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Biomedical subjects

G Flemström

Publications and source records attributed to G Flemström.

At least 37 records · Page 2Linked to original sources
PubMed1993

Proximal duodenal enterocyte transport: evidence for Na(+)-H+ and Cl(-)-HCO3- exchange and NaHCO3 cotransport.

The duodenum, in contrast to the jejunum, actively secretes HCO3- at a high rate, a process that protects the mucosa from acid/peptic injury. Our purpose was to define the mechanisms involved in HCO3- transport by studying the acid-base transport processes in isolated duodenal enterocytes. Individual rat duodenocytes, isolated by a combination of Ca2+ chelation and collagenase, attached to a collagen matrix were loaded with the pH-sensitive fluoroprobe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM), and intracellular pH was monitored by microfluorospectrophotometry. To identify Na(+)-H+ transport, cells in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid 1) were pulsed with NH4Cl (40 mM) in the absence and presence of amiloride and 2) were removed of Na+. To examine Cl(-)-HCO3- exchange, Cl- was removed from Ringer-HCO3- superfusate in the presence and absence of dihydro-4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (H2DIDS). The NaHCO3 cotransporter was studied by addition and subtraction of Na+ to amiloride-treated and Cl(-)-depleted enterocytes perfused with Na(+)- and Cl(-)-free Ringer-HCO3- buffer with and without H2DIDS. Mammalian duodenocytes contain at least three acid-base transporters: an amiloride-sensitive Na(+)-H+ exchanger that extrudes acid, a DIDS-sensitive Cl(-)-HCO3- exchanger that extrudes base, and a NaHCO3 cotransporter, also DIDS sensitive, that functions as a base loader. These acid-base transporters likely play a key role in duodenal mucosal HCO3- secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Gastroduodenal mucosal protection.

The barrier that protects the undamaged gastroduodenal mucosa from autodigestion by gastric juice is a dynamic multicomponent system. The major elements of this barrier are the adherent mucus gel layer, which is percolated by the HCO3- secretion from the underlying epithelial cells; the epithelial layer itself, which provides a permeability barrier and can rapidly repair superficial damage by a process of cell migration referred to as reepithelization or restitution; and a specially adapted vasculature, which provides a supply of HCO3- for transcellular transport and/or diffusion into the mucus layer. Passive diffusion of intestinal HCO3- into the lumen is particularly important when there is superficial damage resulting in increased leakiness of the mucosal epithelium. The process of reepithelization occurs by the migration of performed cells from gastric pits or duodenal crypts. This process is quite distinct from the wound healing and associated inflammatory response that accompany more severe injury or chronic damage. The adherent mucus gel acts as a physical barrier against luminal pepsin and provides a stable unstirred layer that supports surface neutralization of acid by mucosal HCO3-. Surface neutralization by mucosal HCO3- provides a major mechanism of protection against acid in the proximal duodenum. In the stomach, where luminal acidity can fall to around pH 1, other mechanisms of protection must exist, since the surface pH gradient is reported to collapse when luminal H+ exceeds approximately 10 mM. This collapse of the surface pH gradients may reflect, at least in part, that such studies have been mostly performed on non-acid-secreting mucosa where the supply of HCO3- to the interstitium from the parietal cells will be reduced. However, because the gastric mucosa can withstand prolonged exposure to acid without apparent damage, this implies an intrinsic resistance of the epithelial apical surface. This is amply illustrated within the gastric glands that do not secrete mucus and HCO3- yet are exposed to undiluted pepsin and an isotonic solution of HCl. Bicarbonate and mucus secretions together with mucosal blood flow are under paracrine, endocrine, and neural control. The rate of reepithelialization will depend on local chemotactic factors, adhesion mechanisms, and the creation of an acid/pepsin/irritant-free environment under a protective gelatinous or mucoid cap. If optimal conditions are met, then the rate of reepithelialization appears to depend primarily on the intrinsic properties of the migrating cells themselves rather than control by exogenous mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

Acids↗
PubMed1991

Effects of diazepam and Ro 15-1788 on duodenal bicarbonate secretion in the rat.

Bicarbonate secretion by duodenal mucosa just distal to the Brunner's glands area and devoid of pancreatic secretions was titrated in situ in anesthetized rats. Intravenous injection of diazepam (0.1 and 0.5 mg/kg) significantly increased the secretion; this stimulation was abolished by proximal bilateral vagotomy. Ro 15-1788, a benzodiazepine antagonist that also has well-known intrinsic activity, caused similar stimulation of the secretion when administered IV (0.01 and 0.1 mg/kg). Intracerebroventricular infusion of Ro 15-1788 (10 micrograms/h) resulted in a greater increase in secretion; again, this stimulation was prevented by vagotomy. Adrenoceptor blockade by phentolamine increased basal alkaline secretion but did not affect the stimulation by diazepam. The tricyclic antidepressant trimipramine (2.5 mg/kg IV) did not affect the duodenal bicarbonate secretion. For comparison, effects of diazepam and Ro 15-1788 (10(-6)-10(-4) mol/L) were also tested in isolated bullfrog duodenal mucosa. Neither drug effected the alkaline secretion in vitro. The combined results strongly suggest that benzodiazepines, as previously shown for certain brain peptides, influence the central nervous control of duodenal mucosal alkaline secretion and that their stimulation of secretion is vagally mediated. This action benzodiazepines might be used in modulating mucosal protection against acid.

Animals↗
PubMed1990

Effects of cigarette smoke and nicotine on duodenal bicarbonate secretion in the rabbit and the rat.

The effects of short-time exposure to cigarette smoke on duodenal mucosal bicarbonate secretion were studied in anesthetized rabbits and rats. The bicarbonate secretion was measured by continuous titration of recirculating luminal perfusate. In artificially ventilated rabbits, intermittent exposure to cigarette smoke during two 10-min periods caused a marked (approximately 40%) decrease (p less than 0.01) in duodenal bicarbonate secretion. After the exposures, secretion gradually recovered and had returned to the pre-exposure rate after 50 min. The decrease in secretion was associated with decreases in heart rate (approximately 15%) and blood pressure (approximately 30%) that, however, were of shorter duration. Neither reduced amounts of smoke (1/6 or 1/3) nor nicotine (25-1,000 micrograms/kg, intravenously) had any major effect on the bicarbonate secretion. In the spontaneously breathing rat, smoke was administered for 1-2 breaths every 30 s during a 5-min period. This exposure resulted in a significant (p less than 0.05) decrease in bicarbonate secretion and some increase in the blood pressure. Exposure to smoke had no effect on the secretion in rats with both splanchnic nerves cut, suggesting neural sympathetic mediation of the smoke-induced inhibition.

Animals↗
PubMed1990

Microscopy of acid transport at the gastric surface in vivo.

In vivo microscopy of the gastric surface, and pH-sensitive dyes, were used to study the movement of acid formed in the gastric crypts across the mucus layer adherent to the gastric surface and into the lumen. Rats were anaesthetized and the stomach gently exteriorized. When the pH-sensitive dye Congo red was applied luminally to stain the gel, predominantly red spots (pH greater than 5) and occasional blue spots (pH less than 3), located above the outlets of the crypts, were observed in spontaneously-secreting mucosae. Maximal stimulation of acid secretion (pentagastrin, 40 micrograms kg-1 h-1) resulted in the appearance only of blue spots, but the pH in the mucus gel between the crypts remained more alkaline, as indicated by pink staining. The fluorescence dye acridine orange was injected intravenously to an estimated blood concentration of 10(-5)M in another type of experiment. This dye is concentrated and secreted by the parietal cells. Pronounced fluorescence was observed within spots of the gastric surface corresponding to the outlets of the gastric crypts, but no fluorescence was detected outside these areas. The results obtained with both dyes strongly suggest that acid (and pepsin) is transported across the mucus gel only at restricted sites.

Acridine Orange↗
PubMed1990

Duodenal alkaline secretion in rabbits: influence of artificial ventilation.

The effect of artificial ventilation on duodenal alkaline secretion and blood flow was studied in sodium pentobarbital-anaesthetized rabbits. A duodenal segment (approximately 3 cm) was cannulated in situ and continuously perfused with isotonic saline, and the bicarbonate secretion was titrated by pH-stat. Compared with the spontaneous breathing state, artificial ventilation improved the respiratory status of the animal, increasing Po2 and decreasing both Pco2 and plasma bicarbonate. Duodenal blood flow as measured with laser-Doppler flowmetry was not altered but the alkaline secretion was reduced. Pretreatment with the alpha 2-adrenoceptor antagonist yohimbine (0.5 mg kg-1 i.v., followed by 0.5 mg kg-1 h-1 i.v.) or the ganglionic blocker hexamethonium (10 mg kg-1 i.v.) did not affect the decline in duodenal alkaline secretion in response to artificial ventilation. Nor did these pretreatments affect the changes in plasma bicarbonate and Pco2 or significantly alter the blood flow. Increasing Pco2 in the respirator air increased the plasma Pco2 and bicarbonate concentration as well as the duodenal bicarbonate secretion. Pretreatment with the carbonic anhydrase inhibitor acetazolamide (80 mg kg-1 i.v.) reduced the bicarbonate secretion, and artificial ventilation induced a further reduction. Increasing Pco2 in the respirator in the animals pretreated with acetazolamide did not affect the bicarbonate secretion. Duodenal alkaline secretion was thus always reduced on artificial ventilation. The mechanism for this reduction does not seem to involve the sympathetic nervous system or the blood flow, but appears to be the consequence of alterations in the plasma concentration of bicarbonate and the plasma Pco2.

Acetazolamide↗
PubMed1989

Stimulation of duodenal mucosal bicarbonate secretion in the rat by brain peptides.

Bicarbonate secretion by duodenal mucosa free of Brunner's glands was titrated in situ in anesthetized rats. Intracerebroventricular infusion of thyrotropin-releasing hormone (0.01-1 microgram/h), bombesin, gastrin-releasing peptide, or corticotropin-releasing factor increased the bicarbonate secretion and the transmucosal electrical potential difference. The increase in secretion in response to thyrotropin-releasing hormone and bombesin was prevented by cervical vagotomy. Intravenous administration of the alpha-adrenoceptor antagonist phentolamine increased the magnitude and duration of the response, suggesting that these two peptides in addition to eliciting vagal stimulation of the duodenal secretion, by sympathetic activation, inhibit the secretion. Intravenous thyrotropin-releasing hormone (3.6 mg/kg) did not affect the secretion, further indicating that effects were elicited within the central nervous system. Intracerebroventricular infusion of cholecystokinin-octapeptide or beta-endorphin had no effect on duodenal bicarbonate secretion or on the potential difference. The latter peptide was a potent stimulant of the secretion when injected intravenously and probably acts at a peripheral site. The central nervous control of duodenal mucosal bicarbonate secretion is thus influenced by some specific peptides that are known to occur in brain tissue, and duodenal protection against acid might be modulated by agents affecting this control.

Animals↗
PubMed1989

Carbonic anhydrase in the normal rat stomach and duodenum and after treatment with omeprazole and ranitidine.

A low pH in the lumen of the stomach and duodenum stimulates gastroduodenal mucosal secretion of bicarbonate, particularly in the duodenum. Long-term deprivation of this acid stimulus might affect the ability of the mucosa to secrete bicarbonate, with a consequent decrease in mucosal protection against the acid. This could occur by 'down-regulation' of carbonic anhydrase (CA) activity in the bicarbonate-transporting cells. Levels of CA activity and amounts of CA isoenzymes in rat gastric and duodenal mucosa were determined by biochemical assay and histochemical and immunohistochemical staining. Control animals and animals pre-treated for 4-6 weeks with the histamine H2-receptor antagonist ranitidine (600 mg kg-1 daily) or the H+,K+-ATPase inhibitor omeprazole (28 mg kg-1 daily) were examined. Both drugs are potent inhibitors of gastric secretion of acid. Both gastric and duodenal mucosal total CA activity and the distribution of isoenzymes were very similar in control animals and animals treated with these drugs. In the stomach, CA II was found in the surface epithelial and parietal cells. In the duodenum both CA I and CA II were observed. The staining for CA I was restricted to a small number of villus cells which looked like ordinary duodenal enterocytes. CA II in the duodenum was found in all villus cells, except the goblet cells. The staining decreased gradually from the top to the bottom of the villi and was absent in the crypts. Duodenal bicarbonate secretion is dependent on mucosal CA activity, and the distribution of CA II thus suggests that this alkaline secretion is of villous rather than cryptal origin.

Animals↗
PubMed1989

Alkaline secretion by Necturus proximal duodenal mucosa.

Proximal duodenum from the amphibian Necturus was stripped of muscle layers and the mucosa was mounted as a tube for studies of alkali transport or as a flat sheet for intracellular impalement by voltage-sensitive glass micro-electrodes. The mucosa alkalinized the unbuffered luminal perfusate at a high rate (3.4 muequiv. cm-1 h-1) and developed a transepithelial electric potential difference of 5.7 mV (lumen negative). Transport was inhibited by 2,4-dinitrophenol (10(-4) M) and by furosemide (10(-3) M) and SITS (10(-3) M) on the seros but not on the mucosal side, indicating dependence on tissue metabolism and on serosal membrane Cl-/HCO3- exchange. Prostaglandin E2 (10(-7)-10(-5) M) and dibutyryl cyclic AMP (10(-6)-10(-4) M) had no effects on the secretion or transepithelial electrical potential difference. removal of serosal HCO3- decreased luminal alkalinization by 75%, indicating a contribution by passive migration of HCO3- and/or a dependence of transcellular transport on the nutrient supply of this ion. Administration of HCO3- (17.8 mM) to the luminal perfusate affected neither the transepithelial nor transmembrane electrical potential differences nor the resistance ratio. It is thus unlikely that the luminal membrane possesses any major HCO3- conductance.

2,4-Dinitrophenol↗
PubMed1989

Duodenal mucosal bicarbonate secretion in man. Stimulation by acid and inhibition by the alpha 2-adrenoceptor agonist clonidine.

A multi-channel small diameter tube was used to study the secretion of bicarbonate by 3 cm long segments of the proximal duodenum isolated between balloons. The tube had an outer diameter of 5.3 mm and two central and four smaller, peripheral channels. Measurements of infused phenol red, 14C-PEG and vitamin B12 and of trypsin activity were performed to rule out contamination of the perfusate by gastric and pancreatic secretions. Basal secretion of bicarbonate by the duodenal mucosa in healthy subjects varied between 135 and 220 mumol/cm of intestine per hour. Perfusion of the lumen with acid (100 mM HCl for five minutes) increased the secretion to greater than 400 mumol/cm/h and the alpha 2-adrenoreceptor agonist clonidine (150 micrograms iv) decreased the HCO3- secretion by 70 mumol/cm/h. Clonidine simultaneously reduced the mean arterial blood pressure and plasma noradrenaline concentration, but did not affect the plasma glucose or adrenaline concentration. Duodenal bicarbonate secretion is important in the protection of this mucosa against acid discharged from the stomach. Increased sympathetic activity may, by inhibiting the bicarbonate secretion, decrease the protection in proximal duodenum in man and facilitate ulceration.

Adult↗
PubMed1988

Effects of leukotriene D4, the antagonist L-649-923, and arachidonic acid on duodenal bicarbonate secretion in the rat in vivo.

Prostaglandins of the E type stimulate bicarbonate secretion by the duodenal mucosa and inhibit gastric acid secretion, effects that have been related to their anti-ulcer activity. Leukotrienes constitute a more recently discovered branch of the arachidonic acid cascade, and C4 and D4 have been suggested to be ulcerogenic in the stomach. We have studied the effects of luminal administration of leukotriene D4 and the leukotriene C4/D4 antagonist L-649-923 on duodenal mucosal alkaline secretion in the anaesthetized rat. Leukotriene D4 (10(-8)-10(-6) M) had no significant effects, but the antagonist dose-dependently increased the bicarbonate secretion and also transiently increased the transmucosal electric potential difference. The precursor arachidonic acid (10(-7)-10(-6) M) caused a small increase in secretion. The increase in bicarbonate secretion in response to 10(-3) M of the antagonist was of about the same magnitude as that observed with 10(-5) of prostaglandin E2, and it was abolished by pretreatment with the cyclooxygenase inhibitor indomethacin. The gastroduodenal protective effects of L-649-923 in vivo may reflect an increase in mucosal prostaglandin production rather than leukotriene antagonism.

Animals↗
PubMed1987

Bicarbonate secretion by the rabbit duodenum in vivo: effects of prostaglandins, vagal stimulation and some drugs.

Duodenal HCO-3 secretion in anaesthetized rabbits was measured by continuous titration of the recirculating luminal perfusate at pH 7.4. The segment under study started 3-4 cm distal to the pylorus and was devoid of pancreatic and biliary HCO-3 secretion. On histological examination the submucosa was seen to contain Brunner's glands, mainly of a mucous type. Duodenum in rabbit secreted HCO3- at a considerably higher basal rate (100-125 mu equiv h-1 cm-1 of intestine) than has previously been found in the rat, cat or dog. The cyclo-oxygenase inhibitor indomethacin (20 mg kg-1) reduced the secretion by 30%, while prostaglandin E2 (5-80 microM, luminal) caused a dose-dependent increase. Prostaglandins thus seem to be important in regulation of duodenal HCO3- secretion in the rabbit and may play a role in duodenal protection against acid. Carbachol (1 and 10 micrograms kg-1) and atropine (0.5 and 1 mg kg-1) had no effects whereas hexamethonium (10 mg kg-1) caused a persistent decrease (25%) in secretion. Effects of electrical stimulation of the vagal nerves or injection of the alpha 2-adrenergic agonist clonidine markedly depended on the agent used for anaesthesia. In urethane-anaesthetized animals, clonidine (0.75-75 micrograms kg-1) tended to increase the secretion whereas with nembutal, clonidine (5-150 micrograms kg-1) decreased it significantly. Electrical stimulation of the cervical vagal nerves decreased the HCO3- secretion in urethane-anaesthetized animals but had no significant effect during nembutal anaesthesia. The responses in the nembutal-anaesthetized rabbit are similar to those previously observed in the cat, rat or dog.

Adrenergic alpha-Agonists↗
PubMed1987

Vagal influence on gastroduodenal HCO3- secretion in the cat in vivo.

Gastric and duodenal secretions of HCO3- were studied simultaneously in chloralose-anesthetized cats. The adrenals were ligated, and the cervical vagal as well as the abdominal splanchnic nerves were cut. Gastric secretions of H+ and HCO3- were calculated from measurements of the pH and PCO2 in the luminal perfusate. A duodenal segment devoid of Brunner's glands and pancreaticobilary secretions was cannulated in situ and the alkaline secretion determined by continuous titration at luminal pH 7.4. Electrical stimulation in the distal direction for 10-15 min of the cervical vagal nerves resulted in a 6- to 10-fold increase in gastric H+ and in a 20-60% rise in gastric HCO-3 secretion. Duodenal HCO3- secretion increased by 65-155%. Gastric basal secretions of H+ and HCO3- were not affected by atropine or hexamethonium, but both agents inhibited basal duodenal HCO3- secretion. Hexamethonium abolished and atropine reduced the rise in all secretions in response to vagal nerve stimulation. Thus gastroduodenal mucosal HCO3- secretion is stimulated by vagal mechanisms involving action on nicotinic as well as on muscarinic receptors and possibly also noncholinergic neurotransmission.

Animals↗
PubMed1987

HCO3- secretion in rat duodenum after treatment with omeprazole and ranitidine.

The bicarbonate secretion by the duodenal mucosa, which is stimulated by luminal acid, is very probably important in mucosal protection against the acid. It was of interest to investigate whether long-term deprivation of the mucosa of this acid stimulus affected the alkali secretion. Sprague-Dawley rats were treated for 4-6 weeks with either omeprazole, 14 mg/kg body weight twice daily, or ranitidine, 300 mg/kg twice daily, by means of gastric intubation. The rate of bicarbonate secretion by the duodenal mucosa was determined in situ by continuous titration. Neither the basal secretion nor the increase in secretion in response to stimulation by prostaglandin E2 or luminal acid (pH 2.0 for 5 or 60 min) differed in treated animals from that in controls that had received placebo (p greater than 0.05). Thus, 4-6 weeks of treatment with omeprazole or ranitidine did not reduce duodenal mucosal bicarbonate secretion in the rat, nor did these drugs diminish the ability of this mucosa to respond to prolonged luminal acidification or luminally administered prostaglandin E2.

Animals↗
PubMed1986

Gastroduodenal mucosal secretion of bicarbonate and mucus. Physiologic control and stimulation by prostaglandins.

Bicarbonate secretion by the surface epithelium in the stomach and duodenum maintains a nearly neutral pH in the mucus gel adherent to the surface despite acidities as high as pH 2.0 to 3.0 in the gastric lumen and pH 1.5 to 2.0 in the duodenal lumen. This strongly suggests that the alkaline secretion, together with the mucus gel, provides a first-line of protection in the stomach, and this may be the main mechanism of defense in the duodenum. Bicarbonate secretion is increased by physiologic stimuli such as sham-feeding or the presence of acid in the lumen. Endogenous mucosal production of prostaglandins is important in mediating the response to the latter. Administration of E-type prostaglandins stimulates alkaline secretion in both the stomach and duodenum and also increases the thickness of the mucus layer adherent to the mucosa. The consequent increase in surface alkalinity most likely potentiates the mucosal resistance to luminal acid and pepsin.

16,16-Dimethylprostaglandin E2↗
PubMed1986

beta-Endorphin and enkephalins stimulate duodenal mucosal alkaline secretion in the rat in vivo.

Secretion of HCO3- by duodenum just distal to the Brunner's glands area and devoid of pancreatic HCO3- was titrated in situ in anesthetized rats. Secretion increased significantly after intravenous injection of small amounts (10-20 ng/kg) of the opioid peptides beta-endorphin, methionine-enkephalin, and leucine-enkephalin. Maximum (approximately twofold) stimulation by beta-endorphin and leucine-enkephalin occurred at 20 ng/kg. Morphine (50 micrograms/kg) caused a similar stimulation and the mu-selective opiate antagonist naloxone prevented the stimulation by beta-endorphin and morphine. The synthetic analogue [D-Ala2,D-Leu5]-enkephalin (500 ng/kg), which is an agonist primarily at delta-opiate receptors, had no effect, further suggesting that the stimulation of duodenal HCO3- secretion is mediated by mu-receptors. Naloxone alone did not affect basal HCO3- secretion but reduced the duration of the rise in secretion in response to a 5-min exposure to luminal acid (pH 2.00). Endogenous opioid peptides may thus have a role in the humoral or neural control, or both, of duodenal surface epithelial HCO3- secretion and mucosal protection.

Animals↗
PubMed1986

Effects of alpha-adrenoceptor agonists and antagonists on duodenal surface epithelial HCO3-secretion in the rat in vivo.

In anesthetized rats a 12 mm segment of duodenum, distal to the Brunner's gland area and devoid of pancreatic and bile secretions, was cannulated in situ. Secretion of HCO3- by the surface epithelium was measured by continuous titration at luminal pH 7.40. Noradrenaline at doses of 25-200 micrograms kg-1 h-1 had no (net) effect on duodenal HCO3- secretion while the non-selective alpha-adrenoceptor antagonist phentolamine (20-1000 micrograms kg-1 intravenously) dose-dependently increased secretion. The phentolamine-induced rise in alkaline secretion was partially inhibited by noradrenaline but this effect was transient and was followed by an increase in secretion in spite of continuous infusion of noradrenaline. The alpha 1-adrenoceptor agonist, phenylephrine (100 and 500 micrograms kg-1 h-1) stimulated HCO3- secretion in a dose-dependent manner and this response was abolished by the alpha 1-adrenoceptor antagonist prazosin (0.5 mg kg-1) while the beta-adrenoceptor antagonist propranolol (1 mg kg-1) was without effect. Basal secretion, as well as secretion stimulated by phentolamine and/or phenylephrine, was inhibited by the alpha 2-adrenoceptor agonist clonidine (0.75-15.0 micrograms kg-1). The results thus strongly suggest that alpha 1-adrenoceptor stimulation increases while alpha 2-adrenoceptor stimulation decreases duodenal surface epithelial HCO3(-)-secretion. This might explain the absence of a net effect of noradrenaline.

Adrenergic alpha-Agonists↗