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Biomedical subjects

J M Ritter

Publications and source records attributed to J M Ritter.

At least 109 records · Page 6Linked to original sources
PubMed1989

Calcitonin gene related peptide (CGRP) activates adenylate cyclase of bovine aortic endothelial cells: guanosine 5' triphosphate dependence and partial agonist activity of a tyrosinated analogue.

Human calcitonin gene related peptide (hCGRP) has been shown to release prostacyclin from cultured human endothelial cells and activate adenylate cyclase in endothelial cell membrane preparations. Human endothelial cells are difficult to obtain, so a bovine aortic endothelial cell model has been used to investigate the actions of hCGRP further. Bovine aortic endothelial cells were cultured and membranes prepared from them. In these membrane fractions there was a concentration dependent activation of adenylate cyclase by hCGRP, which required the presence of guanosine 5' triphosphate. Basal activity of adenylate cyclase was 41.5 pmol.min-1.mg-1 protein. The concentration for half maximum activation of adenylate cyclase (Kact) by hCGRP was 842 nM. The maximum increase in adenylate cyclase activity above basal in response to hCGRP was 180 pmol cyclic adenosine monophosphate.min-1.mg-1 protein. A [tyr degree] substituted analogue of hCGRP [( tyr degree]-hCGRP) also activated adenylate cyclase (Kact 2.2 microM) but the maximum stimulation by [tyr degree]-hCGRP was less than that obtained with native peptide. The same analogue partially inhibited the hCGRP dependent activation of adenylate cyclase (Ki = 2 microM). These studies show that hCGRP acts on a receptor on endothelial cells to activate adenylate cyclase and that [tyr degree]-hCGPO is a partial agonist at this receptor. The potent vasodilator properties of hCGRP may be mediated through or modified by its interaction with endothelial cells.

Adenylyl Cyclases↗
PubMed1989

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

1. Effects of a single intravenous dose of aspirin (600 mg) on bradykinin-stimulated prostaglandin (PG) and on thromboxane (TX) biosynthesis were determined in nine healthy male volunteers. Plasma concentrations of 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha were measured in samples obtained during repeated 10 min intravenous infusions of bradykinin before and up to 6 h after the dose of aspirin. TXB2 was measured in serum from blood allowed to clot at 37 degrees C. 2. Aspirin inhibited bradykinin stimulated PG and platelet TX biosynthesis 0.5 h after the dose. Serum TXB2 remained low, whereas PG synthesis recovered within 6 h. 3. Effects of intravenous sodium salicylate (600 mg) were studied identically in eight subjects. Prostanoid biosynthesis was not inhibited. 4. Biosynthesis of prostacyclin and TXA2 under basal conditions was studied in eight subjects by measuring 2,3-dinor-6-oxo-PGF1 alpha and 2,3-dinor-TXB2 in hourly urine samples obtained during and after intravenous infusion of aspirin and, on a separate occasion, of vehicle. 5. Aspirin infusion reduced urinary excretion of both metabolites greater than 90%, but excretion of 2,3-dinor-6-oxo-PGF1 alpha recovered more rapidly than did that of 2,3-dinor-TXB2. 6. We conclude that cyclo-oxygenase is rapidly synthesised in bradykinin-responsive tissues in vivo and that this reflects similarly rapid enzyme biosynthesis in tissues that produce PGI2 under basal conditions.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Actions of bradykinin and related peptides on rabbit coeliac artery rings.

1. Rabbit coeliac artery rings were mounted in tissue baths containing Krebs solution at 37 degrees C in order to determine whether their response to bradykinin is initiated by B1- or B2-receptors. Tension was recorded isometrically. 2. Phenylephrine contracted the tissue. Subsequent addition of bradykinin or des Arg10-kallidin caused relaxation which was not dependent on an intact endothelium. Des Arg10-kallidin, a B1-receptor selective agonist, was more potent than bradykinin. 3. [beta-Thienyl alanyl6,9, D-Phe8]-kallidin and [Leu9]-des Arg10-kallidin antagonized bradykinin and des Arg10-kallidin. [Leu9]-des Arg10-kallidin, a B1-receptor selective antagonist, was more potent than [Thi6,9, D-Phe8]-kallidin, a less selective drug that acts on both B1- and B2-receptors. 4. Kinin-induced relaxation was reversibly antagonized by ibuprofen (a cyclo-oxygenase inhibitor) and by 5-(N,N-hexamethylene)amiloride (an inhibitor of Na+/H+ exchange). Ibuprofen caused a parallel shift to the right of a semi-logarithmic plot of the agonist concentration-effect relationship, whereas the amiloride analogue depressed the maximum response and reduced the slope. 5. We conclude that bradykinin and des Arg10-kallidin relax rabbit coeliac artery by combining with B1-receptors. The response is mediated by a cyclo-oxygenase product and may be influenced by cellular Na+/H+ exchange.

Animals↗
PubMed1989

Local inhibition of converting enzyme and vascular responses to angiotensin and bradykinin in the human forearm.

1. The function of angiotensin converting enzyme was investigated in twenty-four healthy men. Forearm blood flow was measured under basal conditions and during administration of enalaprilat (a converting enzyme inhibitor) and/or peptide substrates of converting enzyme into the left brachial artery. Blood flow was compared in the two arms. 2. Enalaprilat had no effect on basal blood flow. The concentration of enalaprilat in venous blood from the control arm was low, and plasma renin activity was not increased, indicating that systemic inhibition of converting enzyme did not occur. 3. Effects of angiotensin and of bradykinin, administered intra-arterially, were limited to the infused arm. Enalaprilat (13 nmol min-1) inhibited converting enzyme in the infused arm, in which it caused approximately a 100-fold reduction in sensitivity to angiotensin I, while having no effect on the vasoconstriction caused by angiotensin II. Enalaprilat increased vasodilatation caused by bradykinin. 4. Aspirin, an inhibitor of cyclo-oxygenase, did not inhibit vasodilatation caused by bradykinin whether infused alone or with enalaprilat, indicating that these responses are not mediated by prostaglandins. 5. We conclude that under basal conditions neither conversion of angiotensin I to angiotensin II nor degradation of bradykinin determines resistance vessel tone in the human forearm. Converting enzyme may affect vascular tone in situations in which intravascular concentrations of peptides are increased over those present under basal conditions.

Adult↗
PubMed1988

Prostaglandin and thromboxane synthesis by tissue slices from human aortic aneurysms.

Sliced portions of the walls of human aortic aneurysms were incubated with extracts of human plasma and serum to determine the profile of prostanoid production. 6-Oxo-prostaglandin (PG) F1 alpha, PGE2, PGF2 alpha, and thromboxane (TX) B2 were measured by gas chromatography/electron capture mass spectrometry. 6-Oxo-PGF1 alpha, the stable hydrolysis product of PGI2, was the major cyclooxygenase product but substantial amounts of TXB2 (the hydrolysis product of TXA2), with smaller amounts of PGE2 and PGF2 alpha were also synthesised. These prostanoids could contribute to the response of the vascular wall to injury, thereby influencing the disease process. Serum extracts stimulated PGI2 and TXA2 synthesis, probably as a result of their Ca2+ content.

Adult↗
PubMed1988

In vitro studies with an anti-platelet monoclonal antibody; P256.

P256 is a platelet-specific monoclonal antibody. It has potential as a diagnostic agent for use in thrombus detection by radioimmunoscintigraphy. However, the whole antibody has been reported to cause platelet aggregation. The object of the present study was to determine the effects of the F(ab')2 and Fab' fragments of P256 on human platelets in vitro. Gel-filtered platelets were prepared from citrated venous blood, and aggregation was studied at 37 degrees C using the method of Born. The whole antibody caused aggregation over the concentration range 10(-9)-10(-7) M, with a maximum of 70% aggregation. The F(ab')2 fragment was less potent with a maximum response of only 45%. The monovalent Fab' fragment caused no aggregation at concentrations up to 10(-7) M. However, binding studies with 111In-labelled monovalent Fab' fragment demonstrated saturable displaceable binding (Kd = 9.1 x 10(-9) M). Aggregation induced by the divalent forms of the antibody was partially dependent upon added fibrinogen. It is concluded that the monovalent Fab' fragment of P256 may be used in platelet-labelling studies without risk of inducing aggregation irrespective of concentration. The whole antibody, or its divalent F(ab')2 fragment, may also be used provided their concentrations are kept below 10(-9) M.

Antibodies, Monoclonal↗
PubMed1987

Teratogenicity of di(2-ethylhexyl) phthalate, 2-ethylhexanol, 2-ethylhexanoic acid, and valproic acid, and potentiation by caffeine.

It is hypothesized that the teratogen di(2-ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2-ethylhexanol (2-EHXO), which in turn is metabolized to 2-ethylhexanoic acid (2-EHXA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of gestation. On an equimolar basis DEHP was least potent, 2-EHXO was intermediate, and 2-EXHA was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2-EHXA as the proximate teratogen. All three agents were potentiated by caffeine. Valproic acid, which is an isomer of 2-EXHA, also produced similar defects, and was approximately twice as potent as 2-EHXA.

Abnormalities, Drug-Induced↗
PubMed1987

Predominance of locally-produced prostaglandin E2 over prostacyclin in skin incisions in man.

Blood was collected from skin incisions made by the 'Simplate' technique in 8 healthy men. Prostaglandin (PG) E2, but not 6-oxo-PGF1 alpha, the stable hydrolysis product of prostacyclin (PGI2), was tentatively identified using capillary column gas chromatography/electron capture mass spectrometry. It was not possible to quantify PGE2 because of the small volumes of blood generated by this method. Larger blood samples were then collected from 22 skin incisions in 13 patients undergoing cardiothoracic surgery. Concentrations of PGE2 were substantially greater than 6-oxo-PGF1 alpha in every sample. 13,14-Dihydro-15-oxo-PGF2 alpha, a pulmonary metabolite of PGE2, was not elevated, indicating that the PGE2 was synthesised locally at the site of incision. In 6 further patients undergoing cardiac surgery, blood sampled from an antecubital vein before and during operation contained little or no PGE2. We conclude that a substantial proportion of the PGE2 in blood emerging from skin incisions may be formed locally by the traumatised microvessels, consistent with the hypothesis that PGE2 is the principle prostaglandin synthesised by human cutaneous microvessels in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Low dose aspirin treatment in late pregnancy differentially inhibits cyclo-oxygenase in maternal platelets.

Eighteen pregnant women were treated with aspirin, 37.5 mg once daily by mouth. Treatment was started two weeks before the expected date of delivery, and continued until delivery. Seventeen untreated women were studied concurrently. Platelet thromboxane (TX) production was determined by radioimmunoassay of TXB2 in serum from blood incubated for one hour with thrombin at 37 degrees C. Maternal blood was studied before treatment and at delivery. Fetal blood, from the cord, was studied at delivery. Prostacyclin (PGI2) production by rings of umbilical artery incubated in Hanks' solution at 37 degrees C for one hour was determined by radio-immunoassay of its hydrolysis product, 6-oxo-prostaglandin (PG) F1 alpha. Maternal and fetal blood from untreated women produced similar amounts of TXB2. Aspirin, in the dose regimen used, significantly inhibited TXB2 production in maternal but not in fetal blood, and did not impair PGI2 synthesis by umbilical artery rings. This differential effect on the cyclo-oxygenase of maternal platelets is probably due to the unusual kinetic properties of aspirin, and may prove therapeutically useful.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Identification of 13,14-dihydro-15-oxo-prostaglandin F2 alpha in the circulation during infusions of bradykinin and prostaglandin E2 in man.

Bradykinin, prostaglandin E2 (PGE2), PGD2 and vehicle (saline) were each administered intravenously on separate occasions to 6 healthy men for a period of 60 min. 13,14-Dihydro-15-oxo-PGF2 alpha was identified in plasma samples obtained during intravenous infusions of bradykinin and PGE2 but not during infusions of PGD2 or saline. The structure of this metabolite was verified by comparison of three different derivatives with authentic standards, using gas chromatography/electron capture mass spectrometry. Bradykinin increased plasma concentrations of 13,14-dihydro-15-oxo-PGF2 alpha from baseline values in the range less than 5-10 pg ml-1 to 28-403 pg ml-1. PGE2 increased plasma concentrations of 13,14-dihydro-15-oxo-PGF2 alpha from baseline values in the range less than 5-17 pg ml-1 to 160-603 pg ml-1. Neither PGD2 nor the vehicle affected 13,14-dihydro-15-oxo-PGF2 alpha concentrations. We conclude that bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2 alpha may be derived from PGE2 or PGF2 alpha. The possibility that these prostaglandins are synthesized by stimulation of microvascular endothelium during bradykinin infusion is discussed.

Adult↗
PubMed1987

Recovery of prostacyclin synthesis by rabbit aortic endothelium and other tissues after inhibition by aspirin.

The effect of aspirin on prostacyclin (PGI2) and thromboxane B2 (TXB2) synthesis was studied in rabbits. Tissues were removed from animals killed at intervals after injection of aspirin, and incubated with Hanks' solution. PGI2 synthesis was monitored by radioimmunoassay of its hydrolysis product, 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha). TXB2 production in clotted blood, also measured by radioimmunoassay, was determined as an index of platelet cyclo-oxygenase activity. 6-oxo-PGF1 alpha and TXB2 production 0.5 h after aspirin were similarly inhibited to less than 5% of control in all incubations. Subsequent recovery of PGI2 synthesis occurred more rapidly in aortic endothelium than in other tissues, including aorta denuded of endothelium. Recovery of TXB2 production was slower than that of PGI2. Intravenous cycloheximide prevented the partial recovery of PGI2 synthesis that otherwise occurred 6 h after aspirin, while intravenous epidermal growth factor increased recovery. It is concluded that in the rabbit, cyclo-oxygenase is synthesized more rapidly in aortic endothelium than in deep layers of aorta, or in the other tissues studied.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

pH-dependent stimulation by Ca2+ of prostacyclin synthesis in rat aortic rings: effects of drugs and inorganic ions.

Fresh rat aortic rings were incubated in HEPES-buffered salt solutions. Extracellular Ca2+ stimulated the production of prostacyclin (PGI2), as determined by radioimmunoassay of its stable hydrolysis product 6-oxo-prostaglandin F1 alpha. This action of Ca2+ was modified by H+ over the pH range 8.0-6.5. Stimulation by calcium ionophore A23187 was not pH-dependent. In parallel incubations of aortic rings with 45Ca2+, followed by washing in the presence of La3+, tissue uptake of 45Ca2+ increased progressively as extracellular pH was increased from 6.5-8.0. Over this range intracellular pH, estimated by the distribution of [14C]-dimethadione, varied from 5.9-7.4. Stimulation by Ca2+ of PGI2 synthesis was concentration-dependent over the range 0.7-20 mM. The maximum effect was an increase of approx. 4 fold. Nifedipine, but not verapamil or diltiazem, inhibited Ca2+-stimulated PGI2 synthesis. A dihydropyridine compound that activates voltage-dependent Ca2+ channels, Bay K 8644, did not increase PGI2 synthesis. 8-(N, N-diethylamino)-octyl-3,4,5 timethoxybenzoate (TMB-8), an antagonist of intracellular Ca2+ mobilisation, inhibited basal and Ca2+-stimulated PGI2 synthesis to a similar extent. A solution containing 40 mM K+ reduced Ca2+-stimulated PGI2 production. Mg2+ stimulated PGI2 synthesis in a pH-dependent manner but was less potent than Ca2+. Other divalent cations (Mn2+, Ba2+ and Sr2+), and La3+ had little or no effect on basal or Ca2+-stimulated PGI2 synthesis.

Animals↗
PubMed1987

Actions of amiloride analogues on prostacyclin synthesis by rat aortic rings.

1 Fresh rat aortic rings were incubated in HEPES-buffered salt solutions (pH 8.0) in the presence or absence of amiloride analogues. The effect of these drugs on prostacyclin (PGI2) synthesis was determined by radioimmunoassay of the stable hydrolysis product 6-oxo-prostaglandin (PG)F1 alpha. 2 Amiloride and phenamil (potent inhibitors of epithelial Na+ transport) had no significant effect on basal or Ca2+-stimulated PGI2 synthesis. 3 Several analogues previously reported to inhibit Na+/Ca2+ exchange caused a dose-related increase in 6-oxo-PGF1 alpha production in media containing NaCl 120 mM and CaCl2 2.5 mM. 2',3'-Benzobenzamil was the most potent analogue with a maximum stimulation of 4.51 +/- 0.89 fold, and an EC50 of 3 x 10(-5) M. 4 Amiloride analogues bearing substituents on the 5-amino group of the pyrazine ring have been reported to inhibit Na+/H+ exchange more potently than Na+/Ca2+ exchange. Three of these compounds inhibited Ca2+-stimulated 6-oxo-PGF1 alpha production at concentrations that did not significantly influence basal 6-oxo-PGF1 alpha production.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Bradykinin-stimulated prostaglandin synthesis in conscious rabbits.

1 Bradykinin was infused intravenously into conscious rabbits to determine its effect on the concentration of prostaglandins in plasma. 6-Oxo-prostaglandin (PG) F1 alpha, the stable hydrolysis product of prostacyclin, and 13,14-dihydro-15-oxo-PGF2 alpha, a metabolite derived from PGE2 and PGF2 alpha, were measured by gas chromatography-electron capture mass spectrometry. 2 Incremental infusions of bradykinin (0.4-3.2 micrograms kg-1 min-1) increased plasma concentrations of both 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha. 3 Aspirin (10 mg kg-1, i.v.) inhibited bradykinin-stimulated 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha synthesis at 30 min and 6 h. At 24 h, the mean bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2 alpha concentration was 66% of its original value, whilst 6-oxo-PGF1 alpha remained substantially inhibited. 4 The different rates of recovery of bradykinin-stimulated production of the two prostaglandins after inhibition by aspirin suggests that intravenous bradykinin stimulates prostacyclin and PGE2/PGF2 alpha production in distinct cell populations which synthesize cyclo-oxygenase at different rates.

Animals↗
PubMed1987

Location of extra-adrenal catecholamine secreting tumours by selective venous sampling and nuclear magnetic resonance scanning.

Iodinated meta-iodobenzylguanidine (MIBG) scanning is a safe non-invasive method for locating extra-adrenal paragangliomas. However, a positive result is dependent on the presence of an uptake mechanism in the tumour. We report two cases of MIBG negative intracranial catecholamine secreting tumours successfully located by selective venous sampling and nuclear magnetic resonance scanning.

3-Iodobenzylguanidine↗