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Biomedical subjects

M Field

Publications and source records attributed to M Field.

At least 109 records · Page 6Linked to original sources
PubMed1981

Physiologic and pharmacologic effects of glucocorticoids on ion transport across rabbit ileal mucosa in vitro.

Physiologic and pharmacologic effects of glucocorticoids on ileal ion transport were examined in vitro. Tissues were obtained from the three following groups of rabbits: (a) normal; (b) glucocorticoid deficient, which were treated with aminoglutethimide (AG), 100 mg twice daily for 3 d, with a resulting marked reduction in urinary cortisol excretion but no decrease in urinary aldosterone; and (c) methylprednisolone-treated (MP), 40 mg daily for 2 d. Transileal NaCl fluxes were measured with radioisotopes under short-circuit conditions, and the net HCO(3) flux was assumed equal to that portion of the short-circuit current (I(sc)) not accounted for by Na and Cl. In NaCl Ringer's solution containing 25 mM HCO(3) (pH 7.4), normals absorbed both Na and Cl and secreted HCO(3); the I(sc) was greater in both AG and MP groups than in normals; in the AG group, no Na was absorbed, and Cl as well as HCO(3) was secreted; in the MP group, more Na was absorbed and more HCO(3) secreted than in normals. Addition of glucose to the luminal side caused similar increments in I(sc) in all three groups, suggesting similar rates of Na-coupled glucose absorption. Secretory response was assessed with a maximal secretory simulus (8-Br-cAMP) and also a submaximal, cGMP-related secretory stimulus (Escherichia coli heat-stable enterotoxin). After addition of 8-Br-cAMP, the rates of net Cl secretion were similar in all three groups, suggesting no effect of glucocorticoids on maximal secretory capacity. Because the AG group was already secreting Cl, however, the cAMP-induced change in net Cl flux was least in this group. After addition of heat-stable enterotoxin, there were similar changes in net Cl flux in all three groups. To examine specifically Cl-independent, electrogenic Na transport, we used a 10 mM HCO(3), Cl-free SO(4)-Ringer (ph 7.2) in which net Na absorption was previously shown to be equal to the I(sc). Under these conditions, I(sc) was greatest in the MP group and least in the AG group. In vitro addition of hydrocortisone, 50 mug/ml, to AG tissues had no effect on Cl fluxes or I(sc) over a 3.5-h period. No differences among groups were observed with respect to morphology, electrical resistance, or cGMP concentration. We conclude that (a) the effect of glucocorticoid deficiency is similar to that of a submaximal secretory stimulus in that Na absorption is inhibited and some Cl secretion develops; (b) electrogenic Na absorption is depressed in glucocorticoid deficiency and enhanced in glucocorticoid excess; (c) glucocorticoid excess increases HCO(3) secretion; and (d) glucocorticoid status does not affect maximal secretory capacity.

Aminoglutethimide↗
PubMed1981

Antisecretory effects of indomethacin on rabbit ileal mucosa in vitro.

Prior in vivo studies have shown that indomethacin, which inhibits prostaglandin (PG) synthesis, affects fluid transport in the small bowel, enhancing spontaneous fluid absorption and reducing the amount of fluid that accumulates in response to cholera toxin and other secretory stimuli. To further explore the mechanisms involved, we determined the effects of indomethacin on ion transport, cAMP concentration, and PGE2 production in rabbit ileal mucosa in vitro. Indomethacin (1 mM), when added alone, had no significant effect on short-circuit current (either basal or glucose-stimulated), Cl fluxes, or cAMP concentration. Indomethacin did, however, inhibit the ion transport changes caused by several secretagogues: Effects of theophylline, Ca-ionophore A23187, and arachidonate were reversibly inhibited by at least 65%, whereas effects of dibutyryl cAMP, 16,16-dimethyl PGE2, cholera toxin, and heat-stable Escherichia coli enterotoxin were inhibited by about 30%. Indomethacin also inhibited the theophylline-evoked increase in cAMP concentration. Indomethacin decreased PGE2 production under basal conditions and in the presence of theophylline and A23187, which may partly explain the antisecretory action of the drug. Since arachidonate increased PGE2 release from the mucosa more than 10-fold and indomethacin did not inhibit this effect, indomethacin at high concentration (0.5-1 mM) appears to also inhibit the action of intestinal secretagogues by a prostaglandin-independent mechanism. This study also demonstrates that the antisecretory effect of indomethacin is not simply due to stimulation of an unrelated absorptive process.

Animals↗
PubMed1981

Inhibition of intestinal secretion in rats by colchicine and vinblastine.

The role of microtubules in small intestinal electrolyte secretion was investigated in rats by testing the effects of colchicine and vinblastine, both of which inhibit microtubule assembly. In the intact rat, intraperitoneal injection of colchicine (5 mg/kg) inhibited cholera toxin and prostaglandin-stimulated secretion without inhibiting their effects on adenylate cyclase or cAMP concentration. Pretreatment with colchicine had no effect on fluid transport in the absence of secretory stimuli. When added to rat ileum in vitro, colchicine reduced by 60% the short-circuit current (Isc) response to dibutyryl cAMP added 4 h later, whereas its structural isomer, lumicolchicine, which does not inhibit microtubule assembly, was ineffective. Vinblastine reduced by 55% the Isc response to dibutyryl cAMP and theophylline added 2 h later. Two hour pretreatment with vinblastine also reduced by 40% the Isc response to the cholinergic agonist, carbamylcholine, a Ca-dependent secretory stimulus which does not increase cAMP concentration. In contrast to their antisecretory actions, neither colchicine nor vinblastine inhibited glucose-stimulated active Na absorption. These results suggest a role for microtubules in active electrolyte secretion in the small intestine.

Adenylyl Cyclases↗
PubMed1980

Mode of action of heat-stable Escherichia coli enterotoxin. Tissue and subcellular specificities and role of cyclic GMP.

Some enteric strains of Escherichia coli release a heat-stable enterotoxin which, in contrast to cholera and heat-labile E. coli enterotoxins, stimulates guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2). We have examined the tissue spcificity of its action and the relation of its action to those of the 8-bromo analogues of cyclic GMP and cyclic AMP. Heat-stable enterotoxin stimulated guanylate cyclase activity and increased cyclic GMP concentration throughout the small and large intestine. It increased transepithelial electric potential difference and short-circuit current in the jejunum, ileum and caecum but not in the duodenum or distal colon. This pattern of electrical responses was mimicked by 8-bromo-cyclic GMP. However, 8-bromo-cyclic AMP produced an electrical response in all intestinal segments. The enterotoxin failed to stimulate guanylate cyclase inliver, lung, pancreas or gastric antral mucosa. In the intestines, it stimulated only the particulate and not the soluble form of the enzyme. Preincubation of the toxin with intestinal membranes did not render it capable of stimulating pancreatic guanylate cyclase. Cytosol factors did not enhance the toxin's stimulation of intestinal guanylate cyclase. This study supports the role of cyclic GMP as intracellular mediator for heat-stable enterotoxin and suggests that the toxin affects a membrane-mediated mechanism for guanylate cyclase activation that is unique to the intestines.

Animals↗
PubMed1980

Ion transport across the isolated intestinal mucosa of the winter flounder, Pseudopleuronectes americans: II. effects of cyclic AMP.

Addition of cyclic AMP and theophylline to the intestinal mucosa of the winter flounder, Pseudopleuronectes americanus decreased short-circuit current and net Na and Cl absorption and increased total conductance and the serosa-to-mucosa unidirectional Cl flux (JsmCl). The last two changes were independent of the original rate of NaCl absorption and persisted even when net absorption of Na and Cl had been abolished by ouabain. Voltage clamp experiments revealed that the increment in JsmCl produced by cyclic AMP is PD-insensitive and therefore not due to an increase in the Cl conductance of the paracellular shunt. Cyclic AMP appears, therefore, both to inhibit net NaCl absorption and to increase the Cl permeability and total conductance of the intestinal epithelial cells; its failure to stimulate secretion (in contrast to its action on mammalian intestine) may be related to the absence of crypts in flounder intestinal epithelium.

Animals↗
PubMed1980

Control of guinea pig intestinal electrolyte secretion by a delta-opiate receptor.

The effects of opioids on transepithelial potential difference and short-circuit current across guinea pig ileum stripped of one muscle layer were measured in vitro in Ussing chambers. Opioid peptides such as [DAla2, DLeu5]enkephalin and [DAla2, DMet5]enkephalin, which are primarily agonists at delta-opiate receptors, were able to reduce transepithelial potential difference and short-circuit current at concentrations as low as 1 nM. The narcotic drug etorphine was also very potent in reducing short-circuit current, but fentanyl and morphine, which are primarily agonists at mu-opiate receptors, were almost completely ineffective. Ketocyclazocine was relatively ineffective, and beta-endorphin had intermediate potency. All opioid effects could be reversed by the opiate antagonist naloxone. Somatostatin also reduced short-circuit current, but its effect was not reduced by naloxone. Chloride flux measurements indicated that the effect of etorphine on short-circuit current is associated with an enhancement of active Cl- absorption. The relative effects of opioids in this system suggest that their actions are being mediated by a specific delta-opiate receptor. In contrast, opioid effects on guinea pig intestinal smooth muscle seem to be primarily mediated by a mu-opiate receptor.

Animals↗
PubMed1980

In vitro antisecretory effects of trifluoperazine and other neuroleptics in rabbit and human small intestine.

The inhibitory effects of several neuroleptic agents on intestinal secretion were examined in vitro by measuring short-circuit current, net Cl flux, and cyclic nucleotide concentration, In rabbit ileal mu cosa, trifluoperazine (0.2-0.5 mM) did not significantly alter basal transport rates, but partially inhibited responses to the following secretagogues: theophylline, 8-Br-cAMP, VIP, dimethyl-PGE2 and heat-stable Escherichia coli enterotoxin (a cGMP agonist). Trifluoperazine completely inhibited the response to Ca ionophore A23187. In human small intestinal mucosa, trifluoperazine (0.1-0.5 mM) inhibited electrical responses to VIP and theophylline almost completely. The inhibitory action of trifluoperazine was manifest only on serosal addition. Trifluoperazine did not significantly alter cAMP or cGMP concentrations either under basal conditions or in the presence of secretagogues. It also did not diminish the electrical response to luminally added D-glucose. Three other neuroleptics were tested and found to have antisecretory action; the order of potencies were trifluoperazine greater than chlorpromazine greater than haloperidol greater chlorprothixene. Since all four agents are potent inhibitors of calcium-dependent regulator in bovine brain, this ubiquitous protein may also be the target for their antisecretory action in intestine.

16,16-Dimethylprostaglandin E2↗
PubMed1979

Coupled sodium-chloride influx across brush border of flounder intestine.

Measurements of the unidirectional influxes of Na and Cl from the mucosal solution into the epithelium (Jme) of flounder intestine under short-circuit conditions reveal the presence of a coupled NaCl influx process at the brush border membrane which appears to be essential for the absorption of these ions. JClme and JName were inhibited by replacing Na or Cl, respectively, in the bathing media with non-transported ions which also reduced the short-circuit current (Isc) to near-zero values. Addition of furosemide to the mucosal solution alone inhibited the Isc and reduced JClme and JName under control conditions, but not in the absence of Na or Cl, respectively. The reductions in JClme and JName elicited by ion replacement or furosemide were approximately equal, suggesting that the coupled influx mechanism mediates a one-for-one entry of these ions into the cell from the mucosal solution. Furosemide inhibited Cl absorption by reducing the unidirectional Cl flux from mucosa to serosa, consistent with its inhibition of the influx process. As in other epithelia, coupled NaCl influx is inhibited by cyclic AMP, which accounts for the decrease in Cl absorption elicited by cyclic nucleotides. These results support the notion that transcellular NaCl transport is a neutrla process and that the serosa-negative transepithelial electrical potential difference and preponderance of Cl over Na absorption under short-circuit conditions result from dissimilar permeabilities of the paracellular pathway to Na and Cl.

Animals↗
PubMed1979

Mechanisms of action of cholera and Escherichia coli enterotoxins.

Current information is reviewed on the mechanism of secretion in small intestine, including how it is altered by cyclic 3',5'-adenosine monophosphate and on the structures and properties of cholera and both heat-labile and heat-stable Escherichia coli enterotoxins. Two separate active ion transport processes are altered by cyclic 3',5'-adenosine monophosphate: 1) coupled absorption of NaCl is inhibited in villus cells and 2) active anion secretion is stimulated, probably in crypt cells. Cholera and heat-labile E. coli toxins exert their secretory effect by stimulating intestinal mucosal adenylate cyclase. This stimulation results from the A1 subunit catalyzed transfer of adenosine diphosphate ribose from NAD to a membrane-bound guanosine triphosphatase, thereby inhibiting the enzyme, which normally represses adenylate cyclase. Heat-stable E. coli enterotoxin stimulates intestinal mucosal guanylate cyclase, which appears to be the basis for its enterotoxicity.

Animals↗
PubMed1979

Effects of heat-stable enterotoxin of Yersinia enterocolitica on ion transport and cyclic guanosine 3',5'-monophosphate metabolism in rabbit ileum.

Strains of Yersinia enterocolitica produce a heat-stable enterotoxin which is positive in the suckling mouse bioassay. Partial purification by a procedure previously worked out for heat-stable Escherichia coli enterotoxin yielded a substance which increases particulate guanylate cyclase activity and short-circuit current and inhibits active Cl-absorption in rabbit ileal mucosa. These effects of Y. enterocolitica enterotoxin are similar to those of heat-stable E. coli enterotoxin, suggesting a common mechanism of action.

Animals↗
PubMed1979

Sodium-coupled chloride transport by epithelial tissues.

There is compelling evidence that active Cl absorption by a variety of epithelia, widely distributed throughout the animal kingdom, is the result of an electrically neutral Na-coupled transport process at the luminal membrane and that the energy for transcellular Cl movement is derived from the Na gradient across that barrier. These co-transport processes are found predominantly in "leaky" or "moderately leaky" epithelia and permit these tissues to absorb Na and Cl with high degrees of efficacy. In addition, there is a growing body of evidence that cyclic AMP and Ca-induced electrogenic Cl secretion by a wide variety of epithelia may involve electrically neutral, Na-coupled Cl entry across the contraluminal membrane and that the energy for these secretory processes is derived from the Na-gradient across that barrier. A model for electrogenic Cl secretion that accounts for the available data is presented.

Absorption↗