Does gastric aminopyrine clearance reflect gastric mucosal blood flow or parietal cell function?

Gastric aminopyrine clearance was measured in human volunteers and dogs with untreated basal secretion, in human volunteers and dogs treated with secretory inhibitors, in dogs treated with histamine, and in patients with pernicious anaemia. When aminopyrine was given as a bolus to man or dog, aminopyrine clearance and the ratio aminopyrine concentration in gastric juice/aminopyrine concentration in plasma showed an initial peak two to three times over steady state levels. When aminopyrine was given with histamine, the peaks were even higher. No peaks occurred when an aminopyrine bolus was given to patients with pernicious anaemia or to healthy volunteers treated with secretory inhibitors. The height of the peaks paralleled the acid secretory rate. The peaks may best be explained by aminopyrine accumulation in the parietal cells and washing out of aminopyrine by volume flow. The steady state levels might reflect both parietal cell function and gastric mucosal blood flow.     

Comparison of gastric mucosal blood flow as determined by aminopyrine clearance and gamma-labeled microspheres.

Gastric mucosal blood flow was simultaneously determined by aminopyrine clearance and gamma-labeled microspheres (15 +/- 5 mu in diameter) in anesthetized dogs prepared with a chambered segment of stomach greater curvature. Paired flow measurements were made in 11 dogs (n = 28) secreting in response to intravenous histamine (1mug per kg per min), in 11 (n = 21) nonsecreting dogs given intravenous isoproterenol (0.5 or 1.0 mug per kg per min), and in 9 (n = 10) dogs given no drugs to stimulate secretion or blood flow (resting dogs). Eight additional injections were done in dogs receiving various combinations of isoproterenol and histamine. Isotonic HCl was maintained on the mucosal surface during all experiments. Regression analysis demonstrated a highly significant linear correlation between clearance and microsphere-measured flow in the histamine (P less than 0.001, r = 0.96) and isoproterenol (P less than 0.001, r = 0.78) experiments, with clearance averaging 83% of microsphere flow during histamine stimulation but only 25% during isoproterenol. The relationship between clearance and microsphere flow was not significantly different for the resting and isoproterenol experiments. Mucosal perfusion measured by microspheres was about 5 times the resting value for both histamine and isoproterenol-stimulated dogs. Perfusion calculated from aminopyrine clearance averaged 46, 38, and 90% of the microsphere value in the resting, isoproterenol, and histamine experiments, respectively. Pooled data from secreting dogs demonstrated a fairly constant ratio of microsphere-measured flow to clearance (1.25 +/- 0.06 mean +/- SEM), regardless of the secretory rate. Our results indicate that aminopyrine clearance reflects only a small fraction of mucosal blood flow in the nonsecreting stomach, even in the presence of exogenous acid.     

Regional gastric mucosal blood flow measurements by hydrogen gas clearance in the anesthetized rat and rabbit

Hydrogen gas clearance using 3% hydrogen in air and platinum contact electrodes was employed for measuring antral and corpus mucosal blood flow in anesthetized animals. Significantly greater antral than corpus mucosal blood flow was consistently demonstrated. Corpus but not antral mucosal blood flow showed a significant dose-related increase with intravenous pentagastrin. Vasopressin induced a significant dose-related decrease in both antral and corpus mucosal blood flow. Simultaneous measurement of basal corpus mucosal blood flow by hydrogen gas clearance and of gastric mucosal blood flow by aminopyrine clearance gave similar values, but the changes with intravenous pentagastrin or vasopressin measured by aminopyrine clearance were of a much higher order of magnitude. Hydrogen gas clearance, however, reflected changes in left gastric artery blood flow much more closely than did aminopyrine clearance. Therefore, we conclude that the hydrogen gas clearance technique as described is valid for measuring regional gastric mucosal blood flow. It is safe and has potential application in human studies.     

Exogenous serotonin and gastric mucosal blood flow in conscious dogs

The effects of serotonin on pentagastrin- and bethanechol-stimulated gastric mucosal blood flow (GMBF) and acid secretion were evaluated. Conscious gastric fistula dogs were used, with neutral red clearance as the method to estimate the mucosal blood flow. Serotonin inhibited the acid secretion, with a counteracting effect of propranolol and methysergide. Serotonin inhibited the pentagastrin- and bethanechol-stimulated GMBF after 15 min of infusion. The ratio between GMBF and acid secretion was increased during serotonin infusion, which suggests primary and independent changes in both variables. Propranolol and methysergide counteracted the serotonin inhibition of the GMBF. It may be concluded from this study that the acid-inhibitory effect of serotonin is not mediated by changes in the GMBF. The actions of serotonin on acid secretion and GMBF are mediated by specific receptors.     

Endoscopic measurement of gastric corpus mucosal blood flow in conscious dogs

This study reports the feasibility of applying the hydrogen gas clearance technique with 3% hydrogen in air and platinum contact electrode to measure corpus mucosal blood flow in conscious dogs. Three percent hydrogen in air is safe and does not produce hypoxia during inhalation. A specially prepared, six-inch polyvinyl chloride pipe was used as a bite-block. The platinum contact electrode, attached to (but not within) a soft rubber suction cup, was passed into the stomach with the aid of a gastroscope. Because of gastric contractions, low, continuous suction was required to maintain the electrode in contact with the corpus mucosa. Stable baseline corpus mucosal blood flow measurements were obtained on control and experimental days in five of 10 dogs. In these five dogs during 2 g/kg/hr pentagastrin infusion, which induced submaximal acid secretion, corpus mucosal blood flow and gastric acid output were increased significantly (P<0.05) by 26±4% and 238±79%, respectively. These increases were similar to those previously observed in anesthetized rats, cats, rabbits, and dogs. In an anesthetized rat study, the measurement of corpus mucosal blood flow was found to be unaffected by the low continuous suction. Since the use of 3% hydrogen in air is safe, the technique deserves to be further evaluated in human studies.     

Endoscopic measurements of canine colonic mucosal blood flow using hydrogen gas clearance

We have examined the feasibility of hydrogen (H2) clearance for endoscopic measurements of colonic mucosal blood flow in anesthetized dogs. In 6 animals, measurements of H2 clearance did not differ significantly in different regions of the sigmoid colon and they were highly reproducible (p less than 0.001) on different days. In a total of 12 dogs, measurements of H2 clearance correlated closely with those obtained using radioactive microspheres under resting conditions and, in 4 dogs, during infusion of vasopressin (slope = 0.94, p less than 0.001). In 8 dogs, ligation of the major arteries supplying the sigmoid colon resulted in an acute 60% decrease in sigmoid mucosal blood flow (p less than 0.001); however, in 5 animals that survived the procedure, mucosal blood flow returned nearly to control levels as early as 3 days after operation. Endoscopic H2 clearance thus appears to be feasible for measuring mucosal blood flow in the colon. Serial measurements of H2 clearance may prove useful in characterizing the role of mucosal blood flow in the pathogenesis of various forms of human colonic disease.     

Somatostatin increases the ratio between gastric mucosal blood flow and gastric acid and pepsin secretion in dogs

The effects of somatostatin on gastric mucosal blood flow (GMBF), acid secretion, and pepsin secretion were evaluated. Conscious gastric fistula dogs were used, with neutral red clearance as the method for estimating the mucosal blood flow. Somatostatin inhibited the pentagastrin- and bethanechol-stimulated gastric acid and pepsin secretion and resulted in an absolute decrease in mucosal blood flow. The ratios between GMBF and secretion (acid and pepsin) were increased during somatostatin infusion, which suggests a relative increase in mucosal blood flow and independent inhibition of gastric secretion. It may be concluded from this study that the acid- and pepsin-inhibitory effects of somatostatin are not mediated by changes in the GMBF.     

Effect of dopamine on pentagastrin-stimulated gastric acid secretion and mucosal blood flow in dogs with gastric fistula

The purpose of this study was to elucidate the effect of intravenously administered dopamine on dopamine receptors and adrenergic receptors in terms of its effect on gastric acid secretion, the kinetic mechanism, blood flow, and antral motility. Dopamine was used alone and in conjunction with selective blockade of alpha-, beta-, and dopaminergic receptors. A significant inhibition of gastric acid secretion was found with the highest dose of dopamine used (40 micrograms/kg/min). The kinetic study showed characteristics of a non-competitive type. The anti-secretory effect dopamine was significantly blocked by non-selective beta-blockade or by selective beta-blockade but not by alpha- or dopaminergic receptor blockade. This suggests that the inhibitory effect of dopamine on gastric secretion is mediated by beta-receptors. There was no significant effect on gastric mucosal blood flow, but the ratio between blood flow and acid secretion was significantly elevated during dopamine infusion, indicating that the acid inhibition was not secondary to changes in blood flow. It is concluded that the dopamine inhibition of acid secretion is mediated by beta 1-receptors, unlike the effect on antral gastric motility, which is mediated by dopamine receptors.     

胃粘膜血流变化的影响因素

维持和增加胃粘膜血流(gastric mucosal blood flow,GMBF)被认为是增加胃粘膜保护机制的关键因素,对GMBF影响因素的研究为临床防治消化性溃疡、慢性胃炎、胃癌等疾病提供了依据。影响GMBF的因素很多,现综述如下。 1 神经因素中枢神经系统中主要是下丘脑和延髓对GMBF有影响,下丘脑对GMBF的影响可能是由去甲肾上腺素介导的。交感神经节后纤维分布于胃血管壁周围,主要通过释放去甲肾上腺素使胃粘膜血管收缩,使GMBF减少。α受体拮抗剂能减少电刺激交感神经或动脉灌注儿茶酚胺所引起的GMBF减少,电刺激迷走神经,其节前纤维主要释放乙酰胆碱增加,致     

Role of gastric mucosal blood flow in cytoprotection

We compared the effects of graded doses of misoprostol (50-200 mg), omeprazole (12.5-50 mg), cimetidine (6.25-50 mg) and sucralfate (50-200 mg) on gastric mucosal blood flow as measured by laser Doppler flowmetry and gastric mucosal injury induced by ethanol. The results demonstrated that sucralfate, misoprostol and omeprazole, but not cimetidine, increased gastric mucosal blood flow in a dose-dependent manner and protected the mucosa against ethanol damage. The peak and summation blood flow were significantly greater with sucralfate than with misoprostol and omeprazole, but the degree of mucosal protection was similar. These results indicate that the increase in gastric mucosal blood flow, an action which is common to the three drugs, plays an important role in gastric mucosal protection, but other factors are also involved.     

电针对狗胃粘膜血流量的影响及与血浆胃肠激素的关系

目的观察电针对狗胃粘膜血流量、血浆胃肠激素水平的影响及两者间变化的关系，以探讨电针对胃粘膜保护作用机制．方法将２０条狗随机分为４组，即：空白对照组，非经非穴组，上巨虚组，足三里组（每组５条）．采用激光多普勒血流仪测定狗胃粘膜血流量．用ＲＩＡ法同步测定血浆促胃液素（ＧＴ），生长抑素（ＳＳ），内皮素（ＥＴ）含量，用生化法测定一氧化氮（ＮＯ）含量，分析其电针前后的变化，并观察变化规律．结果电针后足三里组胃粘膜血流量显著升高（Ｖ，４６±０７→６９±１１，Ｐ＜００１），其他组无显著变化．电针后足三里组血浆ＧＴ，ＮＯ含量也显著升高（ｎｇ／Ｌ，６５±１２→１０２±２１，Ｐ＜００１），而ＳＳ，ＥＴ含量显著下降（ｎｇ／Ｌ，２３１±１８→１９４±２７，Ｐ＜００５；９７８±１７９→５５８±１５３，Ｐ＜００５）；上巨虚组ＮＯ含量显著上升，ＥＴ显著下降（Ｐ＜００５），但足三里组的变化趋势更明显．空白对照组，非经非穴组则无显著变化．结论电针足三里穴可使狗胃粘膜血流量增加，与通过影响胃粘膜血流量的某些活性物质的含量改变有关，并具有一定的穴位特异性．     

Autoregulation of canine gastric mucosal blood flow

Although autoregulation of total blood flow has been demonstrated in the stomach, autoregulation of gastric mucosal blood flow has not been investigated due to the limitations of previously available mucosal blood flow measuring techniques. We recently evaluated laser-Doppler velocimetry for use in the stomach and found it to yield continuous, superficial measurements of either mucosal or muscularis blood flow. In the present study, simultaneous measurements of total, mucosal, and muscularis blood flows and arteriovenous oxygen difference were made during step decreases in perfusion pressure in chambered segments of resting canine stomach. As perfusion pressure was decreased from 180 to 35 mmHg, oxygen consumption remained relatively constant at 1.5 ml/min X 100 g and only became blood flow-dependent when perfusion pressure was set below 90 mmHg and total blood flow fell below 35 ml/min X 100 g. Oxygen consumption was maintained partly by increased oxygen extraction; however, there was also a progressive increase in the tendency for total blood flow autoregulation after each drop in perfusion pressure. Mucosal blood flow was also well autoregulated over the physiologic range of perfusion pressure and remained relatively constant during the plateau portion of the oxygen consumption curve. Our results indicate that in the resting stomach, oxygen consumption is maintained by changes in oxygen extraction in conjunction with autoregulation of mucosal and total blood flow.     

Gastric blood flow and the gastric mucosal barrier

The basic mechanisms underlying cytoprotection of gastrointestinal mucosae against damage are not understood. One hypothesis is that the initial and primary system affected by a cytoprotective agent is the local circulation of the tissue that is being protected. According to this circulatory hypothesis, a cytoprotective prostaglandin would increase gastric mucosal blood flow, thereby ameliorating the effect of topical damaging agents, such as ethanol, aspirin or bile salts. Four questions need to be considered in order to evaluate the circulatory hypothesis: (i) What degree of ischemia is necessary to break the gastric mucosal barrier? (ii) Is peptic ulcer disease due to local ischemia of the mucosa? (iii) Do mucosal damaging agents invariably reduce gastric blood flow? (iv) Do cytoprotective agents invariably increase gastric blood flow? A survey of available literature concerning blood flow and damage to the gastric mucosa suggests that: (i) severe degrees of gastric ischemia are necessary to impair vital functions of the epithelial cells of the stomach; (ii) peptic ulcer disease is not a manifestation of isolated gastric ischemia; (iii) mucosal damaging agents do not invariably reduce gastric blood flow; and (iv) cytoprotective drugs do not invariably increase gastric mucosal blood flow. The weight of available evidence does not support the circulatory hypothesis about the mechanism of cytoprotection.     

Dopaminergic control of gastric mucosal blood flow in humans

We studied the dopaminergic regulation of the gastric mucosal blood flow (GMBF) measured with an endoscopic laser Doppler flowmetry in 27 healthy volunteers. They were randomly assigned to receive an endoscopic gastric submucosal injection (0.5 ml) of physiological saline (control group,N=10), 50 g of dopamine (DA) hydrochloride (N=8), and 500 g of a DA antagonist, metoclopramide (MCP) (N=9). The drugs were dissolved in the same saline volume (0.5 ml) as used in control group and were injected via the mucosal area where the baseline GMBF was measured and the postdose GMBF was monitored until 5 min postdose. There was no significant difference in the mean (±sem) baseline laser Doppler signals among the control, DA, and MCP groups (92.6±9.3, 81.8±9.0 and 96.9±13.3 mV, respectively). In the control group, no significant postdose changes in the laser Doppler signals occurred until 5 min postinjection. In contrast, the DA group exhibited a significant (P<0.05 or 0.01) increase in the laser Doppler signals at 2, 3, 4, and 5 min postdose (118.9±18.8, 128.5±16.9, 146.6±18.6, and 131.2±14.2 mV, respectively), whereas the MCP group exhibited a significant (P<0.05 or 0.01) decrease in the signals at 4 and 5 min postdose (67.9±5.3 and 64.8±3.5 mV, respectively), as compared not only with the respective baseline values but also with those obtained from other two groups at the corresponding postinjection periods. There was a significant (P<0.001) and negative correlation (r=–0.94) between the predose laser Doppler signals and their corresponding postinjection changes in the MCP group. Our data suggest that a tonic, dopaminergic stimulation may play a role in maintaining the GMBF in humansin vivo.This study was supported by grant-in-aids from the Ministry of Human Health and Welfare, Tokyo, and from the Pathophysiology Research Institute, Tokyo.     

Local control of canine gastric mucosal blood flow

The hemodynamic responses to venous pressure elevation and the effect of metabolic stimulation on reactive hyperemia and autoregulation were assessed in chambered segments of the canine gastric corpus perfused by a pressurized reservoir. Arteriovenous oxygen difference, mucosal pH, and total, mucosal, and muscularis blood flow were monitored continuously. Pentagastrin increased acid secretion, oxygen consumption, and both total and mucosal blood flow. Before and after pentagastrin, the magnitude of reactive hyperemia was correlated with the occlusion duration. During stepwise reductions in perfusion pressure, oxygen consumption was relatively constant and blood flow-independent over most of the pressure range. Mucosal blood flow was well maintained except at the lowest perfusion pressure. Pentagastrin did not enhance autoregulation in the mucosa or muscularis, but did enhance the autoregulation of total blood flow. A myogenic vasoconstriction occurred during 20-mmHg venous pressure elevations. Our results indicate that both metabolic and myogenic mechanisms regulate the gastric mucosal circulation.