Gastric diversion or pylorus ligation for gastric mucosal integrity and acid secretion studies in the rat?

The advantages of gastric diversion over pylorus ligation in rat gastric mucosal integrity and acid secretion studies over 6 hr were investigated. Mucosal injury developed in 80% of pylorus-ligation controls. Atropine (5 mg/kg) or cimetidine (40 mg/kg) had no effect on this injury (2.9 mm²±0.9 and 2.8 mm²±0.7, respectively, vs 3.1 mm²±1, mean±sem, N=10; however vagotomy increased it (13.7 mm²±Pylorus-ligation H⁺ output was higher than that of gastric diversion (390.5 mol±54.8 vs 61 mol±2.5, mean±sem, N=10, P<0.001). Cimetidine (40 mg/kg) depressed H⁺ output of gastric diversion (21.3 mol±1.2 vs 61 mol±2.5, mean±sem, N=10, P<0.001), but not of pylorus ligation (424 mol±74.2 vs 390.5 mol±54.8, mean±sem, N=10). Vagotomy or atropine depressed pylorus-ligation H⁺ output (P<0.001), but each allowed an output (36.6 mol±5.5 and 120 mol±29, respectively, mean±sem, N=10) significantly (P<0.001) higher than that associated with it in gastric diversion (16 mol±1.4 and 17.1 mol±1.6, respectively, mean±sem, N=10). This study demonstrates that in the rat pylorus ligation, in contrast to gastric diversion, injures the gastric mucosa, stimulates H⁺ secretion, and overshadows the efficacy of antisecretory agents.     

Secretory component and lactoferrin in pure pancreatic juice in chronic pancreatitis

To evaluate pathophysiological roles of proteins in pancreatic secretion, immunoreactive lactoferrin (LF) and secretory component (SC) were measured in the first fraction of the pure pancreatic juice obtained endoscopically from 17 control, 21 suspected (SCP), 14 noncalcified (NCP), and 14 calcified chronic pancreatitis (CCP) subjects. The protein and amylase tended to decrease both in concentration and output from control to CCP. LF concentration was elevated in CCP (18.0±4.9/ml) when compared with controls (2.3±0.2g/ml), and LF output in NCP (12.3±3.8 g/min) was increased from controls (3.8±0.6 g/min). The combination of high LF concentration with low protein output was observed in 10/14 in CCP but 0/14 in NCP and can be a biochemical discriminator of CCP from NCP. SC concentrations were also elevated in NCP (8.5±2.0 g/ml) and CCP (5.6±1.6 g/ml) from controls (1.2±0.2 g/ml). SC outputs in SCP (9.8±3.1 g/min) and NCP (21.1±4.8 g/min) were increased from controls (1.7±0.3 g/min), but there was no further increase in CCP. Hypersecretion of LF and SC in chronic pancreatitis is different, especially in CCP, although the mechanisms for hypersecretion are unknown.This study was supported in part by a research grant for intractable pancreatic disease from the Ministry of Health and Welfare, Japan.     

Granulocyte Elastase in Cirrhotic Patients with Spontaneous Bacterial Peritonitis

Granulocyte elastase (GE) is a powerfulproteolytic enzyme that is released by PMNs whendegranulated in infectious processes. The aim of thisstudy was to measure GE in ascites and plasma ofcirrhotic patients with spontaneous bacterial peritonitis(SBP). We studied 29 cirrhotic patients, 17 of themhaving SBP (group A). Twelve patients with noninfectedascites formed the control group (group B). At the time of diagnosis of SBP, GE levels inascites (183.17 ± 86.11 g/liter) and plasma(114.6 ± 35.99 g/liter) were higher in groupA than in group B (27.41 ± 11.54 g/liter, P< 0.00001 and 82.54 ± 20.52 g/liter, P = 0.01,respectively). Levels of GE in ascites had a high valuefor discriminating between patients with and withoutSBP. In the patients who responded to the initialantibiotic treatment, these values significantly decreasedin ascites (67.69 ± 54.22 g/liter, P = 0.003)and plasma (67 ± 22.39 g/liter, P = 0.01) 48hr after therapy was started, in parallel with thedecrease of PMN in ascites. In patients who did notrespond, the production of GE remained elevated.Patients who developed renal insufficiency following SBPhad more marked elevation of GE in plasma (144.8± 33.43 g/liter) than those with normal renalfunction (99.5 ± 27.53 g/liter, P = 0.02).These results suggest that the measurement of GE may behelpful for the diagnosis of SBP in patients withcirrhosis and for assessing the efficacy of therapy. Inaddition, the release of GE into plasma may contributeto the impairment of renal function that follows SBP insome patients.     

Diagnosis of malignant ascites

The ascitic fluid concentrations of cholesterol and fibronectin and the serum-ascites albumin difference were compared with two conventional tests of ascitic fluid, total protein and LDH, in their diagnostic ability for detection of malignancy in ascitic samples from 69 patients with ascites: 54 with ascites due to liver disease and 15 whose ascites was caused by peritoneal metastases. Sixteen cirrhotic patients with superimposed hepatocellular carcinoma in whom ascites was of uncertain etiology were considered separately. The mean ascitic fluid total protein, LDH, cholesterol, and fibronectin values in the peritoneal metastases group were 3.70±1.20 g/dl, 247.26±148.14 units/liter, 109. 06±29.85 mg/dl, and 91.57±41.52 g/ml, respectively, and all were significantly higher than the corresponding values in the liver disease group (P<0.001), which were 1.37±0.59 g/dl, 75.40±110.70 units/liter, 23.75±11.22 mg/dl, and 31.86±10.51 g/ml,respectively. Mean serum-ascites albumin difference in the peritoneal metastases group was 0.62±0.38 g/dl, which was significantly different from the corresponding value in the liver disease group (1.92±0.41 g/dl, P <0.001). Both ascitic cholesterol above 46 mg/dl and an ascitic fibronectin concentration >50 g/mlhad high diagnostic accuracy (97%) for malignancy, being higher than that achieved using a serum-ascites albumin difference under 1.1 g/dl and an ascitic total protein above 2.5 g/dl, which had accuracies of 94% and 93%, respectively. Ascitic fluid LDH was the least reliable test. No differences in the ascitic fluid analysis were found between cirrhotic patients with and without hepatocellular carcinoma. We conclude that both ascitic cholesterol and ascitic fibronectin are clinically more accurate than the serum-ascites albumin difference, ascitic total protein,and ascitic LDH in the diagnosis of malignant ascites. Of these tests, the determination of ascitic cholesterol may be the preferred one because of its simplicity and cost effectiveness.     

Experimental streptozotocin-induced diabetes and intestinal glucose metabolism in the rat,in vivo and in vitro

The intestine has a high glycolytic activity, but its metabolic role could be altered in diabetes mellitus. The aim of the present work was to investigate in vivo the glucose retained and the lactate produced by the intestine of normal and diabetic rats and in vitro the effect of different arterial glucose concentrations on glucose utilization and lactate, alanine, and pyruvate production in normal and diabetic rats when the glucose is supplied to the intestine exclusively via the vascular route. In vivo, the normal and diabetic rats retained similar percentages of the arterially supplied glucose (14.7±3.2 and 12.6±2.4, respectively). In vitro, when the preparations were perfused under hyperglycemic conditions, the glucose consumed, as a fraction of the quantity infused, was significantly lower (P<0.05) in the diabetic (247.0±22.8 mol/mmol infused glucose) than in normal (315.0±16.3 mol/mmol infused glucose) rats. The lactate produced was significantly higher in diabetic than in normal rats whether the preparations were perfused under isoglycemic (P<0.01; 1916.4±124.0 vs 1284±67.7 mol/mmol consumed glucose) or hyperglycemic (P<0.05; 1356.4±199.7 vs 898.0±87.3 mol/mmol consumed glucose) conditions. There was significantly (P<0.05) greater alanine release from the diabetic (123.7±21.8 mol/mmol consumed glucose) than from the normal (40.7±10.3 mol/mmol consumed glucose) rat preparations perfused under isoglycemic conditions.     

Surgery or chemoneurolysis for complete vagal denervation of rat stomach?

This study compared the completeness of vagal denervation of the rat stomach by transection vagotomy to that by chemoneurolysis (30% ethyl alcohol) alone or supplemented by truncal vagotomy. The H⁺ output over 6 hr with vagotomy by chemoneurolysis (10.5±0.7 mol, mean±sem,N=10) or truncal vagotomy and chemoneurolysis (10.9 ±1.1 mol, mean±sem,N=10) was similar to that with transection vagotomy, but significantly (P<0.01) lower than that with truncal vagotomy by chemoneurolysis (17.9 ±1.1 mol,N=10). The latter output was similar to that of truncal vagotomy performed surgically (18.2±1.3 mol,N=10). Reserpine (0.1 mg/kg intraperitoneal) stimulated gastric acid secretion relative to control values (207±3.1 mol vs 67±3.2 mol,N=10),P<0.001) and transection vagotomy, vagotomy by chemoneurolysis, or truncal vagotomy and chemoneurolysis were more effective (P<0.01) than truncal vagotomy performed surgically or by chemoneurolysis in preventing this stimulation. Insulin stimulated the H⁺ output (184±2.9 mol vs 62±3.1 mol,N=10,P<0.001) and transection vagotomy, vagotomy by chemoneurolysis, or truncal vagotomy and chemoneurolysis were more effective (P<0.01) than truncal vagotomy done surgically or by chemoneurolysis in preventing this action. These results were reproducible in experiments done after three months. This investigation shows that transection vagotomy, vagotomy by chemoneurolysis, and truncal vagotomy plus chemoneurolysis are equally effective in achieving vagal denervation of the rat stomach and are superior in this respect to truncal vagotomy done surgically or by chemoneurolysis.     

Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin-dependent) diabetes mellitus

Summary To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol · m^2–1 · min^–1) clamp studies combined with indirect calorimetry and infusion of [3-³H]-glucose and [1-¹⁴C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151±36 mol/1, (2) 949±178 mol/l, and (3) 65±9 mol/l; in healthy control subjects 93±13 mol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p<0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255±42 vs 51±29 mol/min, p<0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231±49 mol/min), whereas Acipimox significantly enhanced the suppression (21±53 mol/min, p<0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.     

Age-related Variations in the Neuroendocrine Control,More Than Impaired Receptor Sensitivity,Cause The Reduction in the GH-releasing Activity of GHRPs in Human Aging

The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66–81 yr) and 12 young controls (Y, 24–28 yr) we studied the effects of 1.0, 2.0 and 3.0 g/kg iv Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 g/kg), GHRH (2.0 g/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 g/kg; AUC0;v–120 ± SEM: 1728.4 ± 406.4 vs. 2265.9 ± 298.4 vs. 2934.3 ± 482.2 g//L/h, p < 0.05 for 1.0 vs. 2.0 g/kg) and GHRH (649.6 ± 111.4 vs. 792.2 ± 117.6 vs. 1402.6 ± 363.0 g/L/h) showed a progressive increase. Two g/kg HEX and 1 g/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 ± 50.0 vs. 742.8 ± 157.9 vs. 1205.1 ± 178.1 g/L/h, p < 0.05 for 1.0 vs. 2 g/kg, p < 0.001 for 1.0 vs. 3.0 g/kg and p < 0.03 for 2.0 vs. 3.0 g/kg) and GHRH (183.8 ± 27.3 vs. 260.9 ± 17.3 vs. 356.1 ± 46.3 g/L/h, p < 0.005 for 1.0 vs. 3.0 g/kg and p < 0.05 for 2.0 vs. 3.0 g/kg) showed a progressive increase. In E the GH response to 3 g/kg HEX or GHRH were clearly higher than those to 2 g/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 ± 308.0 g/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 ± 273.6 g/L/h, p < 0.01) but not the HEX-induced one (2371.7 ± 387.2 g/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 ± 360.8 g/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 ± 306.0 g/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 ± 172.8 g/L/h, p < 0.01) and even those to HEX (2069.5 ± 528.7 g/L/h, p < 0.01) and HEX + GHRH (4406.0 ± 1079.2 g/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.     

Effect of portal hypertension onIn Vivo bile acid-mediated small intestinal mucosal injury in the rat

This study's purpose was to determine whether portal hypertension adversely affects small intestinal mucosal injury. Portal hypertension was produced in male Sprague-Dawley rats by two-stage ligation of the portal vein. Sham-operated rats were used as controls. Two weeks later, intestinal injury was produced byin vivo perfusion with 5 mM chenodeoxycholic acid for 30 min. Intestinal injury was assessed by quantitative morphometry and by measuring intestinal water and mannitol absorption. Portal hypertension resulted in more injury in the distal perfused intestine as manifested by increased villus tip denudation [portal hypertensive 52.5±9.6sem) vs controls 28.1±5.7m, P=0.05). Additionally there was a significant decrease in the unperfused duodenal villus height in portal hypertensive rats (portal hypertensive 755±22 vs controls 848±28m, P<0.02). Portal hypertension had no significant effect on the increase in mannitol absorption or water secretion caused by chenodeoxycholic acid perfusion. This study suggests that portal hypertension alters small intestinal mucosa and increases susceptibility to injury.This work was supported in part by a grant from the Research Service of the Veterans Administration.     

Site of Bismuth Absorption from Bismuth Subsalicylate

Poorly absorbed bismuth preparations may benefit a variety of chronic colonic conditions including ulcerative colitis. Bismuth-induced neurotoxicity is a potential complication of the chronic use of these preparations, and a less-absorbable form of bismuth is needed. If bismuth absorption occurs primarily in the upper gut, a delayed-release bismuth preparation could reduce absorption. We studied the site of bismuth absorption from bismuth subsalicylate (BSS) in rats. For 15 days, BSS (50 mg/day) was ingested or infused directly into the cecum via a chronically implanted cannula. Oral BSS resulted in serum and urine bismuth levels many times higher (3.5 ± 0.3 g/liter and 1570 ± 286 g/g creatinine, respectively) than with cecal administration (undetectable (<1.5 g/liter) and 75 ± 25 g/g creatinine). Thus, bismuth absorption from BSS occurred almost entirely in the upper gut. These findings provide a rationale for a similar study of delayed-release bismuth preparations in humans.     

Mechanism of bradykinin-induced cyclic GMP accumulation in bovine tracheal smooth muscle

Bradykinin (10^–8-10^–5M) caused a concentration-dependent increase in cyclic GMP (cGMP) production in bovine tracheal smooth muscle in the absence of epithelium. The effect was calcium-dependent and was inhibited by pyrogallol (10 M) and methylene blue (10 M). The inhibition of pyrogallol was reversed by superoxide dismutase (100 Usnowml). Nitric oxide (NO) synthase inhibitors, N ^G-methyl-l-arginine (10–100 M) and N ^G-nitro-l-arginine (10–100 M) reduced cGMP accumulation induced by bradykinin in a concentration-dependent fashion, and the inhibition was reversed by l-arginine. Immunohistochemistry with a specific antibody against neuronal NO synthase from rat cerebellum showed positive staining localized in some nerve fibers. Bradykinin-induced cGMP accumulation appears to be related to the release of NO, part of which is probably synthesized in nonadrenergic noncholinergic nerve in bovine trachea.Offprint requests to: Dr. Hong Sheng     

Loss of glycogen during preconditioning is not a prerequisite for protection of the rabbit heart

Depletion of gycogen has been proposed as the mechanism of protection from ischemic preconditioning. The hypothesis was tested by seeing whether pharmacological manipublation of preconditioning causes parallel changes in cardiac glycogen content. Five groups of isolated rabbit hearts were studied. Group 1 experienced 30 min of ischemia only. Group 2 (PC) was preconditioned with 5 min of global ischemia followed by 10 min of reperfusion. Group 3 was preconditioned with 5 min exposure to 400 nM bradykinin followed by a 10 min washout period. Group 4 experienced exposure to 10 M adenosine followed by a 10 min washout period, and the fifth group was also preconditioned with 5 min ischemia and 10 min reperfusion but 100 M8-(p-sulfophenyl) theophylline (SPT), which blocks adenosine receptors, was included in the buffer to block preconditioning's protection. Transmural biopsies were taken before treatment, just prior to the 30 min period of global ischemia, and after 30 min of global ischemia. Glycogen in the samples was digested with amyloglucosidase and the resulting glucose was assayed. Baseline glycogen averaged 17.3±0.6 mol glucose/g wet weight. After preconditioning glycogen decreased to 13.3±1.3 mol glucose/g wet weight (p<0.005 vs. baseline). Glycogen was similarly depleted after pharmacological preconditioning with adenosine (14.0±1.0 mol glucose/g wet weight, p<0.05 vs. baseline) suggesting a correlation. However, when proconditioning was performed in the pressence of SPT, which blocks protection, glycogen was also depleted by the same amount (13.3±0.7 mol glucose/g wet weight, p=ns vs. PC). Bradykinin, which also mimics preconditioning, caused no depletion of glycogen (16.3±0.8 mol glucoseig wet weight, p=ns vs. baseline). Because preconditioning with bradykinin did not deplete glycogen and because glycogen continued to be low when protection from preconditioning was blocked with SPT, we conclude that loss of glycogen per se does not cause the protection of preconditioning.     

Analysis of ascitic fluid in cirrhosis

In order to determine the composition of normal ascitic fluid, the results of analysis of the first paracentesis on 347 consecutive cirrhotic patients with ascites at the West Haven Veterans Administration Hospital between 1955 and 1976 were examined. The ascites was considered normal in 259 patients. Bacterial peritonitis was present in 51, malignant ascites in 18, pancreatitic ascites in 15, and ascites of other types in 4 patients. Normal ascites is sterile, usually clear, and contains 281±25 leukocytes/mm³ (mean±Sem), 27±2% of which are polymorphonuclear. Inspontaneous bacterial peritonitis the fluid is usually cloudy, contains 6084±858 white blood cells/mm³, 77±4% of which were PMN and culture is positive for a single bacterial species, usually enteric in origin.Malignant andpancreatitis ascites are sterile, often cloudy, and contain an average of 696±273 and 1821±833 leukocytes/mm³, respectively, about half of which are polymorphonuclear. Amylase activity is increased in pancreatitic ascites, but not in other types of ascites. Stained smears of sediment for bacteria are often positive in bacterial peritonitis, but not in the other categories. Neither the specific gravity, protein concentration, nor glucose level is useful in the differential diagnosis of ascites. Based on the critical number of leukocytes alone, (500/mm³), one can accurately differentiate infected from uninfected fluid in over 90% of ascitic patients.     

Inhibition of iron absorption by omeprazole in rat model

Since gastric acid is an important luminal factor in the absorption of non-heme iron, the effect of omeprazole on the absorption of iron in a rat model was studied. Iron absorption studies were performed on rats on a normal diet (N=42) and rats fed an iron-deficient diet (N=43) for three weeks. Rats were orally dosed with 40 mol/kg of omeprazole or placebo daily for two days prior to iron absorption studies. Rats were orally dosed with 1 mmol of ferrous chloride, ferric chloride or food iron (dietary suspension) containing 11 g of iron and labeled with 1 Ci of⁵⁹Fe. Omeprazole-treated rats on the normal diet had no significant reduction in the absorption of ferric, ferrous, or food iron. In the rats on the iron-deficient diet, the absorption of ferrous iron decreased from 76±7.5% (mean±se) in control rats to 38±8.5% in the omeprazole-treated rats (P<0.003) and the absorption of food iron decreased from 65±7.5% in control rats to 37±6.5% in the omeprazole-treated rats (P<0.016). There was no significant reduction in the absorption of ferric iron. Omeprazole therapy is unlikely to be associated with significant iron malabsorption in normal patients but may reduce iron absorption in pathological states associated with increased iron absorption such as iron deficiency.     

Increased plasma fibronectin in patients with systemic lupus erythematosus

Summary To add to our knowledge of collagen diseases, plasma fibronectin (FN) in patients with systemic lupus erythematosus (SLE) has been measured, and it was determined that the plasma FN value in those with SLE was 454±36 g/ml, is significantly higher than the FN value in normal subjects (234±21 g/ml. Further, the plasma FN value of patients with active SLE was significantly higher (591±46 g/ml than that of patients with non-active SLE (287±31 g/ml. The plasma FN value of SLE patients was also seen to be associated with the peripheral blood platelet count and with the dose level of the corticosteroid hormone administered to patients. In active SLE patients, it was similarly found that the plasma FN value had a significant correlation with the peripheral blood lymphocyte count and with the dose level of the corticosteroid hormone given to patients. Since the plasma FN value is known to be high in untreated SLE patients, it was felt that the increase of the FN value in SLE patients is not due to the effect of the corticosteroid but to the disease itself.     

Serum Unconjugated Bile Acids as a Test for Intestinal Bacterial Overgrowth in Dogs

Small intestinal bacterial overgrowth (SIBO) has a high incidence in dogs and, as in humans, is difficult to diagnose. The aim of this study was to determine the diagnostic significance of serum unconjugated bile acid concentrations in dogs with bacterial overgrowth. Fasting sera were obtained from 23 dogs: 10 with culture-proven SIBO, 8 with indirectly diagnosed SIBO (normal pancreatic function but small intestinal disease associated with subnormal serum cobalamin and supranormal folate concentrations), and 5 healthy controls. Unconjugated bile acids were determined using gas chromatography–mass spectrometry after isolation by liquid–solid extraction and anion-exchange chromatography. Mean serum unconjugated bile acid concentrations were significantly elevated in dogs with SIBO (mean ± sd: 0.91 ± 1.03 mol/liter), and in dogs with indirectly diagnosed SIBO (2.11 ± 2.20 mol/liter) compared to clinically healthy dogs (0.015 ± 0.015 mol/liter, P < 0.005). Cholic acid was the predominant unconjugated bile acid in the serum of dogs with SIBO. In conclusion serum unconjugated bile acid concentrations of healthy dogs are significantly lower than reported values for humans, and this fraction represents a relatively small proportion (0–2.3%; mean 0.8%) of the total bile acids in dogs. Unconjugated bile acids increased 10- to 20-fold in dogs with SIBO indicating the clinical utility of serum unconjugated bile acids for diagnosis of intestinal bacterial overgrowth in dogs.     

Cholinergic Stimulation and Nonadrenergic, Noncholinergic Relaxation of Human Colonic Circular Muscle in Idiopathic Chronic Constipation

The aim of our study was to further investigatethe pathophysiological mechanism underlying idiopathicchronic constipation (ICC), a disorder of colonicmotility. A possible alteration of excitatory and inhibitory neurotransmission and also the roleof inhibitory neurotransmitters such as nitric oxide(NO), 5-adenosine triphosphate (ATP), andvasoactive intestinal peptide (VIP) has been evaluatedon preparations of distal colon from patients with or withoutICC. The isometric tension was recorded from isolatedcircular muscle strips of both experimental groupsduring pharmacological and electrical field stimulation (EFS). The contractile response obtained byacetylcholine (ACh 20 M), EFS (20 Hz, 20 V, 1 msec,pulse trains lasting 1 min) and substance P (SP 1 M)was significantly lower in ICC than in controlpreparations. The effect of inhibitory nonadrenergic,noncholinergic innervation was evaluated using EFS atlow frequencies (0.5-8 Hz), after cholinergic andsympathetic blockade with atropine (3 M) andguanethidine (3 M). The maximum relaxation valueexpressed as percentage of inhibition of SP-inducedcontraction was significantly higher in ICC than incontrol preparations (87 ± 2.4 and 67 ±6.3, respectively; P < 0.05). Experiments with substances thatantagonize or reduce the effect of putative inhibitorymediators (VIP 6-28, apamin andN^G-nitro-L-arginine) suggest that analteration in NO and ATP release is present in ICC preparations. In particularat a higher inhibitory frequency NO-mediated relaxationis enhanced in ICC vs control, supporting the hypothesisthat excessive NO production may be involved in pathophysiological mechanism ofconstipation.     

Depressed selenium and vitamin E levels in an alcoholic population

Serum selenium and vitamin E levels have been measured in subjects with established alcoholic liver disease, in alcoholics within the community, and in appropriate controls. Both serum selenium and vitamin E levels were shown to be significantly depressed (P<0.01) in the alcoholic study groups and serum selenium was more markedly depressed in subjects with established liver disease (controls, serum selenium 108±13 g/liter, vitamin E 27.6±7.2 mol/liter; community alcoholics, serum selenium 94±19 g/liter, vitamin E 15.3±3.4 mol/liter; alcoholic liver disease, serum selenium 78±15 g/liter, vitamin E 14.7±5.6 mol/liter). Depressed serum selenium levels correlated closely with poor nutritional status (r=0.91). There were no changes in serum glutathione peroxidase activity. Liver disease activity, as judged by transaminase (AST), was more markedly abnormal in subjects with combined vitamin E and selenium deficiency compared to those with normal levels or isolated deficiencies (no deficiency, AST 48±19 units, combined deficiency, AST 75±21 units,P<0.03). Serum lipid peroxides were elevated in those with combined deficiency and the values correlated significantly with serum transaminases (r=0.40,P=0.03).     

Influence of glucagon on plasma levels of potassium in man

Summary To investigate the role played by glucagon in the regulation of plasma potassium, we have examined the behaviour of this ion during four 2 h infusions of saline, glucagon (200 ng/min), cyclic somatostatin (priming dose of 50 g followed by 5.8 g/min) and somatostatin plus glucagon in 6 normal volunteers. Glucagon alone produced no change in potassium, despite an increase in insulin. Somatostatin, in addition to depressing insulin, produced a slight but significant (p < 0.01) increase in potassium ( max: 0.2–0.8 mmol/l: mean ± SEM, 0.4±0.1). Infusion of somatostatin together with glucagon suppressed the glucagon-induced increase in insulin and greatly augmented the increase in blood glucose. Potassium rose significantly more (p < 0.02) than after somatostatin alone ( max: 0.5–1.3 mmol/l; mean 0.9±0.1), indicating that hyperkalaemia results from hyperglucagonaemia in the absence of insulin. Evidence is presented that this last phenomenon is not mediated by hyperglycaemia or by a reduction in aldosterone secretion. It is suggested that low blood insulin and increased glucagon could be one of the mechanisms that underlie or magnify the hyperkalaemia observed in cases of serious stress or decompensated diabetes.     

Antiplatelet and Antithrombotic Activity of Cilostazol is Potentiated by Dipyridamole in Rabbits and Dissociated from Bleeding Time Prolongation

Purpose: To determine the antiplatelet effect of cilostazol (Pletal^®) and its interaction with dipyridamole in in vitro and in vivo rabbit models, and to see if it can be dissociated from bleeding time prolongation.Methods: In vitro collagen-induced platelet aggregation was measured by an impedance-based aggregometer. The in vivo antithrombotic effect was evaluated in a rabbit carotid artery cyclic flow reduction (CFR) model, in which repetitive thrombosis was induced by mechanical injuries of the artery and stenosis. Template bleeding time was determined in rabbit ear arterioles and hindlimb nail cuticles.Results: In vitro platelet aggregation was slightly inhibited by 4 M cilostazol (22 ± 6%), and modestly by 13 M (57 ± 3% of aggregation). While dipyridamole itself up to 13 M had no significant inhibition, it potentiated the effect from cilostazol: in the presence of 4 M dipyridamole, 4 M cilostazol inhibited aggregation by 47 ± 6%. Dipyridamole also potentiated the CFR reducing effect of cilostazol: combination of dipyridamole (no effect by itself) and cilostazol at 1 M decreased CFRs to levels achieved by 3–4 M cilostazol alone. Bleeding times were similar in controls and animals treated with cilostazol, or with cilostazol and dipyridamole. In contrast, aspirin (4 mg/kg), while reducing CFRs, significantly increased bleeding time.Conclusion: These results suggest that dipyridamole potentiates the antiplatelet effect of cilostazol without prolongation of the bleeding time, implying a potential novel combination antithrombotic therapy.