Biomedical subjects

R L Guerrant

Publications and source records attributed to R L Guerrant.

At least 37 records · Page 2Linked to original sources

PubMed2000

Supernatants from macrophages stimulated with microcystin-LR induce electrogenic intestinal response in rabbit ileum.

Microcystin-LR is a cyclic heptapeptide hepatotoxin produced by the cyanobacterium Microcystis aeruginosa. This microorganism often forms toxic blooms in freshwater lakes and reservoirs for drinking water supply, producing serious disorders in humans and animals. Some have suggested that certain biological activities of microcystin may depend upon the stimulation of immune cells. Therefore, the aims of this research were to examine electrogenic intestinal secretion, in vitro, caused by the supernatants from macrophages stimulated with microcystin-LR, as well as to investigate the presence of interleukin-1beta and tumour necrosis factor-alpha in these supernatants. We found that the supernatants of macrophages stimulated with microcystin-LR (0.1, 0.3 and 1.0 microg/ml) caused electrogenic intestinal effects (change in short circuit currents (delta SCC)=57.6, 50.8 and 73.3, respectively, versus control=19.6 microA.cm(-2)) in a time-dependent way (microcystin-LR (1.0 microg/ml)=63.2, 108.8, 120.4 and 132.3 microA.cm(-2) at time 0, 40, 50 and 60 min., respectively). In addition, the intestinal secretory activity present in these supernatants was blocked (57%) by the prior treatment of macrophages with dexamethasone. We also demonstrated that microcystin-LR (0.1, 0.3 and 1.0 ,microg/ml) is capable of stimulating the synthesis of tumour necrosis factor-alpha (375.4, 369.0 and 610.8 pg/ml, respectively, versus control=165.0 pg/ml) and interleukin-1beta (198.9, 189.3 and 522.1 pg/ml, respectively, versus control=39.7 pg/ml). These findings demonstrate that microcystin-LR induces the release of interleukin-1beta and tumour necrosis factor-alpha by peritoneal macrophages in vitro, and that the supernatants from these macrophages induce electrogenic secretion in rabbit ileal mucosa.

Animals↗

PubMed2000

Transforming growth factor beta1 ameliorates intestinal epithelial barrier disruption by Cryptosporidium parvum in vitro in the absence of mucosal T lymphocytes.

Exposure to oocysts of the protozoan Cryptosporidium parvum causes intestinal epithelial cell dysfunction in vivo and in vitro, but effective means by which mucosal injury might be prevented remain unclear. We examined the ability of transforming growth factor beta1 (TGF-beta1)-a cytokine synthesized and released by cells in the intestine-to preserve the barrier function of human colonic epithelia when challenged with C. parvum oocysts and then studied the mechanisms involved. Epithelial barrier function was monitored electrophysiologically, receptors for TGF-beta1 were localized by confocal microscopy, and TGF-beta1-induced protein kinase C activation was detected intracellularly by translocation of its alpha isozyme. TGF-beta1 alone enhanced intestinal epithelial barrier function, while exposure to C. parvum oocysts (> or =10(5)/monolayer) markedly reduced barrier function to < or =40% of that of the control. When epithelial monolayers were pretreated with TGF-beta1 at 5.0 ng/ml, the barrier-disrupting effect of C. parvum oocysts was almost completely abrogated for 96 h. Further investigation showed that (i) the RI and RII receptors for TGF-beta1 were present on 55 and 65% of human epithelial cell line cells, respectively, over a 1-log-unit range of receptor protein expression, as shown by flow cytometry and confirmed by confocal microscopy; (ii) only basolateral and not apical TGF-beta1 exposure of the polarized epithelial monolayer resulted in a protective effect; and (iii) TGF-beta1 had no direct effect on the organism in reducing its tissue-disruptive effects. In exploring mechanisms to account for the barrier-preserving effects of TGF-beta1 on epithelium, we found that the protein kinase C pathway was activated, as shown by translocation of its 80-kDa alpha isozyme within 30 s of epithelial exposure to TGF-beta1; the permeability of epithelial monolayers to passage of macromolecules was reduced by 42% with TGF-beta1, even in the face of active protozoal infection; and epithelial cell necrosis monitored by lactate dehydrogenase release was decreased by 50% 70 h after oocyst exposure. Changes in epithelial function, initiated through an established set of surface receptors, likely accounts for the remarkable barrier-sparing effect of nanogram-per-milliliter concentrations of TGF-beta1 when human colonic epithelium is exposed to an important human pathogen, C. parvum.

Animals↗

PubMed2000

Lactoferrin and eosinophilic cationic protein in nasal secretions of patients with experimental rhinovirus colds, natural colds, and presumed acute community-acquired bacterial sinusitis.

To distinguish sinusitis from uncomplicated "colds," we examined lactoferrin and eosinophilic cationic protein (ECP) in nasal secretions. Lactoferrin titers were >/=1:400 in 4% of persons with uncomplicated colds and controls but in 79% of persons with sinusitis or purulent sputa. ECP levels were >200 ng/ml in 61% of persons with colds and >3,000 ng/ml in 62% of persons with sinusitis. Nasal lactoferrin helps distinguish sinusitis from colds.

Bacterial Infections↗

PubMed2000

Enteroaggregative Escherichia coli expresses a novel flagellin that causes IL-8 release from intestinal epithelial cells.

Enteroaggregative Escherichia coli (EAEC) is an emerging cause of acute and persistent diarrhea worldwide. EAEC infections are associated with intestinal inflammation and growth impairment in infected children, even in the absence of diarrhea. We previously reported that prototype EAEC strains rapidly induce IL-8 production by Caco-2 intestinal epithelial cells, and that this effect is mediated by a soluble, heat-stable factor released by these bacteria in culture. We herein report the cloning, sequencing, and expression of this biologically active IL-8-releasing factor from EAEC, and its identification as a flagellin that is unique among known expressed proteins. Flagella purified from EAEC 042 and several other EAEC isolates potently release IL-8 from Caco-2 cells; an engineered aflagellar mutant of 042 does not release IL-8. Finally, cloned EAEC flagellin expressed in nonpathogenic E. coli as a polyhistidine-tagged fusion protein maintains its proinflammatory activity. These findings demonstrate a major new means by which EAEC may cause intestinal inflammation, persistent diarrhea, and growth impairment that characterize human infection with these organisms. Furthermore, they open new approaches for diagnosis and vaccine development. This novel pathogenic mechanism of EAEC extends an emerging paradigm of bacterial flagella as inflammatory stimuli.

Amino Acid Sequence↗

PubMed1999

Mechanisms and impact of enteric infections.

The increased recognition of both old and new enteric pathogens and their potential impact requires an improved understanding of pathogenesis and effective interventions. While the overwhelming mortality (> 3 million children per year) due to diarrheal diseases is well-recognized, the potential long-term impacts of enteric infections and early childhood diarrhea morbidity are just beginning to be appreciated. Furthermore, several enteric infections are now being recognized as causes of growth shortfalls with or without diarrhea; i.e., malnutrition may be one of the greatest yet of the "emerging infectious diseases." The increased appreciation of this extended impact calls for further quantification and improved understanding of the deranged physiology. In particular, persistent diarrheal illnesses exhibit common themes of blunted villi, disruption of intestinal barrier function and varying degrees of sub-mucosal inflammation for which lactulose/mannitol permeability and fecal lactoferrin provide respective quantification. Finally, such improved understanding will allow targeted interventions among those most vulnerable, which will enable further documentation of cost effectiveness and the potential for improved human development which is critical to reducing the widening disparity and population overgrowth which increasingly threaten our global security.

Animals↗

PubMed1999

Longitudinal study of Cryptosporidium infection in children in northeastern Brazil.

A prospective, 4-year cohort study of children born in an urban slum in northeastern Brazil was undertaken to elucidate the epidemiology of Cryptosporidium infection in an endemic setting, describe factors associated with Cryptosporidium-associated persistent diarrhea, and clarify the importance of copathogens in symptomatic cryptosporidiosis. A total of 1476 episodes of diarrhea, accounting for 7581 days of illness (5.25 episodes/child-year), were recorded: of these, 102 episodes (6.9%) were persistent. Cryptosporidium oocysts were identified in 7.4% of all stools, and they were found more frequently in children with persistent diarrhea (16.5%) than in those with acute (8.4%) or no (4.0%) diarrhea (P<.001). Low-birth-weight children and those living in densely crowded subdivisions were at greater risk for symptomatic infection. Disease course was highly variable and was not associated with the presence of copathogens. Recurrent Cryptosporidium infection and relapsing diarrhea associated with it were moderately common. In light of these data, the applicability of the current World Health Organization diarrheal definitions to Cryptosporidium-associated diarrheal episodes may need to be reconsidered.

Analysis of Variance↗

PubMed1999

How intestinal bacteria cause disease.

An improved understanding of how intestinal bacteria cause disease has become increasingly important because of the emergence of new enteric pathogens, increasing threats of drug resistance, and a growing awareness of their importance in malnutrition and diarrhea. Reviewed here are the varied ways that intestinal bacteria cause disease, which provide fundamental lessons about microbial pathogenesis as well as cell signaling. Following colonization, enteric pathogens may adhere to or invade the epithelium or may produce secretory exotoxins or cytotoxins. In addition, by direct or indirect effects, they may trigger secondary mediator release of cytokines that attract inflammatory cells, which release further products, such as prostaglandins or platelet-activating factor, which can also trigger secretion. An improved understanding of pathogenesis not only opens new approaches to treatment and control but may also suggest improved simple means of diagnosis and even vaccine development.

Animals↗

PubMed1999

Threats to global health and survival: the growing crises of tropical infectious diseases--our "unfinished agenda".

Health, one of our most unassailable human values, transcends all geographic, political, and cultural boundaries. The health problems of the rapidly growing 80% of the world's population that live in the tropical developing countries of Asia, Africa, and Latin America pose major threats to industrialized as well as developing regions. These threats can be divided into three areas, or three "E"s: (1) emerging, reemerging, and antimicrobial-resistant infections; (2) exploding populations without improved health; and (3) erosion of our humanity or leadership if we ignore the growing health problems of the poor. Our assessment of current trends in global population distribution and resource consumption; DALY calculations, causes, and distribution of global mortality and morbidity; and the misperceptions about and maldistribution of resources for health point to the critical importance of addressing tropical infectious diseases and global health for preservation of democracy and civilization as we know it.

Communicable Diseases↗

PubMed1999

Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum.

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.

Angiotensin II↗

PubMed1999

Measurement of intestinal permeability using mannitol and lactulose in children with diarrheal diseases.

The excretion ratio of lactulose/mannitol in urine has been used to assess the extension of malabsorption and impairment of intestinal permeability. The recovery of lactulose and mannitol in urine was employed to evaluate intestinal permeability in children with and without diarrhea. Lactulose and mannitol probes were measured using high-performance liquid chromatography with pulsed amperometric detection (HPLC-PAD). Two groups of solutions containing 60 microM sugars were prepared. Group I consisted of glucosamine, mannitol, melibiose and lactulose, and group II of inositol, sorbitol, glucose and lactose. In the study of intra-experiment variation, a sample of 50 microl from each group was submitted to 4 successive determinations. The recovered amounts and retention times of each sugar showed a variation <2 and 1%, respectively. The estimated recovery was >97%. In the study of inter-experiment variation, we prepared 4 independent samples from groups I and II at the following concentrations: 1.0, 0.3, 0.1, 0.03 and 0.01 mM. The amounts of the sugars recovered varied by <10%, whereas the retention times showed an average variation <1%. The linear correlation coefficients were >99%. Retention (k'), selectivity (alpha) and efficiency (N) were used to assess the chromatographic conditions. All three parameters were in the normal range. Children with diarrhea presented a greater lactulose/mannitol ratio compared to children without diarrhea.

Child, Preschool↗

PubMed1999

Association of early childhood diarrhea and cryptosporidiosis with impaired physical fitness and cognitive function four-seven years later in a poor urban community in northeast Brazil.

To determine potential, long-term deficits associated with early childhood diarrhea and parasitic infections, we studied the physical fitness (by the Harvard Step Test) and cognitive function (by standardized tests noted below) of 26 children who had complete surveillance for diarrhea in their first 2 years of life and who had continued surveillance until 6-9 years of age in a poor urban community (favela) in Fortaleza in northeast Brazil. Early childhood diarrhea at 0-2 years of age correlated with reduced fitness by the Harvard Step Test at 6-9 years of age (P = 0.03) even after controlling for anthropometric and muscle area effects, anemia, intestinal helminths, Giardia infections, respiratory illnesses, and socioeconomic variables. Early childhood cryptosporidial infections (6 with diarrhea and 3 without diarrhea) were also associated with reduced fitness at 6-9 year of age, even when controlling for current nutritional status. Early diarrhea did not correlate with activity scores (P = 0.697), and early diarrhea remained significantly correlated with fitness scores (P = 0.035) after controlling for activity scores. Early diarrhea burdens also correlated in pilot studies with impaired cognitive function using a McCarthy Draw-A-Design (P = 0.01; P = 0.017 when controlling for early helminth infections), Wechsler Intelligence Scale for Children coding tasks (P = 0.031), and backward digit span tests (P = 0.045). These findings document for the first time a potentially substantial impact of early childhood diarrhea and cryptosporidial infections on subsequent functional status. If confirmed, these findings have major implications for calculations of global disability adjusted life years and for the importance and potential cost effectiveness of targeted interventions for early childhood diarrhea.

Animals↗

PubMed1998

Persistent diarrhea in the returned traveler.

In conclusion, the causes of chronic diarrhea in the returned traveler are protean. Careful evaluation requires an understanding of where the traveler has been, when they were there, the type of diarrheal illness, medications taken, and knowledge of the patients' other medical problems. Protozoa, particularly G. lamblia, C. parvum, and C. cayatenensis, are among the more commonly identified agents. If the patient is immunocompromised, microsporidia and Isospora become more likely, and a prior history of antimicrobial use raises the possibility of C. difficile colitis. Occasionally helminths, which establish intimate contact with the intestinal mucosa, may also cause prolonged diarrhea. If these and other gastrointestinal insults, such as tropical sprue, small bowel overgrowth, lactose intolerance, and processes unrelated to travel are excluded by more invasive studies or clinical history, the patient can be reassured that idiopathic chronic diarrhea is usually self-limited.

Animals↗

PubMed1998

Enteroaggregative Escherichia coli produce intestinal inflammation and growth impairment and cause interleukin-8 release from intestinal epithelial cells.

Enteroaggregative E. coli (EAggEC) are emerging as an important cause of persistent diarrhea, especially in children in the developing world, yet the pathogenesis of EAggEC infection is poorly understood. In an ongoing prospective study of childhood diarrhea in an urban Brazilian slum, EAggEC are the leading cause of persistent diarrhea. Children from this study with EAggEC and persistent diarrhea had significant elevations in fecal lactoferrin, interleukin (IL)-8, and IL-1beta. Moreover, children with EAggEC without diarrhea had elevated fecal lactoferrin and IL-1beta concentrations. The children with EAggEC in their stool had significant growth impairment after their positive culture, regardless of the presence or absence of diarrhea. Finally, 2 EAggEC strains were shown to cause IL-8 release from Caco-2 cells, apparently via a novel heat-stable, high-molecular-weight protein. These findings suggest that EAggEC may contribute to childhood malnutrition, trigger intestinal inflammation in vivo, and induce IL-8 secretion in vitro.

Brazil↗

PubMed1998

Cryptosporidiosis in northeastern Brazilian children: association with increased diarrhea morbidity.

To evaluate the impact of Cryptosporidium infection on diarrheal disease burden and nutrition status, a nested case-control study was done among children who were followed from birth in Fortaleza, Brazil. The diarrhea history and growth records of 43 children with a symptomatic diarrhea episode of cryptosporidiosis (case-children) were compared with those of 43 age-matched controls with no history of cryptosporidiosis. After Cryptosporidium infection, case-children < or = 1 year old experienced an excessive and protracted (nearly 2 years) diarrheal disease burden. Case-children < or = 1 year old with no history of diarrhea prior to their Cryptosporidium infection also experienced a subsequent increased diarrheal disease burden with an associated decline in growth. Control subjects experienced no change in their diarrhea burden over time. This study suggests that an episode of symptomatic Cryptosporidium infection in children < or = 1 year of age is a marker for increased diarrhea morbidity.

Age Factors↗

PubMed1998

Efficacy of a glutamine-based oral rehydration solution on the electrolyte and water absorption in a rabbit model of secretory diarrhea induced by cholera toxin.

BACKGROUND: Glutamine is absorbed in the intestinal tract coupled with sodium and is the principal metabolic substrate for the enterocyte. Therefore, an oral rehydration solution containing this substance might provide an effective oral means of restoring electrolyte losses as well as speeding repair of mucosal damage. The objective of this work was to investigate the use of an oral rehydration solution based on glutamine in vivo in the perfused rabbit ileal loop model of secretory diarrhea induced by choleratoxin. METHODS: Phenolsulfonphthalein (PSP, 50 mg/l) was used as a nonabsorbable marker for calculations of net water and electrolyte transport. Solutions tested included: (a) a glutamine-based oral rehydration solution with 111 mmol/l glutamine, (Gln-ORS); (b) the oral rehydration solution recommended by the World Health Organization; (c) modified Ringer's solution. Choleratoxin (1 microg/ml) was injected into the lumen of the ileal rabbit segments for 30 minutes prior to the initiation of the perfusion. RESULTS: Choleratoxin induced significant secretion of sodium in the control modified Ringer's solution (10.8 +/- 2.95 vs -14.05 +/- 5.95 microEq/g/min, n = 10; p < 0.01) and of water (0.06 +/- 0.03 vs -0.15 +/- 0.06 ml/g/min, n = 10; p < 0.01) with a maximum effect at 60 minutes after initiation of perfusion. World Health Organization oral rehydration solution was able to significantly reduce the intestinal secretion of sodium (control with cholera = -14.34 +/- 2.18 vs oral rehydration solution with cholera = -0.50 +/- 0.48 microEq/g/min, n = 10; p < 0.01) and water (-0.15 +/- 0.02 vs -0.012 +/- 0.005 ml/g/min, n = 10; p < 0.01). For comparison, glutamine-based oral rehydration solution had an even greater effect on sodium and water absorption (glutamine-based oral rehydration solution with choleratoxin = 10.31 +/- 1.21 microEq/g/min, n = 5; p < 0.01 for sodium and 0.08 +/- 0.008 ml water/g/min; n = 5; p < 0.01). Choleratoxin did not change the effect of glutamine-based oral rehydration solution on sodium and water absorption (12.90 +/- -1.09 microEq sodium/g/min, n = 5; and 0.11 +/- 0.01 ml water/g/min; n = 5). In addition glutamine-based oral rehydration solution also induced a greater absorption of potassium and chloride in the intestinal ileal segments treated with choleratoxin compared with World Health Organization glutamine-based oral rehydration solution. CONCLUSIONS: These results demonstrate the superior efficacy of glutamine-based oral rehydration solution in electrolyte and water absorption compared with modified Ringer's control solution or even with World Health Organization-recommended oral rehydration solution.

Animals↗

PubMed1998

Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea.

OBJECTIVE: The utility of tests for fecal neutrophils in the setting of chronic diarrhea has not been established. The purpose of this study was to determine the causes of chronic diarrhea associated with fecal neutrophils. METHODS: One fecal specimen from each of 10 normal subjects, 26 patients with known microscopic colitis, 13 with celiac sprue, eight with Crohn's disease, four with ulcerative colitis, and 103 with chronic diarrhea of unknown origin, as well as 10 fecal specimens from a patient with chronic nongranulomatous enterocolitis were analyzed blindly for the presence of a neutrophil granule protein called lactoferrin using a commercial latex agglutination kit. Diagnostic evaluation of the 103 patients with chronic diarrhea was carried out to determine the diagnostic accuracy of this test for chronic inflammatory bowel disease. RESULTS: None of the normal control subjects, three of 39 patients with microscopic colitis or celiac sprue, all 10 specimens from the patient with enterocolitis, and all 12 control patients with ulcerative colitis or Crohn's disease had a positive fecal lactoferrin test. Eleven of 103 patients with chronic diarrhea presenting without a diagnosis had a positive test, and all were diagnosed with an inflammatory condition of the colon (five-, ulcerative colitis; four-, Crohn's disease; one-, ischemic colitis; and one-, microscopic colitis). Only one patient with inflammatory bowel disease had a negative lactoferrin test. The sensitivity, specificity, and positive and negative predictive values of the fecal lactoferrin test for ulcerative or Crohn's colitis were 90%, 98%, 82%, and 99%, respectively. CONCLUSION: The major cause of fecal neutrophils in patients with chronic diarrhea is chronic inflammatory bowel disease of the colon. The latex agglutination test for fecal lactoferrin offers a highly sensitive, specific, and simple means for detection of fecal neutrophils in these patients.

Celiac Disease↗

PubMed1998

Intestinal secretory factor released by macrophages stimulated with Clostridium difficile toxin A: role of interleukin 1beta.

Clostridium difficile toxin A is associated with enterocolitis in animals and humans. However, the mechanisms of its secretory and damaging effects are not totally understood. In this work, we examined the intestinal secretion of electrolytes and water caused by supernatants from macrophages stimulated with toxin A in rabbit ileal mucosa mounted in Ussing chambers. We also investigated the mechanism by which the intestinal secretory factor (ISF) is released from stimulated macrophages. Supernatants from macrophages stimulated with toxin A caused potent intestinal secretion (change in short-circuit current [DeltaIsc], 76 microA x cm-2; P < 0.01). The release of the ISF was pertussis toxin sensitive (reduction, 61%; P < 0.01) and was also reduced (P < 0.05) by a protein synthesis inhibitor (67%), protease inhibitors (57%), a phospholipase A2 inhibitor (54%), a cyclo-oxygenase inhibitor (62%), a dual cyclo- and lipoxygenase inhibitor (48%), a platelet-activating factor (PAF) receptor antagonist (55%), and tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors (48%). However, this release was not inhibited by a lipo-oxygenase inhibitor. Monoclonal anti-interleukin 1beta (IL-1beta) but not anti-IL-1alpha antibody blocked (72%; P < 0.01) the secretory action of the ISF, as did recombinant human IL-1 receptor antagonist (80%; P < 0.01). High levels of IL-1beta (3,476 pg/ml) were detected by an enzyme-linked immunosorbent assay in the above supernatants. Furthermore, the addition of IL-1beta to the serosal side caused a potent secretory effect (DeltaIsc, 80 microA x cm-2; P < 0.01). These results show that macrophages stimulated with toxin A release an ISF capable of provoking intestinal secretion. The regulation of this factor is dependent upon the activation of the G protein. In addition, prostaglandins, PAF, and TNF-alpha are involved in the release of the ISF. We conclude that IL-1beta is probably the ISF released by macrophages in response to toxin A.

Animals↗

PubMed1998

Regulation of jejunal sodium and water absorption by angiotensin subtype receptors.

The purpose of this study was to determine the precise role of angiotensin subtype-1 (AT1) and -2 (AT2) receptors and the mechanisms by which they act to alter fluid transport in the rat jejunum. In rats on normal sodium intake, ANG II at low dose stimulated net jejunal fluid absorption, whereas at a high dose the peptide inhibited absorption. Low-dose ANG II-stimulated fluid absorption was blocked completely by the specific AT2 receptor antagonist PD-123319 (PD) but was unchanged by the AT1 receptor antagonist losartan (Los). The AT2 receptor agonist CGP-42112A, caused an inversely dose-dependent increase in fluid absorption, which also was totally prevented by PD but was unaltered by Los. Conversely, high-dose ANG II inhibition of absorption was blocked by Los but not by PD. In animals receiving normal sodium intake, neither Los nor PD alone altered fluid absorption. In sodium-restricted animals, however, Los alone increased absorption and PD alone inhibited absorption. In rats on normal sodium intake, low-dose ANG II increased jejunal interstitial and luminal (loop) fluid concentrations of cGMP. These increases in cGMP were blocked with PD but not with Los. 8-Bromoguanosine-3',5'-cyclic monophosphate administered via the mesenteric artery or the submucosal interstitial space markedly increased absorption, but it inhibited absorption when administered into the loop. High-dose ANG II decreased jejunal interstitial and loop fluid cAMP and increased PGE2. The increase in PGE2 was blocked by Los but not by PD. The data demonstrate that ANG II mediates jejunal sodium and water absorption by an action at the AT2 receptor involving cGMP formation. The data also show that ANG II inhibits absorption via the AT1 receptor by a mechanism that is both negatively coupled to cAMP and increases jejunal PGE2 production.

Adrenergic alpha-1 Receptor Antagonists↗