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Biomedical subjects

R D Zipser

Publications and source records attributed to R D Zipser.

At least 37 records · Page 2Linked to original sources
PubMed1987

Prostaglandin regulation of colonic blood flow in rabbit colitis.

Human and experimental colitis are associated with release of both vasoconstrictor and vasodilator eicosanoids. To determine the pattern of colonic blood flow in vivo and the role of prostaglandins and thromboxanes, immune complex-mediated colitis and delayed hypersensitivity-mediated colitis were induced in rabbits. Organ blood flow was determined in conscious animals by radiolabeled microspheres before and after cyclooxygenase or thromboxane synthetase inhibition. Colonic blood flow was twofold higher in colitis than in control animals. Thromboxane synthetase inhibition with dazoxiben caused a slight further increase of colon perfusion in animals with colitis, but thromboxane receptor blockade had no effect. Prostaglandin inhibition with indomethacin and ibuprofen did not affect blood flow in controls, but in animals with colitis these drugs markedly reduced colonic blood flow to the level of control animals. The data demonstrate that vasodilatory prostaglandins enhance colonic blood flow in acute colon inflammation.

Animals↗
PubMed1987

Effects of captopril on renal function in patients with cirrhosis and ascites.

Blockade of angiotensin-converting enzyme has been variously reported to increase or to decrease sodium excretion in patients with cirrhosis and ascites. We administered captopril (50-150 mg) to 11 patients with cirrhosis and ascites to determine the effects on blood pressure, renal blood flow and sodium excretion. Plasma renin activity increased and mean blood pressure fell (by 14 mm Hg). Para-aminohippurate clearances increased from 321 +/- 53 to 559 +/- 83 ml/min (P less than 0.005), but inulin clearances were minimally altered (73 +/- 8 to 76 +/- 7 ml/min), suggesting preferential dilation of glomerular efferent arterioles. Despite unchanged glomerular delivery of sodium, urinary sodium excretion fell in all subjects (from 2.70 +/- 1.00 to 0.48 +/- 0.21 mEq/h), urinary volume was reduced (377 +/- 55 to 182 +/- 42 ml/h, P less than 0.005), and the natriuretic effect of furosemide was blunted. The antinatriuretic effect of captopril may be mediated by reduced angiotensin II-mediated sodium excretion, by decreased prostaglandin production, and/or by indirect effects of reduced blood pressure. Captopril impairs rather than promotes sodium excretion.

Adult↗
PubMed1987

Chemotactic peptide stimulation of leukotrienes from healthy and inflamed rabbit colons.

Prostaglandins, thromboxanes and leukotrienes are increased in human and experimental colitis. To evaluate the biosynthesis of these eicosanoids, colon inflammation was induced in rabbits by formalin enema followed by i.v. immune complexes, and the distal colon was perfused ex vivo. Bradykinin increased synthesis of prostaglandin E2 and thromboxane B2 more from colitis than from control colons (both P less than .001) but had no effect on leukotriene synthesis. The inflammatory cell agonist N-formylmethionyl-leucyl-phenylalanine (30 ng) also induced greater synthesis of prostaglandin E2 (70 +/- 13 vs. 14 +/- 6) and thromboxane B2 (84 +/- 22 vs. 20 +/- 11) from colitis than from control colons (P less than .01), but leukotriene B4 (416 +/- 68 vs. 438 +/- 128 ng/5 min) and leukotriene C4 (171 +/- 50 vs. 203 +/- 25 ng/5 min) synthesis were greatly augmented in both colitis and control colons. In vitro incubations demonstrated similar dose-dependent stimulation of leukotriene B4 by N-formylmethionyl-leucyl-phenylalanine in both colitis and control colons. These studies demonstrate that healthy colon tissue as well as colitis tissue can produce proinflammatory leukotrienes in response to bacterial peptides. Leukotriene production may contribute to the induction or mediation of colon inflammation.

Animals↗
PubMed1986

Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease.

Renal prostaglandins have several key functions in patients with severe liver disease and ascites. Increased activity of vasodilatory prostaglandins counters the underlying impairment in renal perfusion and the effects of vasoactive hormones. Prostaglandins also participate in renin secretion, renal diluting ability, sodium excretion, the action of diuretics, and, possibly, the development of the hepatorenal syndrome. Nonsteroidal anti-inflammatory drugs inhibit these compensatory actions of prostaglandins and cause a functional reduction in glomerular filtration rate and an impairment in sodium and fluid excretion. The severity of these nephrotoxic effects depends on the potency of the drug in inhibiting renal prostaglandins and on patient susceptibility. Patients with ascites and avid sodium retention, sodium-restricted diets, or concurrent diuretic use are most at risk. If nonsteroidal anti-inflammatory drugs must be administered to these patients, the type of drug should be carefully selected and renal function should be closely monitored.

Anti-Inflammatory Agents↗
PubMed1986

Implications of nonsteroidal anti-inflammatory drug therapy.

This panel considered the clinical implications of nephrotoxicity due to nonsteroidal anti-inflammatory drugs. Although the clinical benefits and safety of these agents are well established, the drugs may adversely affect renal perfusion, electrolyte balance, and blood pressure in susceptible patients. The renal effects of these agents are directly related to their potency in inhibiting renal prostaglandins as reflected by inhibition of urinary prostaglandin excretion; however, none of the nonsteroidal anti-inflammatory drugs is completely free of the risk. Hyperkalemia is the most frequently observed adverse effect, most commonly occurring in patients with diabetes mellitus, patients with mild to moderate renal insufficiency, and patients receiving beta blockers, angiotensin converting enzyme inhibitors, or potassium-sparing agents. Patients at risk for the development of fluid retention and acute reductions in glomerular filtration rate include those with congestive heart failure, systemic lupus erythematosus, chronic glomerulonephritis, or liver failure with ascites, those receiving diuretics, premature infants, and possibly the elderly. Monitoring of serum creatinine and electrolyte levels, blood pressure, and body weight is suggested for susceptible patients receiving these agents.

Acute Kidney Injury↗
PubMed1986

Effects of sulindac and ibuprofen in patients with cirrhosis and ascites. An explanation for the renal-sparing effect of sulindac.

Nonsteroidal antiinflammatory drugs impair renal function in susceptible patients with cirrhosis and ascites. A new antiinflammatory drug, sulindac, is reported not to affect renal function. To evaluate its renal-sparing mechanism, sulindac was administered for 5 days and ibuprofen for 1 day to 10 patients and paraaminohippurate and inulin clearances, serum and urine eicosanoids, and serum and urine sulindac metabolites were monitored. Ibuprofen reduced renal clearances in the 5 subjects with greatest sodium retention, whereas sulindac had no effect. Plasma concentration of the active sulfide metabolite was markedly increased in liver patients, and this concentration correlated with the inhibition of serum thromboxane (r = 0.75, p = 0.01). The percent inhibition of serum thromboxane with sulindac administration correlated with the inhibition of urinary eicosanoids (r = 0.68-0.81, all p less than 0.02). Ibuprofen was generally a more potent inhibitor of serum and urine eicosanoids. Thus, a major factor in the renal-sparing effect of sulindac appears to be its less potent inhibition of renal and extrarenal cyclooxygenase systems.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Does sucralfate affect the normal gastric mucosa? Histologic, ultrastructural, and functional assessment in the rat.

Although the action of sucralfate on ulcerated mucosa has been demonstrated, its effect on the histology, ultrastructure, and function of normal gastric mucosa is unknown. We investigated the effect of acute administration of sucralfate on the gastric mucosal history, ultrastructure, mucosal potential difference, and luminal release of prostaglandin E2. At 15 min, 1 h, and 3 h after intragastric instillation of sucralfate, whitish incrustations of the drug were firmly adhering to the glandular mucosa. Mucosal histology after sucralfate administration demonstrated the following: disruption and exfoliation of some of the surface epithelial cells, mucosal hyperemia, prominent release of mucus from the surface epithelial cells, and edema of lamina propria and submucosa. These changes were most prominent in the areas where sucralfate was in contact with the mucosal surface. Scanning and transmission electron microscopy confirmed the above changes. Sucralfate produced a drop in gastric mucosal potential difference and a significant increase in luminal release of prostaglandin E2. Sucralfate produces distinct morphologic and functional changes in the normal gastric mucosa, which may account for its preventive and therapeutic efficacy.

Aluminum↗
PubMed1985

Assay methods for 6-keto-prostaglandin F1 alpha in human urine. Comparison of chromatographic techniques with radioimmunoassay and gas chromatography-negative-ion chemical-ionization mass spectrometry.

6-Keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in human urine is considered to be a reflection of renal prostacyclin production. Because of the large amounts of unidentified eicosanoid metabolites in urine that may potentially bind to 6-keto-PGF1 alpha antisera, most radioimmunoassays include chromatographic purification of urine. A comparison of chromatographic techniques and of antisera to 6-keto-PGF1 alpha for the assay of human urine is described. Gas chromatography--negative-ion chemical-ionization mass spectrometry (GC--NICI-MS) was used as the reference method. Radioimmunoassays were performed with each of four antisera combined with each of three chromatographic purification systems (silicic acid, Sephadex LH-20, reversed-phase high-performance liquid chromatography). There was marked variability in the results; however, there was at least one chromatographic method for each antiserum that yielded results comparable to GC--NICI-MS. Direct radioimmunoassay of urine without chromatography yielded markedly elevated and variable results for the four antisera. In contrast, the four antisera gave very similar results with direct assay of media from isolated perfused organs. Thus, for the radioimmunoassay of 6-keto-PGF1 alpha in human urine, each antiserum is sensitive to different contaminants in urine and must be individually matched to a chromatographic purification system.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites: evidence that sulindac affects renal prostaglandins.

Nonsteroidal anti-inflammatory drugs (NSAID) suppress prostaglandin-dependent renal blood flow and furosemide-induced diuresis in patients with cirrhosis and ascites. Since sulindac may selectively spare inhibition of renal prostaglandins, we evaluated the interactions of acute administration of sulindac or indomethacin with furosemide in 15 patients with cirrhosis and ascites. Prior to furosemide, indomethacin reduced creatinine clearance (by 55%), urinary volume (by 82%), sodium (by 93%), and prostaglandin E2 (by 87%) (all P less than 0.05), whereas sulindac had no effect. However, both drugs reduced furosemide-induced diuresis. Indomethacin appeared slightly more potent in reducing the diuresis (55% v 38%), natriuresis (67% v 52%), and prostaglandin E2 (PGE2) release (81% v 74%). In a similar protocol in healthy subjects, furosemide-induced diuresis and natriuresis were also blunted by both drugs. Thus, under conditions of enhanced prostaglandin activity from furosemide, sulindac does affect renal function. These data suggest that renal function should be monitored in patients with cirrhosis and ascites who receive sulindac as well as other NSAID.

Anti-Inflammatory Agents↗
PubMed1985

Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis.

Inflammation of the colon is associated with increased production of prostaglandins (PG) and thromboxanes (Tx), and these eicosanoids may contribute to the inflammatory, secretory, and motility dysfunctions in colitis. To evaluate the potential role of peptide hormones in the enhanced eicosanoid release, colitis was established in rabbits by a delayed-type hypersensitivity reaction to dinitrochlorobenzene and by an immune-complex-mediated reaction. PG and Tx were identified in the venous effluent of isolated perfused colons by radiochromatography after [14C]arachidonic acid prelabeling, as well as by bioassay, and then quantitated by immunoassay. The two colitis models were morphologically similar. Basal release of PGE2, PGI2, and TxA2 was two- to threefold greater from colitis tissue than from control tissue. Bradykinin (BK) and angiotensin II (ANG II) increased release of 14C-labeled eicosanoids, whereas several gastrointestinal hormones had no effect. In control colons, BK and ANG II increased PGE2 and PGI2 release (by about 2-fold) but did not alter TxA2. In contrast, BK and ANG II markedly exaggerated the release of eicosanoids in colitis. BK increased TxA2 release with 10-ng bolus injections in colitis, but there was no response with up to 10-micrograms bolus injections in control colons. The BK-induced Tx release in colitis was associated with an increase in vascular resistance (measured as perfusion pressure). Infusion of the selective Tx inhibitors dazoxiben and OKY-046 reduced TxB2 release by 96% and blunted the transient rise in perfusion pressure (from 17 +/- 5 to 5 +/- 2 mmHg). Since BK and possibly ANG II are increased at sites of inflammation, the hypersensitive eicosanoid response to these peptides may augment the eicosanoid-mediated manifestations of colitis.

Animals↗
PubMed1985

Effects of selective inhibition of thromboxane synthesis on renal function in humans.

Thromboxane A2, a potent vasoconstrictor, is a major metabolite of arachidonic acid in the human kidney. To determine the role of thromboxanes in renal hemodynamics, we administered the new thromboxane inhibitor dazmegrel or placebo to 20 healthy volunteers for 14 days in a double-blind protocol. Dazmegrel reduced urinary thromboxane B2 by an average of 68% and serum thromboxane B2 by 79%, without affecting urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F 1 alpha. Neither p-aminohippurate clearance nor inulin clearance were altered by thromboxane inhibition. Thus it is unlikely that thromboxane A2 plays a major role in the regulation of glomerular function in healthy humans.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Prostaglandins, thromboxanes and leukotrienes in clinical medicine.

Although prostaglandin research began about 50 years ago, many of the most important advances in understanding the biochemistry, physiology and pharmacology have taken place within the past five to ten years. There is great potential for the extension of this research to the clinical practice of medicine. At this time, the most common interaction that clinicians have with the prostaglandin field is in administering nonsteroidal anti-inflammatory drugs, which function by inhibiting prostaglandins. The uses of these drugs include treating not only inflammation, but also dysmenorrhea, some renal disease, thrombotic diseases and some metabolic disorders. Prostaglandin analogs, with their potent effects on uterine contraction, are in common use in obstetrics. Other analogs, with gastric and duodenal cytoprotective effects are useful in treating peptic ulcer disease. Future benefits from prostaglandin and leukotriene research may include new therapy for inflammatory and hypersensitivity diseases such as asthma, inflammatory bowel diseases and dermatitis.

Animals↗
PubMed1984

Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport.

Thromboxane B2 (TxB) is excreted in human urine, but the mechanism of renal excretion and the quantitative relationship of urinary TxB to the active parent compound, thromboxane A2, of renal or extrarenal origin is not established. To determine the effects of vasoactive hormones, uricosuric agents and urinary flow rate on TxB excretion, urinary TxB was measured by radioimmunoassay and mass spectrometry, and renal metabolism of blood TxB was determined by radiochromatography of urine after i.v. [3H]-TxB infusions. Basal TxB was 6.7 +/- 1.1 ng/h during an oral water load, and TxB fell with s.g. antidiuretic hormone (to 3.4 +/- 0.4 ng/h, P less than 0.01) and with fluid restriction (to 2.6 +/- 0.5 ng/hr, P = 0.001) in parallel with urinary volume. Urinary excretion of unmetabolized [3H]-TxB also fell (by 56%) with fluid restriction, implicating altered metabolism rather than synthesis as the mechanism of the urinary flow effect. Angiotensin II infusions slightly reduced both TxB and urine volume, consistent with a flow effect. In contrast, probenecid did not alter urine volume, but increased urinary uric acid (by 244%), TxB (from 5.6 +/- 0.9 to 11.1 +/- 2.9 ng/h) and urinary excretion of blood [3H]-TxB (by 243%) by similar amounts (all P less than 0.05), suggesting that TxB is actively reabsorbed in the proximal tubule, similarly to uric acid. Thus, urinary excretion of TxB of renal and extrarenal origin is regulated by proximal and distal tubule factors.

Adult↗
PubMed1984

Urinary excretion of thromboxane B2 in patients with venous thromboembolic disease.

Platelet activation occurs in the initial phase of venous thrombus formation. To determine if thromboxanes (Tx) are released during this process and if Tx measurements are useful in the diagnosis, urinary immunoreactive TxB2 was measured by a rapid, inexpensive assay in 100 consecutive patients with suspected thromboembolic disease. Urinary iTxB2 was not increased in patients who took aspirin, nor in patients studied several weeks after onset of symptoms. Of the remaining patients, iTxB2 was increased in 11 of 15 with confirmed deep vein thrombosis and in seven of ten with confirmed pulmonary emboli. Of the 54 patients in whom acute thrombosis was excluded, iTxB2 was increased in only four (7 percent). A second study evaluated 25 additional patients with nondiagnostic lung scans who required pulmonary angiography; iTxB2 was increased in seven of ten with positive angiograms and in 0 of 15 with negative angiograms. The three patients with negative iTxB2 and positive angiograms were receiving heparin when studied. These data suggest that, in the absence of aspirin, platelet Tx is released during thrombus formation. In combination with other noninvasive tests, urinary iTxB2 is a useful adjunct to diagnosing acute thromboembolic disease.

Angiography↗
PubMed1984

Therapeutic trial of thromboxane synthesis inhibition in the hepatorenal syndrome.

Urinary excretion of the vasoconstrictor metabolite thromboxane B2 is increased in some patients with the hepatorenal syndrome. To define the role of thromboxanes in this syndrome and to evaluate a potential treatment for the renal impairment, we administered the thromboxane synthetase inhibitor dazoxiben to 5 patients with alcoholic hepatitis and rapidly progressive renal failure. Dazoxiben 200 mg/day followed by 400 mg/day reduced urinary thromboxane B2 by approximately 50% without altering prostaglandin E2 or 6-keto prostaglandin F1 alpha and without improving creatinine clearance (6 +/- 2 to 6 +/- 3 ml/min). In 3 additional patients, a higher dose of dazoxiben of 600 mg/day reduced thromboxane B2 by approximately 75% without consistent improvement in renal function. Thus, as judged by selective thromboxane inhibition with dazoxiben, thromboxanes are unlikely to be the key renal vasoconstrictor factor in the hepatorenal syndrome.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Sucralfate protection of the gastric mucosa against ethanol-induced injury: a prostaglandin-mediated process?

We studied whether sucralfate's protection of the gastric mucosa against ethanol induced injury in the rat is prostaglandin mediated. Rats received intragastric pretreatment: i) saline, ii) sucralfate, and iii) indomethacin-sucralfate. One hour later gastric contents were obtained for measurements of prostaglandin E2 and 2 ml of 100% ethanol were instilled. Rats were sacrificed 1 h later. The gastric mucosa was assessed: a) macroscopically by planimetry, b) by quantitative histology, and c) by measurements of gastric volume, pH and sodium. We found that sucralfate significantly increased gastric luminal release of prostaglandin E2. The increase was completely abolished by indomethacin pretreatment. Sucralfate protected the gastric mucosa against ethanol injury reducing macroscopic and histologic necrosis. Indomethacin (prostaglandin synthetase inhibitor) given 2 h prior to sucralfate markedly abolished its protective action against ethanol induced necrosis by 70%. These findings indicate that prostaglandins mediate some of the protective action of sucralfate. Sucralfate appears to have additional protective action which is prostaglandin independent.

Aluminum↗
PubMed1983

The effect of adrenergic stimulation on urinary prostaglandin E2 and 6 keto PGF1 alpha in man.

To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1 alpha) were determined. PGE2 and 6 keto PGF1 alpha were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196 +/- 40 to 370 +/- 84 ng/4 hrs/g creatinine and 6 keto PGF1 alpha (184 +/- 30 to 326 +/- 36), both p less than 0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1 alpha excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1 alpha varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1 alpha release (370 +/- 84 vs. 381 +/- 80) PGE2 and (326 +/- 50 vs. 315 +/- 40) 6 keto PGF1 alpha both p greater than 0.2). PHT alone stimulated only 6 keto PGF1 alpha. PHB and the specific alpha 1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with alpha 1 characteristics.

6-Ketoprostaglandin F1 alpha↗