diffusion, gross and histological mucosal damage were significantly aggravated. It is concluded that CGRP mediates the gastric hyperemic response to acid back-diffusion and that this gastric hyperemic response is an important protective factor against acid-induced injury.

Animals↗
PubMed1979

Effect of parental aspirin on the gastric mucosal barrier in the rat.

The purpose of the present study was to determine in the rat whether parenteral aspirin, like topical aspirin, injures the gastric mucosa by diffusely disrupting the gastric mucosal barrier to hydrogen ion back-diffusion. Back-diffusion studies, including the ion fluxes and lumenal potential difference, were performed in control situations and either 0.5 or 4 h after the intraperitoneal administration of sodium acetylsalicylate. Gastric mucosal lesions were scored. After 0.5h, lesions developed but the barrier was intact. However, after 4 h, lesion formation was more severe and changes characteristic of diffuse barrier disruption, fall in potential difference and increased loss of hydrogen ion occurred. Since lesions occurred before evidence of diffuse barrier disruption could be detected, we conclude that in the present model diffuse barrier disruption is a consequence rather than a cause of lesions.

Animals↗
PubMed1979

Topical aspirin plus HCl gastric lesions in the rat. Cytoprotective effect of prostaglandin, cimetidine, and probanthine.

The effect of representative agents of three classes of antisecretory compounds; prostaglandins, histamine H2-receptor antagonist, and anticholinergic agents, on acute gastric mucosal lesions produced by topical aspirin (200 mg/kg) plus HCl (150 mM) in the pylorus-ligated rat was studied. Acid was given exogenously so as to negate any antisecretory effect of the drugs studied. Both nonantisecretory and antisecretory doses of each agent as determined by preliminary secretory studies were employed. The postaglandin analogue 16,16-dimethyl prostaglandin E2, the H2-receptor antagonist cimetidine, and the anticholinergic agent probanthine, in both doses studied, all significantly reduced lesion formation. The H1-receptor antagonist mepyramine neither protected by itself nor enhanced the protective effect of cimetidine. Pepsin release into the gastric content increased with increasing mucosal damage. However, addition of pepsin to the gastric instillate had no effect on severity lesions in any group, which indicates that the increased pepsin was the result of, and not the cause of, the mucosal damage. The findings indicate that all three classes of antisecretory agents studied are also cytoprotective, i.e., they can protect against gastric mucosal injury by topical aspirin plus HCl by some mechanism other than inhibition of acid and pepsin secretion.

Animals↗
PubMed1979

Protection by histamine receptor antagonists and prostaglandin against gastric mucosal barrier disruption in the rat.

This study was undertaken to determine if the cytoprotective effect of prostaglandin and the H2 histamine receptor antagonist cimetidine involves protection against disruption of the gastric mucosal barrier. Groups of anesthetized, vagotomized rats received one of the following parenterally: saline (control), mepyramine--an H1 histamine receptor antagonist, cimetidine, cimetidine and mepyramine, or 16,16 dimethyl prostaglandin E2. Parameters of barrier disruption were then determined before and after exposure of the gastric mucosa to 40mM acetylsalicylic acid. At the end of the study, gastric lesions were scored according to size and number. Lesion score and fall in potential difference were significantly lower in rats receiving cimetidine, cimetidine and mepyramine, and prostaglandin. Other parameters of barrier disruption--H+ back diffusion, Na+ and K+ influx, and protein outpouring--exhibited the same pattern and correlated with change in potential difference. We conclude that both prostaglandin and cimetidine, but not mepyramine, protect against barrier disruption by topical aspirin, and this may be a factor in the mechanism of their cytoprotective action.

Administration, Topical↗
PubMed1978

Histamine receptors in the gastric microcirculation.

The types and functions of histamine receptors in the submucosal arterioles of the corpus and antrum of the cat and rat stomach were studied using an in vivo microscopy technique. Change in arteriolar diameter in response to superfusion of histamine with and without antagonists was measured by an image-splitting technique. H1 and H2 histamine receptors subserving vasodilatation were demonstrated in both the antral and corpus submucosal arterioles of the cat and rat. However, the H1 effect was predominant in the antrum (the H2 antagonist inhibited histamine dilatation only in the presence of the H1 antagonist), while H1 and H2 effects were approximately equal and independent in the corpus.

Animals↗
PubMed1978

Histamine receptors in mesenteric circulation of the cat and rat.

This study was designed to ascertain the types and functions of histamine receptors in the mesenteric circulation of the cat and rat. Superior mesenteric artery (SMA) flow was measured via an electromagnetic probe in the cat and intestinal submucosal arteriolar diameter by an image-splitting in vivo microscopy technique in the cat and rat. Histamine infusion into the SMA caused dose-dependent decreases in mesenteric vascular resistance. Mepyramine, an H1 receptor antagonist (H1A), inhibited this effect, displacing the histamine dose-response curve to the right. Metiamide, an H2 receptor antagonist (H2A), alone had no effect, but in the presence of H1A caused further displacement of the curve to the right. In both the cat and the rat, histamine superfusion dilated the submucosal arterioles. H1A attenuated this effect. H2A alone had no effect, but in the presence of H1A there was nearly complete inhibition of the histamine effect. In conclusion, both H1 and H2 histamine receptors, both subserving vasodilatation, are present in the mesenteric circulation and the H1 receptor effect predominates.

Animals↗