Magaldrate stimulates endogenous prostaglandin E2 synthesis in human gastric mucosa in vitro and in vivo.

BACKGROUND/AIMS: Prostaglandin E2 (PGE2) plays an important role in the inhibition of gastric acid production and exerts cytoprotective action. The in vitro and in vivo effect of magaldrate, an aluminum containing antacid, on PGE2 synthesis in the gastric mucosa was investigated. METHODOLOGY: In the first part of the study, magaldrate was added to a suspension of isolated gastric mucosal cells. In the second part, the antacid gel was applied to the gastric mucosa during gastroscopy and biopsies were taken from the same site 5 and 10 min later. RESULTS: The antacid significantly stimulated PGE2 release from the suspension of isolated gastric cells in vitro. The biopsies obtained after the application of magaldrate showed an increased PGE2 production compared to specimens obtained before. CONCLUSIONS: The data suggest that in addition to its neutralizing capacity as an antacid, magaldrate contributes to the cytoprotective activity of the mucosa by stimulating endogenous PGE2 synthesis.

Calcium modulates the synthesis of prostaglandin E2 in isolated colonic mucosal cells.

BACKGROUND/AIMS: The effect of calcium on colonic prostaglandin E2 synthesis was investigated in 26 healthy volunteers. MATERIAL AND METHODS: Biopsy specimens were obtained by colonoscopy and the mucosal cells were separated biochemically. The cells were incubated in EDTA or CaCl2 containing media for 15 and 30 minutes. RESULTS: The PGE2 synthesis was significantly (p < 0.001) diminished in the calcium free suspension (EDTA) compared to the CaCl2 containing suspension. To increase intracellular Ca2+ concentration, calcium ionophore A 23187 was added for the last 15 minutes. It significantly stimulated the prostaglandin production. In addition, the calcium channel blocker verapamil did not alter the PGE2 synthesis, whereas trifluoperazine, a calmodulin inhibitor, markedly decreased the production rate. CONCLUSION: Calcium is an important stimulus of prostaglandin synthesis and inhibition of calmodulin by trifluoperazine decreases the arachidonic metabolism. In these regards, colonic tissue shares features with other tissues. However, in contrast to smooth or cardiac muscle, intracellular calcium concentration in colonic mucosa is not affected by verapamil, indicating that colonic calcium channels have a different affinity to this drug.

Alteration of prostaglandin E2 and leukotriene B4 synthesis in chronic inflammatory bowel disease.

BACKGROUND: Eicosanoid mediators play an important role in the pathogenesis of chronic inflammatory bowel disease. MATERIALS AND METHODS: The synthesis of prostaglandin E2 and leukotriene B4 in biopsied colonic specimens from patients with inflammatory bowel disease was compared with that from healthy controls. In contrast to surgical resection, biopsy by colonoscopy enabled patients with milder disease to be investigated. RESULTS: In subjects with Crohn's disease or ulcerative colitis, the synthesis of PGE2 was significantly (p < 0.05) increased, whereas synthesis of LTB4 remained unaltered. In addition, no differences in PGE2 and LTB4 production were found in different age groups or sex. CONCLUSION: We conclude that prostaglandin E2, compared to leukotriene B4, is the dominant eicosanoid in moderate inflammatory bowel disease.

Increased prostaglandin E2 and leukotriene B4 synthesis in isolated colonic mucosal cells in inflammatory bowel disease. a preliminary report.

The synthesis of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in colonic mucosal cells was investigated in 7 patients and 10 controls. Biopsies obtained from the descending colon were isolated biochemically by a special technique and the suspension of isolated colonic cells was incubated during 45 min. Compared with healthy subjects, patients with an inflammatory bowel disease showed a significantly increased PGE2 production. The LTB4 synthesis was enhanced as well, but this change was not statistical. We conclude that PGE2 is the dominant eicosanoid during less severe inflammatory bowel disease. Age and gender did not influence PGE2 or LTB4 synthesis.

Decreased gastric prostaglandin E2 synthesis in patients with gastric ulcers and in smokers.

BACKGROUND/AIMS: Prostaglandin inhibits gastric acid secretion and exerts protective action on the mucosa of the stomach. We studied the synthesis of prostaglandin E2 (PGE2) to determine the role of PGE2 in peptic ulcer disease. MATERIALS AND METHODS: Mucosal biopsies from 22 persons were obtained and incubated. PGE2 was then determined by radioimmunoassay. RESULTS: Compared to healthy subjects, patients with gastric ulcers or gastritis show diminished accumulation of PGE2 in the incubation medium. Other factors like age, gender, and alcohol consumption were also investigated, however, they do not influence endogenous prostaglandin production. In contrast, PGE2 synthesis was found to be decreased in smokers. CONCLUSIONS: Our data indicates a deficiency in endogenous PGE2 synthesis as one cause of gastric ulcerations and offer an explanation of the higher incidence of gastric ulcer disease in subjects with nicotine abuse.

[Right abdominal flank pain]. / Flankenschmerzen.

A 20-year-old female presented with right flank pain she had felt for two weeks. Colics, dysuria and fever were denied. The father and a sister of the patient were known to have cystic kidneys. Abdominal ultrasound revealed symmetrically enlarged kidneys with multiple cysts. Thus, the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) was made. For a follow-up period of four years renal function has remained normal. An intercurrent urinary tract infection was treated with antibiotics. Blood pressure has been normal over the entire follow-up period. As yet, no specific treatment had to be initiated.

Human atrial natriuretic peptide in non-dialyzed patients with chronic renal failure.

The role of human atrial natriuretic peptide (alpha-hANP) in the regulation of blood pressure (BP) and extracellular fluid volume (ECFV) remains elusive. This is of particular interest in chronic renal failure, in which first, increased sodium and water retention plays a major pathogenetic role in the development of hypertension, and second, altered secretion and/or metabolism of alpha-hANP may contribute to fluid volume and BP regulation. In the present study the relationship between renal function, BP, and circulating alpha-hANP was investigated in 16 non-dialyzed patients with stable chronic renal failure (CRF) without edema. Analysis of potential molecular heterogeneity of immunoreactive (ir) ANP was performed by gel permeation chromatography of plasma extracts from normotensive patients with CRF. Serum creatinine concentrations averaged 435 +/- 76 mumol/l ranging from 127 to 1187 mumol/l, systolic and diastolic BP averaged 158 +/- 4 and 94 +/- 2 mmHg, respectively. Plasma alpha-hANP concentrations ranged from 5 to 75 with a mean of 23 +/- 4 pmol/l as compared to a mean of 10 +/- 1 pmol/l in healthy volunteers (p less than 0.05). A significant linear correlation between plasma alpha-hANP and serum creatinine concentrations (r = 0.92) was observed; a weaker correlation was found between mean arterial pressure and alpha-hANP (r = 0.66). Chromatographic analysis revealed considerable amounts of higher molecular weight circulating ir-ANP, approximately 15,000 Da, in addition to the biologically active small mol wt ANP.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute retrosternal pain]. / Akute retrosternale Schmerzen.

A 52 year old patient was admitted for retrosternal pain not responding to nitroglycerin. Two years before he had suffered myocardial infarction. He had known cholecystolithiasis. Reinfarction was excluded, but the patient developed right upper quadrant abdominal pain with rebound tenderness, fever and leukocytosis. Abdominal sonography supported the diagnosis of acute cholecystitis. Acute illness resolved rapidly without complications under treatment with antibiotics. The patient underwent cholecystectomy during the free interval four weeks after discharge from the hospital. Intraoperative diagnosis was empyema of the gallbladder with cholecystolithiasis.

[Elevated plasma levels and heterogeneity of human atrial natriuretic peptide in patients with progressive chronic renal failure]. / Erhöhte Plasmaspiegel und Heterogenität von humanem atrialen natriuretischen Peptid bei Patienten mit progressivem chronischen Nierenversagen.

The role of human atrial natriuretic peptide (alpha-hANP) in chronic blood pressure (BP) and extracellular fluid volume (ECFV) regulation remains elusive. Hence, the role of alpha-hANP in chronic renal failure is of particular interest since in this pathological condition: (1) increased sodium and water retention plays a major pathogenetic role in the development of hypertension and (2) altered secretion and/or metabolism of alpha-hANP may contribute to fluid volume and BP regulation. To evaluate the relationship between the degree of renal insufficiency, BP and circulating alpha-hANP, we determined plasma alpha-hANP concentrations by radioimmunoassay in 16 nondialyzed patients with progressive chronic renal failure (CRF) of various degrees; subsequently analysis of potential molecular heterogeneity of immunoreactive (ir) ANP was performed by means of gel permeation of plasma extracts from patients with CRF without concomitant hypertension. Serum creatinine concentrations ranged from 127 to 1187 (435 +/- 76) mumol/l, systolic BP from 135 to 200 (158 +/- 4) and diastolic BP from 80 to 110 (94 +/- 2) mmHg, respectively. Plasma alpha-hANP concentrations ranged from 5 to 75 (23 +/- 4) pmol/l which was thus significantly higher as compared to 9 +/- 2 pmol/l found in healthy volunteers (p less than 0.05). A highly significant linear correlation between plasma alpha-hANP and serum creatinine concentrations (r = 0.92; p less than 0.01) was observed; a weaker correlation was found between mean arterial pressure and alpha-hANP (r = 0.66) and serum creatinine concentration (r = 0.59), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The kidney and cardiovascular system in obstructive jaundice: functional and metabolic studies in conscious rats.

1. The effects of jaundice on renal and circulatory function were investigated in chronic bile duct ligated (CBDL) rats 6 days after surgery. Sham operated (SO) animals served as controls. 2. Body weight was significantly reduced, whereas blood pressure remained unaltered, 6 days after bile duct ligation when serum bilirubin had risen to 169 +/- 18 (SEM) as compared with 2.8 +/- 0.3 mumol/l in SO rats. When compared with control values before surgery, urinary volume had significantly increased and absolute excretion of sodium, potassium, chloride and phosphate had decreased on day 6 after CBDL. Endogenous creatinine clearance was markedly depressed when compared with SO rats. Whereas fractional excretion of potassium remained unaltered, fractional excretion of sodium and of phosphate was significantly increased. 3. Except for a significant increase in urinary thromboxane B2 (TXB2) excretion in CBDL rats, no significant changes were observed in urinary excretion of prostaglandin (PG) E2, in the synthesis of PGE2, 6-keto-PGF1 alpha and TXB2 by isolated aortic tissue in vitro, nor in renal and cardiac adenosine triphosphatase activities or renal cortical mitochondrial function. 4. The adenosine triphosphate content of kidney cortex and cardiac mitochondrial function were significantly depressed in CBDL rats. 5. The results demonstrate that jaundice in CBDL rats is associated with functional and metabolic disturbances of the kidney and cardiac muscle, which may contribute to the renal and haemodynamic characteristics observed in jaundiced animals and humans.

Combined treatment of severe essential hypertension with the new angiotensin converting enzyme inhibitor ramipril.

Ramipril is a newly synthesized angiotensin converting enzyme inhibitor without a sulfhydryl group in the molecule but with a prolonged duration of action. Efficacy, tolerance and safety of this drug were evaluated in 10 patients with severe essential hypertension. After a treatment period of at least 4 weeks with the conventional antihypertensive drug combination of a diuretic and a beta-blocking agent with the vasodilator dihydralazine, their systolic and diastolic blood pressures averaged 161 +/- 6 and 111 +/- 2 mm Hg, respectively. Because diastolic blood pressure during this drug regimen was still greater than 105 mm Hg in all patients, the patients received ramipril initially at single daily doses of 5 mg in addition to their previous medication. The first dose of 5 mg ramipril resulted in a moderate but significant decrease in systolic and diastolic blood pressure in 9 of the 10 patients to 142 +/- 5 and 104 +/- 4 mm Hg (p less than 0.01), respectively, between 3 and 6 hours after drug administration. In 1 patient blood pressure was unresponsive to ramipril and 1 patient complained of nausea and vomiting within the first week of treatment with ramipril. Within the following 8-week treatment period with a once-daily intake of 5 or, if necessary, 10 mg of ramipril, diastolic blood pressure normalized in the remaining 8 patients to less than 90 mm Hg. Systolic and diastolic blood pressure averaged 130 +/- 5 and 83 +/- 2 mm Hg, respectively, at the end of the 8-week treatment period with ramipril. Severe hypotension and reflex tachycardia were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of plasma concentrations of human atrial natriuretic peptide to renal function and blood pressure in patients with progressive chronic renal failure.

Recent experimental and clinical findings indicate that immunoreactive human Atrial Natriuretic Peptide (alpha-hANP) is involved in the regulation of blood volume and arterial blood pressure (BP). Whereas the potential regulatory role of alpha-hANP in acute changes of extracellular fluid volume (ECFV) and in the modulation of BP has been demonstrated in various studies, their involvement in the chronic maintenance of sodium and water homeostasis is still equivocal. Moreover the role of alpha-hANP is of particular interest in chronic renal failure, since in this pathological condition increased sodium and water retention plays a major pathogenetic role in the development of hypertension and altered secretion and/or metabolism of alpha-hANP may contribute to fluid volume and BP regulation. To evaluate the relationship between the degree of renal insufficiency, BP and circulating alpha hANP we determined plasma alpha-hANP concentrations in 16 nondialyzed patients with progressive chronic renal failure (CRF) of various degree. Serum creatinine concentrations ranged from 127 to 1187 (435 +/- 76) mumol/l, systolic BP from 135 to 200 (158 +/- 4) and diastolic BP from 80 to 110 (94 +/- 2) mm Hg respectively. Plasma alpha-hANP concentrations ranged from 49 to 753 with a mean of 228 +/- 42 pg/ml which was thus significantly higher as compared to 90.0 +/- 16.2 pg/ml found in healthy volunteers (p less than 0.05). A highly significant linear correlation between plasma alpha-hANP and serum creatinine concentrations (r = 0.92) was observed; a weaker correlation was found between mean arterial pressure and alpha-hANP (r = 0.66) and serum creatinine concentration (r = 0.59), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of standard diuretics and RPH 2823 on transepithelial Na+ transport in isolated frog skin.

Short-circuit current (SCC) techniques were used to monitor the effects of various diuretic agents on Na+ transport in isolated frog skin, a model for the late distal tubule and the collecting duct of the mammalian kidney. Acetazolamide, hydrochlorothiazide, torasemide, and ethacrynic acid did not affect sodium transport (as indicated by the SCC) or transepithelial electrical resistance when added either to the apical (outer) or to the inner (basolateral, corial) bathing solution of the tissue. However, Na+ transport was sensitive to amiloride, the triamterene derivate dimethylamino-hydroxypropoxytriamterene (RPH 2823), and to furosemide. Whereas apical amiloride, and RPH 2823 induced a dose-dependent decrease in SCC and increase in transepithelial electrical resistance, apical furosemide resulted in a dose-dependent increase in SCC and a decrease in electrical resistance. None of the three diuretic agents caused a significant change in SCC when applied to the inner bathing Ringer's solution. The small furosemide-induced decrease in resistance compared with the huge increase in SCC suggests that furosemide affects Cl- permeability as well as Na+ permeability. Evidence for this notion was achieved by the following findings: The decrease in resistance after furosemide was more pronounced in tissues bathed in Cl(-)-free solutions compared with Cl(-)-containing solutions. n contrast, SCC stimulation by apical furosemide is Cl(-)-ion independent, but strongly Na+-ion dependent. SCC stimulation by furosemide is amiloride-sensitive. With respect to the onset, locus, and reversibility of action, it seems reasonable to assume that amiloride, RPH 2823, and furosemide all influence transepithelial Na+ transport by interacting with the Na+ channel or a regulator site of it within the apical membrane. The stoichiometry of the amiloride (RPH 2823)-receptor site interaction revealed Hill-coefficient(s) of less than 1, indicating a negative cooperativity among the receptor sites. The interaction between Na+ ions and amiloride or RPH 2823 displayed mixed competitive-noncompetitive inhibition. Taken together, these results support the hypothesis that amiloride and Na+ as well as RPH 2823 and Na+ may act at different loci on the apical entry mechanism in Rana esculenta skin.

Studies on the tubular effects of atrial extract and of atriopeptin III in conscious rats.

To investigate a tubular action of atrial natriuretic peptide (ANP), in the present study the effects of rat atrial extract (AE) and of synthetic rat atriopeptin III (AP III) were assessed in conscious rats during hypotonic saline infusion. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were estimated by the clearances (C) of PAH and of endogenous creatinine, respectively. CPO4 was used as a marker of proximal tubular function. Distal delivery (DD) and distal fractional absorption of chloride (DFACl), a measure of solute absorption in the diluting segments, were calculated from CH2O and CCl. AE and AP III increased RPF in all groups of animals. Low doses of AP III (40 ng/100 g B.W.) significantly increased urine flow rate and CCl, whereas GFR, CNa, CPO4, and CK remained unaltered. The marked natriuresis at high doses of ANP was associated with a rise in GFR and in absolute and fractional CPO4 as well as an increase in DD and CK. AE and AP III (1 microgram/100 g B.W.) decreased DFACl from 0.94 +/- 0.03 and 0.87 +/- 0.03 to 0.80 +/- 0.07 (p less than 0.05) and 0.54 +/- 0.07 (p less than 0.01), respectively. Some of the effects on tubular reabsorptive capacity probably result from medullary wash-out which thereby contributes to the natriuresis by potentiating the rise in the filtered load of sodium at high ANP levels. In the absence of changes in GFR and CPO4, the tubular action of ANP is more accurately reflected by CCl which may result from decreased absorption in the medullary collecting tubule.

Interaction of renal prostaglandins with the renin-angiotensin and renal adrenergic nervous systems in healthy subjects during dietary changes in sodium intake.

In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2 alpha, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.

Effects of trifluoperazine and verapamil on the hydro-osmotic response to antidiuretic hormone in the urinary bladder of the toad.

To investigate the role of the intracellular calcium-calmodulin complex in the hydro-osmotic response to antidiuretic hormone (ADH), the effects of trifluoperazine (TFP), a well-established inhibitor of calmodulin-mediated functions, and of verapamil (V), a calcium entry blocker, were examined in the urinary bladder of the toad, a model for the late distal tubule and the collecting duct of the mammalian nephron. Preincubation of the hemibladders with TFP at serosal concentrations of 10(-5) and 10(-4) M was without effect on basal water flow but markedly reduced the maximal hydroosmotic response to ADH (50 mU/ml) in a dose-dependent manner as compared to control hemibladders (23.60 +/- 1.23 vs. 42.17 +/- 4.18 mg/min per hemibladder (10(-5) M TFP) and 5.43 +/- 0.59 vs. 52.50 +/- 4.67 mg/min per hemibladder (10(-4) M TFP). This inhibitory effect of TFP on the ADH-stimulated osmotic water flow persisted in the presence of naproxen (10(-5) M), a known inhibitor of prostaglandin synthesis. The hydro-osmotic response to cyclic adenosine 3',5' monophosphate (cAMP, 10(-3) M) was also significantly reduced in TFP-pretreated tissues (11.68 +/- 1.84 vs. 32.83 +/- 3.14 mg/min per hemibladder), suggesting a post-cAMP inhibitory effect of TFP. V (10(-4) M) had no effect on basal water flow but significantly reduced the hydro-osmotic effect of 50 mU/ml ADH (15.17 +/- 1.05 vs. 38.00 +/- 3.39 mg/min per hemibladder). In contrast, cAMP-stimulated osmotic water flow was significantly stimulated in V-treated tissues (48.07 +/- 1.95 vs. 27.13 +/- 1.50 mg/min per hemibladder).(ABSTRACT TRUNCATED AT 250 WORDS)

Digoxin-like immunoreacting substance(s) in the serum of patients with chronic uremia.

In patients with chronic uremia we have previously demonstrated a significant inhibition of the Na-K-ATPase enzyme which represents the specific receptor protein for cardiac glycosides. Since an endogenous inhibitor of this enzyme was previously shown to react with a digoxin antibody, in the present study we determined digoxin-like immunoreacting activity(ies) (DLIA) by a radioimmunoassay in 15 nondialyzed patients with chronic renal failure. In native serum, DLIA ranged from 0 to 1.70 ng/ml and was unrelated to the degree of renal failure. After gel filtration of serum, DLIA exclusively eluted in the small molecular weight salt (FIII) and post-salt (FIV) fractions and averaged 0.22 +/- 0.04 and 0.20 +/- 0.05 ng/ml in fractions III and IV, respectively. Total activities ranged from 0.11 to 0.88 ng/ml with a mean of 0.42 +/- 0.06 ng/ml and closely correlated with the degree of renal impairment (p less than 0.001). The results confirm the presence of small molecular weight digoxin-like immunoreacting substance(s) in uremic serum. The variable activities in native serum and the lack of correlation between the degree of renal failure and DLIA in serum fraction IV previously shown to possess the Na-K-ATPase-inhibiting activity, however, indicate that DLIA may not reflect specifically the endogenous sodium pump inhibitor and that unspecific binding to this digoxin antibody of uremic toxins or other endogenous compounds, such as steroids other than aldosterone, may have occurred.