Calcitonin gene-related peptide mediates the gastric hyperemic response to acid back-diffusion.
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Animals↗
Biomedical subjects
P H Guth
Publications and source records attributed to P H Guth.
Effect of N omega-nitro-L-arginine methyl ester on arterial pressure and on vasodilator and vasoconstrictor responses: influence of initial vascular tone.
Intravenous N omega-nitro-L-arginine methyl ester (L-NAME) 0.3, 3 and 30 mg/kg produced a dose-dependent increase of blood pressure in urethane-anesthetized rats. Similar pressure responses occurred in rats after ganglionic or adrenergic blockade, hemorrhage or acetylcholine infusion. L-NAME potentiated the pressor response to phenylephrine in pentolinium-treated rats. L-NAME increased the depressor effect of acetylcholine and sodium nitroprusside and shortened the acetylcholine response. Phenylephrine potentiated the magnitude but not the duration of the acetylcholine response and had no effect on the duration or magnitude of sodium nitroprusside-induced hypotension. L-NAME potentiated the initial fall of blood pressure induced by a 5 min acetylcholine infusion but had no effect on the pressure drop at the end of infusion. These results suggest that basal production of nitric oxide (NO) is not related to vascular tone and do not support the view that acetylcholine releases NO from resistance vessels in vivo.
Acetylcholine↗
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.
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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↗
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.
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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↗
Spectrum of injury produced in the duodenum by perfusion with luminal acid in the rat.
The dose and time dependence of duodenal mucosal injury by luminal acid perfusion was studied. Saline, 0.01, 0.05, 0.15, and 0.3N HCl, were perfused through the proximal duodena of rats for 5, 15, or 30 minutes and then harvested for histological examination. In a second set of studies, after a 30-minute perfusion, duodena were harvested either immediately or 2, 4, 8, or 24 hours after the perfusion to study the recovery from injury. Acid disappearance (acid delivered minus acid recovered) was measured in all groups. Duodena were examined grossly, then fixed, stained, and scored histologically. Whereas no gross mucosal injury was noted, there was graded histological injury proportional to acid concentration. Injury occurred early in the perfusion and changed little with increased perfusion durations. The initial injury lead to an acid disappearance rate that was proportional to acid concentration and, therefore, the degree of injury. After the initial injury occurred, the rate of acid neutralization was unchanged by increased duration of acid perfusion. This acid neutralization protected against further injury despite the continued presence of acid. Recovery from injury was complete with physiological (0.01 and 0.05N HCl) but not pharmacological (0.15 and 0.3N HCl) concentrations of acid. It is concluded that acid-induced duodenal injury occurs within 5 minutes of exposure, is proportional to the acid concentration, and results in acid neutralization that protects against extension of the injury with continued acid exposure.
Animals↗
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↗
Morphological and functional gastric cytoprotection by prostaglandin in rats receiving absolute ethanol orally.
Pretreatment with prostaglandins at non-antisecretory doses protects the gastric mucosa, including the parietal cells, from deep necrosis produced by intragastric administration of necrotising agents such as absolute ethanol. Whether the parietal cells also retained their ability to secrete acid when rats were pretreated with a prostaglandin, in spite of exposure to ethanol, was investigated. Gastric acid secretion was abolished 4 hours after ethanol, and secretion returned to control values only after 5-6 days. Pretreatment with a single, non-antisecretory dose of 16, 16-dimethyl prostaglandin E2 (dm PGE2) maintained acid secretion, in spite of exposure to absolute ethanol. Absolute ethanol caused histological changes - extensive gastric mucosal necrosis (through the muscularis mucosae), oedema, haemorrhages, polymorphonuclear infiltration, and formation of granulation tissue - that were maximal 24-48 hours after ethanol and persisted for 2 to 4 weeks. None of these changes were present in animals treated with the prostaglandin. It is concluded that a single oral pretreatment with dmPGE2 protects the gastric mucosa against not only the morphological damage of absolute ethanol (preventing necrosis, haemorrhages, and polymorphonuclear infiltration) but also the functional damage (maintaining the acid secretory function of parietal cells).
16,16-Dimethylprostaglandin E2↗
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↗
Renal failure increases gastric mucosal blood flow and acid secretion in rats: role of endothelium-derived nitric oxide.
Because of the contradictory findings in clinical studies, and the complete lack of animal studies, the purpose of this investigation was to characterize the changes in gastric mucosal blood flow (GMBF) and acid secretion in an animal model of chronic renal failure. Rats with chronic renal failure induced by partial kidney infarction had a significantly higher basal GMBF and lower gastric vascular resistance than control rats. The gastric acid secretory and mucosal hyperemic response to pentagastrin were markedly enhanced in renal failure rats. Because endothelial-derived nitric oxide (NO) is an endogenous vasodilator that regulates gastric vascular tone, we hypothesized that NO mediates the gastric hyperemia of renal failure rats. The administration of N omega-nitro-L-arginine methyl ester (L-NAME), a specific inhibitor of NO formation, produced a significantly greater decrease in GMBF in renal failure rats than in control rats, including a low dose inhibiting the basal hyperemia in renal failure rats but having no effect in control rats. It also attenuated pentagastrin-stimulated GMBF in both groups. In contrast, L-NAME produced a similar decrease in basal skeletal muscle blood flow in both renal failure and control rats. We conclude that in the renal failure rat 1) there is an increased basal GMBF and pentagastrin-stimulated acid output and GMBF, and 2) this gastric mucosal hyperemia is mediated by NO.
Animals↗
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↗
Role of calcitonin gene-related peptide in capsaicin-induced gastric submucosal arteriolar dilation.
The response of gastric submucosal arterioles to topical (submucosal) application of calcitonin-gene-related peptide (CGRP) or capsaicin with and without the human CGRP antagonist, hCGRP-(8-37), was studied using in vivo microscopy. CGRP (10(-11) to 10(-8) M) induced dose-dependent dilation. Topical treatment with hCGRP(8-37) (10(-6) M, for 10 min) caused a significant decrease in basal arteriolar diameter from 33 +/- 2 to 27 +/- 2 microns. hCGRP(8-37) did not alter acetylcholine- or adenosine-induced vasodilation but did significantly reduce CGRP 10(-8) M vasodilation from 97.3 +/- 10.1 to 15.9 +/- 4.4% of the maximal response. Topical capsaicin (10(-9) M to 5 x 10(-7) M) induced dose-dependent arteriolar dilation. This vasodilation was markedly attenuated by hCGRP(8-37). Selective ablation of capsaicin-sensitive sensory neurons nearly completely inhibited capsaicin-induced vasodilation, suggesting that this vasodilation is primarily neurogenic in origin. We conclude that 1) topical application of capsaicin stimulates capsaicin-sensitive sensory neurons and induces dose-dependent arteriolar dilation; 2) this vasodilation is mediated in part by CGRP; and 3) CGRP may be involved in modulating the basal tone of gastric resistance vessels.
Animals↗
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↗
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↗
Effect of elevated intracranial pressure on gastric acid secretion, mucosal blood flow and mucosal injury.
Head injury is frequently accompanied by an increase in intracranial pressure and gastric lesion formation. We used a model of controlled intracranial pressure to investigate the effect of elevated intracranial pressure on gastric acid secretion and mucosal blood flow and on the susceptibility of the gastric mucosa to lesion formation. With increasing intracranial pressure, there was a corresponding increase in gastric acid output but no significant change in gastric mucosal blood flow. This imbalance between acid secretion and blood flow could be a factor in the pathogenesis of the gastric lesions seen with head injury. Susceptibility to gastric mucosal injury then was studied in a model that is independent of the acid secretory state--exogenous intragastric HCl plus ethanol. Elevated intracranial pressure did render the gastric mucosa more susceptible to injury in this model, but there was no impairment of the increased gastric mucosal blood flow response to the increased acid back-diffusion. In this situation, factors other than altered overall blood flow appear to be responsible for the increased lesion formation.
Animals↗
Ethanol-induced gastric injury. Role of submucosal venoconstriction and leukotrienes.
Under in vivo microscopic observation, intragastric ethanol instillation has been seen to cause a prompt, marked constriction of submucosal venules, followed by congestion in mucosal capillaries and severe gross mucosal lesion formation. This study was designed to test the hypothesis that the venoconstriction is mediated by leukotrienes and that inhibition of the venoconstriction would protect against ethanol injury. Intragastric application of the leukotriene receptor antagonist MK-571 inhibited both venoconstriction and gross lesion formation. However, although local submucosal application of MK-571 inhibited venoconstriction, it did not protect the overlying gastric mucosa against ethanol injury. We conclude that leukotrienes play a significant pathogenetic role in ethanol-induced gastric mucosal injury, but while the venoconstriction, mediated by leukotrienes, is one of the factors that promote lesion formation, it is not an essential one.
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Sensory neurons signal for an increase in rat gastric mucosal blood flow in the face of pending acid injury.
Disruption of the gastric mucosal barrier is quickly followed by an increase in gastric mucosal blood flow, which is thought to be a defensive reaction to prevent further injury. This study examined how this increase in blood flow is brought about. When the stomach of urethane-anesthetized rats was perfused with 0.15N HCl, disruption of the gastric mucosal barrier with 15% ethanol increased the disappearance of acid from the gastric lumen and enhanced gastric mucosal blood flow. This increase in blood flow was blocked by local arterial infusion of tetrodotoxin (60 ng/min) to the stomach and by chemical ablation of capsaicin-sensitive sensory neurons. Inhibition of the blood flow increase was associated with exaggeration of gross and histological injury to the mucosa. IV injection of atropine (0.2 mg/kg) or pyrilamine (2 mg/kg) did not affect blood flow increase in response to barrier disruption, whereas morphine injection (2 mg/kg) inhibited it. The current findings show that the increase in gastric mucosal blood flow that follows disruption of the gastric mucosal barrier in the presence of acid is mediated by sensory neurons that seem to monitor acid back-diffusion and in turn signal for a protective increase in blood flow.
Animals↗