Regional diastolic function in effort angina pectoris: Assessment with biplane left ventriculography

Summary To investigate left ventricular (LV) regional diastolic function in effort angina pectoris (AP), we performed left ventriculography in 14 patients with AP and isolated left anterior descending artery disease and in 9 normal subjects (N). LV volume (V), regional area (S) [anterior, apex, and inferior], and the first derivative of V and S (dV/dt, dS/dt) were derived from analysis of the left ventriculogram. Normalized peak filling rate (nPFR) and peak atrial filling rate (nPAFR) were derived from dV/dt. The ratio of filling volume to stroke volume during rapid filling and atrial contraction were defined as rapid filling fraction (RFF) and atrial filling fraction (AFF). Similarly, peak area changing rate (PACR), peak area changing rate during atrial contraction (PACRac), rapid area changing fraction (RACF), and atrial area changing fraction (AACF) were derived from S and dS/dt. We also calculated the time constant of LV relaxation (T), and LV global and regional compliance durning atrial contraction [(dV/VdP)ac, (dS/SdP)ac]. The LV global diastolic function (T , nPFR ) was impaired in the angina patients. LV regional diastolic function (nPACR , RACF ) was also impaired in the affected region of the AP group. While their rapid filling was impaired, nPACRac was maintained and AACF was increased in the affected region. Furthermore, nPACR and RACF each showed a significant inverse correlation with AACF in the anterior region [r = –0.57 (P < 0.01),r = –0.92 (P < 0.001)]. In the affected region of the patients with AP, (dS/SdP)ac was increased, but not significantly. Thus, LV global and regional diastolic functions were simultaneously impaired in patients with isolated left anterior descending artery disease. Although rapid filling was impaired, passive filling during atrial contraction was preserved in the affected region.     

Reduction in index of oxygen saturation at margin of active duodenal ulcers may lead to slow healing

This study tested the hypothesis that reduced perfusion of a duodenal ulcer margin (ie, the mucosa 1–2 mm from the edge of the ulcer base) is associated with slow healing. Reflectance spectrophotometric measurement of indices of mucosal hemoglobin concentration (IHB) and mucosal hemoglobin oxygen saturation (ISO₂) were obtained endoscopically in 21 patients at the ulcer margin and the adjacent mucosa (ie, the mucosa 1–2 cm from the edge of the ulcer base). In 17 patients with adequate follow-up, stepwise multilinear regression analysis revealed a significantly negative correlation (r=s-0.69, P < 0.05) between ISO₂ at the ulcer margin minus ISO₂ at the adjacent mucosa (ISO)₂ and ulcer healing time. In addition, smoking, being black, and early relapse since the last ulcer attack were found to be associated with increased duration required for healing. The results of this pilot study suggest factors, in addition to smoking, that may have to be considered in future studies concerned with duodenal ulcer healing.This work was supported by the National Institute of Arthritis and Metabolism and Digestive Diseases Grant AM34840, American Society for Gastrointestinal Endoscopy Career Development Award H850208, Veterans Administration Medical Research Funds, and UCLA Academic Senate Grant 4063.     

Hemodynamics in the colonic mucosa of rats with dextran sulfate-induced colitis in the early phase

We investigated hemodynamics in the colonic mucosa of rats with experimental colitis induced by the administration of dextran sulfate sodium (DSS). As parameters of hemodynamics, we determined the indices of mucosal hemoglobin concentration (IHb) and mucosal oxygen saturation (ISO₂), measured by reflectance spectrophotometry, and an index of colonic mucosal blood flow (Flow), measured by laser-Doppler flowmetry. In the ascending colon, each parameter was measured by a combination of these methods after 1, 3, 5, 7, and 10 days of DSS administration. Histopathological examination was also performed. IHb in the DSS group increased with time; on the 7th day, the value was 126.9±8.32, while that in the control group was 85.0±4.14, IHb in the DSS group being significantly increased (P<0.02). ISO₂ in the DSS group was lower than that in the control group, and on the 7th day, was significantly lower in the DSS group (25.7±1.34) than in the control group (33.4±1.77) (P<0.01). No changes in Flow were observed in either the DSS or the control group during the administration period, and no significant difference in Flow was found between the two groups. On histopathological examination, we observed a time-dependent increase in the infiltration of inflammatory cells in the ascending colon of rats treated with DSS, but changes such as erosion and ulceration were not found in the superficial layer of the mucosa. No histopathological changes were found in the control animals. In the early phase of the experimental colitis, hemodynamic alterations in the colonic mucosa were already present at the time the slight histopathological changes developed. These observations seemed to indicate the involvement of hemodynamic alterations in the subsequent tissue injury.     

Total life consumption of cigarettes as a determinant of coronary artery disease documented by coronary arteriography

The present study investigated the role of cigarette consumption as a clinical indicator of significant coronary artery disease, an application hitherto considered unrealistic. The study was done in two parts: (1) case control men (n=96) with coronary artery disease and men with normal coronary arteries of identical ages (n=96); (2) consecutive patients (n =1016–913 males and 103 females) subjected to diagnostic coronary arteriography and Bruce treadmill exercise testing. Significant coronary artery disease was defined as diameter stenosis =70% for any coronary branch, except for left main stem =50%. Exercise positivity was defined as ST = 1 mm or ST 1 mm in leads without pathological Q waves. It was found that (1) patients with significant coronary artery disease were differentiated significantly (p < 0.001) from persons with normal coronary arteries by the life consumption of cigarettes (pack-years) independently of their age; (2) heavy smoking (>30 packyears) in male patients without a history of typical angina pectoris subjected to coronary arteriography is diagnostically equivalent to electrocardiographic positivity of exercise testing; (3) in the same context, smoking of any quantity in women is diagnostically equivalent to positive exercise testing. It was concluded that among patients addressed for diagnostic coronary arteriography and devoid of history of typical angina pectoris, smoking for women and heavy smoking for men is diagnostically equivalent to positive exercise testing.Presented at the 35th World Congress, International College of Angiology, Copenhagen, Denmark, July 1993     

Irritative and protective activity of mild irritants in rat stomach

Exposure of the stomach for 30 min to acidified sodium taurocholate (TC) (1–20 mM) or sodium salicylate (SA) (10–80 mM) caused a reduction of transmucosal PD and an increase of luminal pH in anesthetized rats, in a concentration-related manner. Acidified aspirin (ASA) (10–80 mM) reduced PD in the same manner, without significant effect on pH. Histologically, these agents similarly produced damage to the surface cells. After a 30-min exposure to either 20 mM TC or 40 mM SA, acid secretion ceased and bicarbonate (0.5–1 mol/10 min) appeared in the lumen, whereas acid secretion persisted in the stomach exposed to 40 mM ASA. However, under cimetidine infusion (8 mg/kg/hr) these agents produced similar degrees of luminal alkalinization (1 mol/10 min). Pretreatment with indomethacin (5 mg/kg, subcutaneously) significantly inhibited the increase of pH seen after exposure to 20 mM TC, but had no effect on the increase of pH caused by 40 mM SA. Concurrent administration of 16,16-dmPGE₂ (3 g/kg, subcutaneously) significantly antagonized the effect of indomethacin in the stomach exposed to 20 mM TC and even increased the pH in the stomach exposed to 40 mM ASA. After a 3-hr exposure to these agents, there was macroscopically apparent damage only in the stomach exposed to ASA, although the PD was similarly reduced in response to either agent. The levels of PGE₂ in the corpus mucosa were significantly increased in stomachs exposed to 20 mM TC and 40 mM SA, but decreased in those exposed to 40 mM ASA. Pretreatment with indomethacin significantly blocked the increased formation of PGE₂ caused by TC and SA. These results suggest that mucosal damaging agents such as TC and SA reduce the PD (surface cell injury) and act as mild irritants to induce gastric alkaline response and adaptive mucosal protection, unless, as in the case of ASA, they have an inhibitory effect on prostaglandin synthesis.     

Measurement of gastric and duodenal mucosal protein turnover in humans

Conventional measurement of mucosal turnover is based on labeling cellular DNA with [³H]thymidine, but because of the risk of genetic damage, this technique is not suitable for studies in normal human subjects. Consequently, we have measured mucosal protein turnover by a primed/continuous intravenous infusion of tracer quantities of [1¹⁴C]leucine and measured its incorporation into mucosal protein at 4 hr in nine healthy adult volunteers. Mucosal samples were obtained by standard endoscopic techniques from the distal duodenum and gastric antrum. In addition, duodenal villous height and width were measured by microscopic micrometric techniques in order to calculate villous growth rate. Results demonstrated a mucosal protein turnover of 57±5%/day in gastric antrum and 39±2%/day in duodenum, suggesting a mucosal replacement rate of 1.8 and 2.6 days, respectively. Average duodenal villous height was 433±77 m, suggesting a villous growth rate of approximately 160 m/day. As our mucosal protein turnover rates are similar to epithelial turnover rates measured by cellular labeling techniques, our results support the intestinal proliferon theory that suggests all mucosal elements follow similar turnover characteristics. In conclusion, the technique should provide a practical alternative method of studying the effect of disease upon mucosal regeneration and repair.     

Bacterial enzymes used for colon-specific drug delivery are decreased in active Crohn's disease

Enzymes produced by colonic microflora have been proposed for triggering local delivery of antiinflammatory azo-bond drugs and prodrugs to the colon. This approach could be advantageous in steroid treatment of inflammatory bowel diseases, thus sparing steroids' side effects. We recently demonstrated that the metabolic activity of digestive flora, assessed on the activity of fecal glycosidases, was decreased in patients with active Crohn's disease. In the present study, the azoreductase activity in feces of 14 patients with active Crohn's disease was decreased (11.39±7.93 mU/g F) as compared with 12 healthy subjects (51.13±21.39 mU/g F). -d-Glucosidase and -d-glucuronidase activities in fecal homogenates incubated under anaerobic conditions were also decreased in patients. These data bring into question the therapeutic usefulness for those patients of azo-bond drugs and glycoside prodrugs. They could explain the therapeutic failure of some of those drugs in active ileocolic and colic Crohn's disease.     

Gut microbial diversity is reduced and is associated with colonic inflammation in a piglet model of short bowel syndrome

Background and objectives

Following small bowel resection (SBR), the luminal environment is altered, which contributes to clinical manifestations of short bowel syndrome (SBS) including malabsorption, mucosal inflammation and bacterial overgrowth. However, the impact of SBR on the colon has not been well-defined. The aims of this study were to characterize the colonic microbiota following SBR and to assess the impact of SBR on mucosal inflammation in the colon.

Results

Analysis of the colonic microbiota demonstrated that there was a significant level of dysbiosis both two and six weeks post-SBR, particularly in the phylum Firmicutes, coupled with a decrease in overall bacterial diversity in the colon. This decrease in diversity was associated with an increase in colonic inflammation six weeks post-surgery.

Methods

Female (4-week old) piglets (5−6/group) received a 75% SBR, a transection (sham) or no surgery. Compositional analysis of the colonic microbiota was performed by high-throughput sequencing, two- and six-weeks post-surgery. The gene expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8, IL-18 and tumor necrosis factor (TNF)-α in the colonic mucosa was assessed by qRT-PCR and the number of macrophages and percentage inducible nitric oxide synthase (iNOS) staining in the colonic epithelium were quantified by immunohistochemistry.

Conclusions

SBR significantly decreased the diversity of the colonic microbiota and this was associated with an increase in colonic mucosal inflammation. This study supports the hypothesis that SBR has a significant impact on the colon and that this may play an important role in defining clinical outcome.     

Involvement of α2-Adrenoceptors in mechanism of intragastric nicotine protection against ethanol injury in rat stomach

To elucidate the role of - and -adrenoceptors in the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury, the following studies were performed. At 0.5-hr prior to the injury study, rats were pretreated with: subcutaneous control, prazosin (0.5 mg/kg) or yohimbine (5 mg/kg) to block ₁- or ₂-adrenoceptors; or intraperitoneal control, metoprolol (2 mg/kg) or butoxamine (4 mg/kg) to block ₁- or ₂-adrenoceptors, respectively. At 1-hr intervals, rats received intragastric vehicle or nicotine (4 mg/kg) and 40% ethanol (10 ml/kg). Total lengths of the linear gastric corpus mucosal lesions were measured by an unbiased observer using a caliper. In a separate study, 0.5-hr after subcutaneous control or yohimbine (5 mg/kg), rats were treated with intragastric vehicle or nicotine (4 mg/kg). One hour later, gastric mucus volume, gastric juice volume and pH, and titratable acid in the gastric juice were measured. In the rat stomach, the intragastric nicotine protection against 40% ethanol-induced mucosal injury was not blocked by selective ₁-(prazosin), ₁-(metoprolol), or ₂-(butoxamine) adrenoceptor antagonists. The protection was significantly reduced although not completely abolished by selective ₂-(yohimbine) adrenoceptor antagonist. Yohimbine also significantly reduced basal and nicotine-stimulated increase in gastric mucus volume. These data suggest that ₂-adrenoceptors are involved in the protective effect of intragastric nicotine against 40% ethanol-induced gastric mucosal injury possibly by a mucus-dependent mechanism.Supported by Veternas Administration Medical Research Funds, and in part by research grants (0162-01, 02, and 291-01) from the Smokeless Tobacco Research Council, Inc., and by funds (1RT 80) provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California to F.W.L. Dr. Endoh is a recipient of the University of California Tobacco-Related Disease Research Program Research Fellowship Award (FT 37).     

Motility of rabbit proximal colon

To better define the physiologic relevance of the cholinergic muscarinic input to the rabbit colon and the role of different muscarinic receptor subtypes, we studied the effects of atropine, telenzepine (M₁ antagonist) and DF594 (M₃ antagonist) on colonic motility in eight conscious rabbits fitted with bipolar electrodes and strain gauges along the proximal colon. In some experiments, the chronotropic and mydriatic effect of the pharmacological agents were also assessed. Two main patterns of spike activity were identified: short spike bursts (SSBs), which were usually stationary, and long spike bursts (LSBs), which were usually propagated. Both myoelectrical patterns were dose-dependently inhibited by atropine (0.06–4 mol/kg). Atropine, at the doses of 2–4 mol/kg, abolished both myoelectrical and mechanical activity. Telenzepine (0.008–0.125 mol/kg) dose-dependently inhibited migrating LSBs without significant effect on SSBs. Higher doses (0.25–0.5 mol/kg) inhibited both LSBs and SSBs. DF594 (0.06–2 mol/kg) dose-dependently inhibited both migrating LSBs and SSBs. The three antimuscarinic agents, at doses that inhibited colonic spike activity by approximately 80% (equiactive doses), behaved as follows on heart rate and pupil diameter: atropine induced tachycardia and mydriasis, telenzepine had no effect, and DF594 induced slight mydriasis with no effect on heart rate. We conclude that spontaneous motility in the rabbit proximal colon depends on a muscarinic excitatory input. M₃ receptors are involved in the control of both LSBs and SSBs, while M₁ receptors play an important role in the regulation of LSBs. The development of selective antimuscarinic drugs, acting on a given motility pattern and with minimal side effects, may offer new perspectives in the treatment of functional bowel motor disorders.This work was supported in part by a grant from the Ministero dell'Università e della Ricerca Scientifica e Tecnologica.A preliminary report of this paper was presented at the Fifth European Symposium on Gastrointestinal Motility held in Augsburg, Germany, June 13–16, 1990, and appears in abstract form inJ Gastrointest Motil 2:156, 1990.     

Colonic mucosal T lymphocytes in ulcerative colitis: Expression of CD7 antigen in relation to MHC class II (HLA-D) antigens

T-cell subsets and their activation state were examined by double-label immunofluorescence of cryostat tissue sections of the colon from 21 patients with ulcerative colitis (UC) and 30 histologically normal controls. Expression of MHC class I (HLA-A, B, C) and class II (HLA-D) antigens was studied in parallel. In the normal colonic mucosa, the CD4CD8 ratio in the epithelial compartment approximated 11, and in the lamina propria, 2.551. Of the CD8⁺ (cytotoxic/suppressor) subset, approximately half did not express the CD5 pan-T marker in either compartment. Virtually no Leu 8⁺ cells were observed, implying that the CD4⁺ subset consisted of helper, rather than suppressor-inducer cells. Classical markers of T-cell activation (CD25, HLA-D) and proliferation were absent, and strong expression of the CD7 immunostimulation marker was approximately equal in both CD4 and CD8 subsets. The epithelium was uniformly negative for class II antigens, but positive for class I. In UC, there were no significant alterations in CD4CD8 ratios in either compartment, and there were no changes with respect to phenotype of the subsets. In 11 of 19 patients (mainly with total colitis), enterocytes were HLA-D⁺. In this HLA-D⁺ group, there was an increase in the percentage of CD4⁺ cells coexpressing CD7; this difference was significant (P<0.02) in the lamina propria. Increased expression of CD7 was also found by the CD6⁺ T cell subset (P<0.05). These results suggest that class II expression is mediated by immunostimulated T helper cells in UC, with consequences for antigen presentation and maintenance of the chronic inflammatory state.HLA-D is used as a generic term for class II major histocompatibility complex (MHC) gene products (HLA-DR, DP, DQ) unless specified otherwise.     

Epithelial induction of serum amyloid A in experimental mucosal inflammation

We previously demonstrated epithelial induction of serum amyloid A in germ-free mice inoculated with luminal bacteria. The aims of the present study were to investigate the role of luminal bacteria and mucosal inflammation in epithelial expression of this acute-phase protein using germ-free and dextran sulfate sodium-treated mice in vivo and HT29 cells in vitro. Immunoreactivity for serum amyloid A was detected in the epithelium of esophagus, stomach, duodenum and rectum regardless of the presence or absence of luminal bacteria. Administration of dextran sulfate sodium resulted in colonic epithelial induction of serum amyloid A at the mRNA and protein levels in parallel with the progression of mucosal inflammation. Epithelial induction of serum amyloid A is possibly relevant to mucosal inflammation because that was observed in bacteria-reconstituted and dextran sulfate sodium-induced colitis in vivo and because interleukin-1 and lipopolysaccharide induced its mRNA in vitro.     

Adrenoceptors and Colocolonic Inhibitory Reflex

The colocolonic inhibitory reflex ischaracterized by inhibition of proximal colonic motilityinduced by distal colonic distension. The aim of thisstudy was to investigate the underlying neuralmechanisms of this reflex, in vivo , using an isolatedloop of canine colon. In five beagle dogs, motility wasrecorded from an exteriorized colonic loop via a serosalstrain gauge connected to a digital data logger and chart recorder. Inflation of a balloon inthe distal colon resulted in inhibition of motility inthe isolated loop. Inhibition of motor activitypersisted following injection of propranolol (100g/kg intravenously), a -adrenoceptorantagonist, but was abolished following administrationof the ₂-adrenoceptor antagonistyohimbine (200 g/kg intravenously). This studyconfirms that the colocolonic inhibitory reflex is mediatedvia the extrinsic nerves to the colon. As the reflex wasabolished by ₂-, but not-adrenoceptor blockade, this indicates that thereflex pathway involves₂-adrenoceptors.     

Flatus-related colorectal and anal motor events

Although complaints of excessive gas symptoms are frequently encountered in clinical practice, the physiologic and pathophysiologic grounds of flatus events are poorly understood, partly because of the social taboos associated with the topic and partly because of technical difficulties in measuring flatus. For these reasons, we studied the colorectal and anal motor events occurring during artificially evoked flatus events and compared them to those that occurred spontaneously. Five healthy male volunteers were studied by multilumen probes placed in the left colon and rectum and across the anal canal, to observe the flatus-related motor events that occurred after instillation of air into the colon. Flatus-related spontaneously occurring motor events were also checked in 24-hr motility tracings obtained in three patients with functional bowel disorders. Analysis of the tracings showed that both artificially induced and spontaneously occurring flatus-related motor phenomena were characterized by colonic propagated contractions associated with a rise in rectal pressure and early relaxation of the anal sphincter, in a sequence resembling that observed following swallowing. Spontaneous flatus events were associated with colonic waves of lesser amplitude than those following insufflation of air into the colon.     

Electrogenic ion transport in mammalian colon involves an ammonia-sensitive apical membrane K+ conductance

It is remarkable that high ammonia concentrations can be present within the colonic lumen without compromising normal epithelial function. We investigated the impact of luminal ammonia on Cl^– secretion in native tissue. Stripped human colonic mucosa and unstripped rat distal colon were used. Paired samples were mounted in modified Ussing chambers for electrophysiological studies. In rat distal colon, apical ammonia dose-dependently blocked forskolin-activated short-circuit current with an IC₅₀ 5 mM. Basolateral NH₄Cl was less effective. Luminal methylamine (50 mM), chromanol 293 B (10–50 M), and Ba²⁺ (5 mM) blocked cAMP-activated short-circuit current but apical clotrimazole (100 M) was without effect. In stripped human colonic mucosa, luminal but not basolateral NH₄Cl (10 mM) and luminal Ba²⁺ (5 mM) suppressed forskolin-activated short-circuit current. Ammonia may be an endogenous regulator of colonic water and salt secretion. Apical K⁺ channels may be involved in the regulation of cAMP-stimulated Cl^– secretion in mammalian colon.     

Extrinsic denervation causes a transient proabsorptive adrenergic hypersensitivity in the canine proximal colon

Our aim was to determine if extrinsic denervation alters the absorptive response of the colon to proabsorptive and prosecretory stimuli. Ten dogs underwent enteric isolation of a 50-cm proximal colonic segment; five were also randomized to undergo extrinsic denervation (DEN). At 2 and 13 wk postoperatively, net absorptive fluxes (mean ± sem) of water and electrolytes were determined during basal conditions and during proabsorptive low-dose (0.3 g/kg/min) or high-dose (3 g/kg/min) norepinephrine or prosecretory VIP (500 pg/kg/min). The net absorptive flux of water under basal conditions was decreased in DEN versus neurally intact controls at two weeks (4.0 ± 0.6 vs 6.6 ± 0.7 l/min/cm, P = 0.03) but did not differ at 13 weeks (5.0 ± 1.0 vs 5.7 ± 0.9, P > 0.05). Low- and high-dose norepinephrine increased water absorption in both groups at two weeks; the change in flux for high-dose norepinephrine was greater in DEN versus controls (4.1 ± 1 vs 2.1 ± 0.6 l/min/cm, P = 0.04). Net absorptive fluxes of Na⁺ and Cl^– followed these trends. VIP did not alter absorption of water or electrolytes. Extrinsic denervation of the proximal colon causes a decrease in net colonic absorption and a transient, proabsorptive adrenergic hypersensitivity in colonic absorption of water and electrolytes. VIP does not have a net secretory effect in the proximal canine colon.     

Adrenergic,purinergic, and endothelial mediators and modulators of norepinephrine-induced mesenteric autoregulatory escape

We evaluated the effects of potential factors in autoregulatory escape from norepinephrine-induced vasoconstriction in rat anterior mesenteric artery. We determined mesenteric artery blood flow velocity with a pulsed Doppler, sonic flowmeter, and systemic arterial blood pressure with a transducer. A 4-min norepinephrine infusion (0.125–1.0 × 10^–8 M/min) intravenously evoked a dose-dependent, initial vasoconstriction that was followed by rapid escape of blood flow toward or above the control value during sustained norepinephrine administration. Neonatal capsaicin treatment enhanced vasoconstrictor responses to norepinephrine but failed to affect escape parameters. Propranolol decreased norepinephrine-induced escape dose dependently. Adenosine deaminase attenuated escape, and the combination of this enzyme plus propranolol nearly abolished escape from norepinephrine-induced vasoconstriction. Methylene blue also diminished autoregulatory escape. These findings suggest that norepinephrine-induced autoregulatory escape involves simultaneous -adrenoceptor, purinergic, and endothelial mediation. Norepinephrine-evoked mesenteric vasoconstriction appears to involve predominantly ₂-adrenoceptors and is modulated by peptidergic sensory nerves and adenosine.NIH grant number supporting these studies: USPHS # DK37050.     

Distribution of β-Adrenoceptor Subtypes in Gastrointestinal Tract of Nondiabetic and Diabetic BB Rats A Longitudinal Study

The effects of aging and diabetes on thedistribution of -adrenoceptor subtypes in the gutwere investigated in the BB rat.[¹²⁵I]Cyanopindolol binding to 10-msections was evaluated using film autoradiography. Cyanopindolol binding to -,₁-, and₂-adrenoceptors was displaced by 1M propranolol, 50 nM ICI-89-406, and 100 nMICI-118-551, respectively. -Adrenoceptor bindingwas highest in the circular muscle of proximal colon and lowest in thepylorus of 4- to 5-month-old rats. Aging (8- to10-month-old vs. 4- to 5-month-old rats) was associatedwith increased -adrenoceptor binding in thepylorus and reduced binding in the proximal colon.Diabetes had a time-dependent effect on the level of-adrenoceptor binding. It was increased in theantral and pyloric stomach but longer periods ofdiabetes caused a reduction in -adrenoceptorbinding in the pylorus. Those in the intestine werereduced time-dependently and involved₁- or ₂-adrenoceptorsor both.     

Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P<0.05), an effect that was prevented by VIP antagonist (1 mol/liter/100 g). A substance P antagonist (1 mol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB₄, LTC₄, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P<0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB₄. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P<0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P<0.05). Ketotifen, a mast cell stabilizer (100 g/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC₄ and LTB₄ (P<0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage. The effective mucosal protection by ketotifen suggests a role for mast cells and their mediators in the pathogenesis of acute gastric mucosal damage.     

Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer

Summary The object of this study was to explore the use of fecal skatole and indole and breath methane and hydrogen as metabolic markers of the anaerobic colonic flora in patients with unresected large bowel cancer or polyps. Patients with descending or sigmoid colon cancer were more likely to be breath methane excretors than control subjects, patients with proximal colon cancer, and patients with rectal cancer. Control subjects excreting breath methane excreted less fecal skatole than breath methane excretors in the following groups: patients with adenomatous polyps, all patients with colorectal cancer, patients with proximal colon cancer, patients with descending and sigmoid colon cancer, and patients with rectal cancer. These data suggest that fecal skatole excretion equal to or greater than 100 g/g feces might be useful to discriminate colorectal cancer patients from control subjects. Twenty-nine percent (8 of 28) of the cancer patients had both high skatole levels and breath methane excretion compared with only 2% (1 of 41) of the control subjects (P<0.01).Supported by Public Health Service Grant CA-29056 from the National Cancer Institute