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J C Frölich

Publications and source records attributed to J C Frölich.

At least 145 records · Page 8Linked to original sources
PubMed1990

Effects of a PAF-antagonist (BN 52063) on bronchoconstriction and platelet activation during exercise induced asthma.

1. The effects of a specific PAF acether antagonist (BN 52063) on the response to isocapnic hyperventilation with dry cold air (ISH study) and exercise (EIA study) were assessed in a single dose and short term treatment study in 10 patients with exercise induced asthma. 2. ISH challenge was performed twice within 1 h after administration of either placebo, 240 mg BN 52063 p.o. or inhalation of 2.4 mg BN 52063. Hyperventilation increased Raw from 0.30 +/- 0.02 to 0.89 kPa s l-1 (P less than 0.001) after the first challenge and from 0.28 +/- 0.04 to 0.84 +/- 0.06 kPa s l-1 (P less than 0.001) after the second challenge. Oral pretreatment with BN 52063 did not result in a reduction of bronchoconstriction during both challenges. A significant increase of Raw was noted immediately after inhalation of BN 52063. An inhibition of PAF induced platelet aggregation (by a factor of 2) occurred after oral administration of BN 52063 after both ISH challenges (P less than 0.05). No significant inhibition of PAF induced platelet aggregation was seen after inhalation of BN 52063. At concentrations up to 30 microM in vitro, BN 52063 inhibited PAF induced platelet aggregation in a dose dependent manner. The IC50 of BN 52063 against the aggregating effect of 1 microM PAF was 7.0 +/- 2.1 microM. 3. In the EIA study the patients were challenged on the third day of treatment with either placebo or 240 mg BN 52063 p.o. or 5 mg BN 52063 by inhalation. Peak expiratory flow rates (PEFR) fell by 155 +/- 37 1 min-1 after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

Effects of acetylsalicylic acid and paracetamol alone and in combination on prostanoid synthesis in man.

1. The present study was designed to investigate the effects of acetylsalicylic acid and paracetamol given separately and in combination on total body and renal PGE2 synthesis in healthy volunteers. 2. In a randomized four-way cross-over study eleven female volunteers received for two consecutive days 3 g day-1 acetylsalicylic acid or 3 g day-1 paracetamol or a combination of 1.5 g day-1 acetylsalicylic acid and 1.5 g day-1 paracetamol, or 1.5 g day-1 acetylsalicylic acid separated by washout phases of at least 5 days. Urinary excretion of the major urinary metabolite of PGE2 (PGE-MUM), PGE2 and creatinine clearance were measured before and on day 2 of each treatment period. Compliance was tested by measuring metabolites of the two drugs in urine. 3. Paracetamol did not reduce urinary excretion of PGE2 whereas both dosages of acetylsalicylic acid caused a significant reduction. 4. The combination of both drugs did not reduce PGE2 excretion more than acetylsalicylic acid alone. 5. All four drug schedules reduced urinary excretion of PGE-MUM significantly.

Acetaminophen↗
PubMed1990

Endothelium-derived relaxing factor influences renal vascular resistance.

The mechanism of action of different vasodilators was investigated in the isolated perfused kidney of the rat. Acetylcholine (ACh, 10 nM-1 microM) and ATP (10 nM-1 microM), compounds known to relax isolated arteries in an endothelium-dependent fashion, caused concentration-dependent decreases in renal vascular resistance (RVR). Also, the endothelium-independent vasodilators verapamil (100 nM-10 microM), glyceryl trinitrate (GTN, 1-100 microM), and sodium nitroprusside (SNP, 1-100 microM) reduced RVR concentration dependently. Gossypol (10 microM, 5 min), an inhibitor of endothelium-derived relaxing factor (EDRF) production and/or release, increased basal RVR by 5% and significantly inhibited the vasodilator effects of ACh and ATP but had no effect on verapamil- or GTN-induced decreases in RVR. Methylene blue (MB) increased RVR dose dependently by up to 50%. About 50% of this effect could be antagonized with phentolamine (1 microM). MB abolished the relaxant response to ATP and attenuated the response to ACh. The dose-response curve of SNP was shifted to the right, and the relaxation to verapamil was slightly reduced. L-NG-methylarginine (100 microM) increased RVR by approximately 20%, and this effect was completely reversed by L-arginine (1 mM). N omega-nitro-L-arginine (100 microM) increased RVR by approximately 40% and attenuated the response to ATP but had no effect on the SNP-induced decrease in RVR. These results suggest that EDRF plays an important role in the regulation of RVR.

Acetylcholine↗
PubMed1990

[Unwanted effects of therapeutic drugs on the structure and function of the lung from a clinico-pharmacologic viewpoint].

Undesirable drug effects occur in the lung with about 35 frequently employed drugs and can be life-threatening or life-shortening. As examples, the clinical pattern, course, pathomechanism and therapy are shown for nitrofurantoin, bleomycin, amiodaron, opiates nitrofurantoin, and acetyl salicylic acid. The kinetic aspects of the occurrence and disappearance of the undesirable drug effects are stressed. If the kinetics of amiodaron, for example, are taken into consideration, the occurrence and course of the pulmonary affection can be understood. The use of steroids in case of pulmonary involvement of bleomycin and amiodaron is critically assessed.

Drug Hypersensitivity↗
PubMed1990

[Effects of intravenous prostaglandin E1 on bronchial histamine reactivity].

The effects of infusion of different doses of prostaglandin E1 (12.5, 25, 50 ng kg-1 min-1) on airway responsiveness to inhaled histamine dichloride were observed in 16 subjects with normal and high bronchial reactivity. Subjects were randomized to receive PGE1 or placebo within an interval of three days. Normal saline was infused on one day and PGE1 on the other days. 10 minutes after starting the PGE1 infusion bronchial provocation was induced by histamine aerosol challenge. The provocation concentration of histaminedihydrochloride causing a 50% increase in bronchial resistance increased from 0.36 +/- 0.12 to 0.57 +/- 0.19 mg/ml in hyperreactive subjects (n.s.) and from 0.77 +/- 0.12 to 1.57 +/- 0.19 mg/ml in normal subjects (beta less than 0.05) after administration of 50 ng kg-1 min-1 PGE1 (p less than 0.05). Partial flow rates measured at maximal bronchoconstriction increased dose-dependently during the infusion of PGE1 (p less than 0.05). We conclude that intravenous administration of PGE1 partially protects against histamine-induced bronchoconstriction. In hyperreactive subjects PGE1 selectively increases flow at low lung volumes indicating an action on peripheral bronchial resistance.

Airway Resistance↗
PubMed1990

Prostacyclin in hypertension.

Prostacyclin (PGI2) is known to cause vasorelaxation and inhibit platelet aggregation by receptor-mediated mechanisms. While cyclic (c)AMP is known to act as a second messenger for platelet aggregation, vasorelaxation by hyperpolarization has been described only recently and may provide an explanation, in addition to stimulation of cAMP, for the PGI2 mechanism of action on blood vessels. When PGI2 is infused into healthy volunteers it reduces blood pressure only at infusion rates that also cause significant side effects, primarily nausea, emesis, flushing, diphoresis and restlessness. In hypertensive patients blood pressure responses are complex and are influenced to some extent by secretion. PGI2 stimulates renin secretion by a direct effect on the juxtaglomerular apparatus, and also has an indirect effect by activating the sympathetic nervous system. Thus it is useless as an antihypertensive agent even apart from its debilitating side effects. Vascular PGI2 is synthesized endogenously by both the endothelial cells and the muscularis of arteries. While the endothelial cells undoubtedly synthesize larger amounts of PGI2, the muscularis comprises a much larger tissue mass so that the overall synthesis is about equally distributed between the endothelial and muscle cells. In patients with pregnancy-induced hypertension and some patients with essential hypertension, endogenous synthesis of PGI2 has been evaluated by measuring 2,3-dinor-6-keto-PGF1 alpha and has proved to be defective. Some drugs (cicletanine, thiazides, propranolol) have been shown to stimulate PGI2 synthesis, and inhibition of cyclooxygenase has been shown to abolish their antihypertensive effects. Whether stimulation of PGI2 synthesis affects the antihypertensive efficacy of these drugs is not yet known.

Animals↗
PubMed1990

[The effect of bronchial epithelium on bronchial contractility].

Removal of the epithelium increases the sensitivity of mammalian airway smooth muscle to several bronchoactive agents. An epithelium derived relaxing factor (EpDRF) of unknown identity has been postulated to modulate smooth muscle tone in the airways. Rings or segments of porcine third order bronchi, from some of which the epithelium had been removed mechanically, were mounted in organ baths for isometric tension recording. Removal of the epithelium affected bronchial reactivity. Metacholine produced concentration-dependent contractions of porcine bronchi. In the absence of epithelium the concentration response curve was shifted to the left (p less than 0.01). The effect of epithelium removal was not inhibited by diclofenac (100 microM), propranolol (5 microM), the inhibitor of endothelium-derived relaxing factor gossypol (10 microM). These observations suggest that the epithelium of porcine bronchi relaxes the tone of the subjacent smooth muscle. The EpDRF probably responsible for this effect is neither a cyclooxygenase product nor a stimulator of soluble guanylate cyclase.

Airway Resistance↗
PubMed1989

Platelet-activating factor induces the production of leukotrienes by human monocytes.

The aim of this study was to evaluate the role of platelet-activating factor (PAF) as a stimulator of leukotriene production by human monocytes. The production of leukotrienes was time- and concentration-dependent. Release of leukotrienes was half-maximal after 2 min and reached a maximum after 10 min. At a concentration of 10(-8) M, PAF induced the production of 0.14 +/- 0.01 ng LTB4/10(6) cells (mean +/- S.E., n = 8). At concentrations of 10(-6) M, PAF induced the production of 1.0 +/- 0.04 ng LTB4 and 0.22 +/- 0.03 ng peptidoleukotrienes (mean +/- S.E., n = 16). There was no metabolism of LTB4 as judged from stability of [3H]LTB4 added to the incubations. LTC4 was slowly metabolized by human monocytes to LTD4 and LTE4. The two specific PAF-receptor antagonists BN 52021 and WEB 2086 in concentrations of 10(-4) and 10(-6) M, respectively, inhibited the PAF (10(-6) M) stimulated LTB4 production completely. In this study, we demonstrate that nanomolar concentrations of PAF can stimulate the production of LTB4 and peptidoleukotrienes in human monocytes by a receptor-mediated mechanism.

Azepines↗
PubMed1989

Cardiovascular effects of leukotrienes.

Leukotrienes have been shown to significantly influence coronary vascular resistance, infarct size, pulmonary vascular resistance, bronchial tone, and renal vascular resistance either directly or indirectly. There is a notable dearth of data on human pathophysiologic conditions. With the advent of specific inhibitors of the synthesis and action of leukotrienes and, more importantly, of methods on the in-vivo synthesis of these potentially important mediators, these gaps in our understanding will be closed.

Animals↗
PubMed1989

An increase in the ratio of thromboxane A2 to prostacyclin in association with increased blood pressure in patients on cyclosporine A.

The aim of this study was to determine the effect of two years of treatment with cyclosporine A on blood pressure and the rates of secretion into the circulation of the vasoconstrictor thromboxane A2 and the vasodilator prostacyclin. Seven patient suffering from multiple sclerosis took part. Their blood pressures and urinary concentrations of 2,3-dinor-thromboxane A2 (a major urinary metabolite of thromboxane A2) and of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) were determined at the end of two years of treatment with cyclosporine A, and once again three months after cessation of this treatment. No other drugs were given during or after cyclosporine A. Mean arterial blood pressure was 113 +/- 5 mmHg (mean +/- SEM) during the cyclosporine A treatment, but fell to 94 +/- 4 mmHg after the three-month's wash-out period. Urinary excretion of the thromboxane metabolite decreased slightly from 674 +/- 150 pg.mg-1 creatinine during cyclosporine A therapy to 503 +/- 90 pg.mg-1-creatinine after the end of therapy. At the same time the prostacyclin metabolite increased significantly from 82 +/- 17 pg.mg-1 creatinine to 113 +/- 23 pg.mg-1 creatinine (P less than 0.05). The ratio of 2,3-dinor-thromboxane B2 to 2,3-dinor-6-keto-prostaglandin F1 alpha (taken as a measure of vasoconstrictor prostanoid activity) fell significantly from 8.4 +/- 0.8 4.7 +/- 0.6 (P less than 0.005). The shift in prostanoid production observed during cyclosporine A treatment could be one causal factor for the hypertensive and thromboembolic events associated with the use of this drug.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Human monocytes convert leukotriene B4 to two dihydro-leukotriene B4-metabolites.

Human monocytes metabolize LTB4 by an additional pathway different from omega-oxidation. Reverse-phase high performance liquid chromatography showed four metabolites: 20-COOH-LTB4, 20-OH-LTB4 and two metabolites less polar than LTB4 with an UV maximum at 232 nm. Gas-chromatography mass-spectrometry showed nearly identical mass spectra for both metabolites. The main mass fragments of the two metabolites were increased by two mass units compared to LTB4. Our findings suggest that LTB4 had been reduced to a known and a new dihydro-metabolite of LTB4. Both metabolites together amounted to 85% of total metabolites. The remaining 15% were omega-oxidation products. Thus, the major pathway of LTB4 metabolism by human monocytes is reduction to dihydro-LTB4.

Chromatography, High Pressure Liquid↗
PubMed1989

LTB4 in nephrotoxic serum nephritis in rats.

We studied leukotriene B4 (LTB4) synthesis in isolated glomeruli of rats with nephrotoxic serum nephritis. This nephritis was induced in male Sprague Dawley rats by injecting one proteinuric dose of nephrotoxic serum (rabbit anti-rat-GBM serum) after prior immunization of the rats with rabbit IgG. Histological and analytical examinations were performed in kidneys perfused until free of blood 6, 12, 24, 48 and 72 hours after induction of the disease. To investigate LTB4 production, glomeruli were isolated and incubated for one hour in the presence of Ca++-ionophore A23187. The supernatants were analyzed for LTB4. The peak comigrating on reverse-phase high performance liquid chromatography (RP-HPLC) with reference LTB4 was isolated. The ethyl ester trimethylsilyl ether derivative of this peak was analyzed by gaschromatography-mass spectrometry (GC/MS). Identical spectra of the glomerular samples and of reference LTB4 in the positive and in the negative ion chemical ionization mode provided unequivocal evidence that the substance released from the nephritic glomeruli was indeed LTB4. Six hours after injection of nephrotoxic serum, glomerular LTB4 release was highest with 5.52 +/- 0.50, then declining to 2.20 +/- 0.10 ng/mg glomerular protein at 12 hours. At 24, 48 and 72 hours no statistically significant difference from control animals was found. No metabolism of LTB4 to 20-hydroxy- or 20-carboxy-LTB4 was detected during the incubation period. Albuminuria developed during the first 24 hours after nephrotoxic serum challenge and rose steadily throughout the observation period up to 277 +/- 25 mg/24 hr after 72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed1989

Endothelium-derived relaxing factor (EDRF): a defence mechanism against platelet aggregation and vasospasm in human coronary arteries.

The goal of this investigation was to examine the interactions that can occur between platelet and endothelial cells, especially in human coronary arteries. In a first series of experiments, the effect of human endothelial cells (cultured on microcarrier beads) was tested on the aggregation of washed human platelets. Endothelial cells completely inhibited platelet aggregation. The prostacyclin-mediated anti-aggregatory component could be blocked with indomethacin. The remaining anti-aggregatory effect of endothelial cells could be prevented with the EDRF inhibitors, gossypol, haemoglobin and methylene blue. This indicates that the endothelial autoacoids, EDRF and prostacyclin, are both inhibitors of platelet aggregation. In a second approach we investigated the effect of aggregating platelets on the tone of human coronary arteries obtained during heart transplantation. Aggregating platelets produced strictly endothelium-dependent relaxations of coronary arterial strips. These relaxations were mainly mediated by EDRF, because inhibition of vascular prostacyclin synthesis with aspirin did not inhibit the relaxations significantly, but the relaxations were abolished by the aforementioned EDRF inhibitors. Platelet-derived adenosine 5'-diphosphate (ADP) is mainly responsible for the stimulation of EDRF production in coronary endothelial cells. ADP was an endothelium-dependent vasodilator, and apyrase (ADP-ase) completely prevented platelet-induced vasodilation. The other platelet products, serotonin and thromboxane A2, were weak and potent constrictors of coronary arteries, respectively. These data suggest that the ADP released by aggregating platelets stimulates the coronary endothelium to produce EDRF. EDRF overrides the constrictor effects of serotonin and thromboxane A2 and exerts an inhibitory effect against further platelet aggregation or adhesion.

Coronary Vasospasm↗
PubMed1989

[Cardiovascular effects of leukotrienes].

Leukotrienes are among the most potent lipid mediators of inflammation. Leukotriene B4 is one of the most potent endogenously synthesized chemotactic substances. It is probable that LTB4 plays an important role in the initial phase of the inflammatory reaction. The peptidoleukotrienes LTC4 and LTD4 are potent broncho- and vasoconstrictors. Administration of LTC4 and LTD4 leads to an increase of blood pressure in most species. These effects are sometimes dependent on the liberation of vasoactive prostaglandins. In addition, peptidoleukotrienes enhance vascular permeability rapidly. Peptidoleukotrienes elicit coronary vasoconstriction which is the most likely reason for the negative inotropic effect of these compounds. Recently the synthesis of peptidoleukotrienes has been demonstrated in the heart under experimental conditions. While the kidney shows a relatively mild vasoconstrictor response to leukotrienes, the pulmonary vascular bed generally responds with a brisk increase of resistance. Pathophysiological roles of leukotrienes require further definition. A striking increase in leukotrienes synthesis has been observed following endotoxin shock.

Animals↗
PubMed1988

Glucocorticoid effect on arachidonic acid metabolism in vivo.

Glucocorticoids have been shown in in vitro systems to inhibit the release of arachidonic acid metabolites, namely prostaglandins (PGs) and leukotrienes, apparently, via the induction of a phospholipase A2 inhibitory protein, called lipocortin. On the basis of these in vitro results, it has been suggested that inhibition of eicosanoid production is, at least partially, responsible for the well-known anti-inflammatory effect of glucocorticoids. There is, however, no firm evidence proving that glucocorticoids also inhibit prostaglandin or leukotriene synthesis in vivo. In a series of studies, we have investigated the effects of anti-inflammatory steroids on the production of six different cyclo-oxygenase products in vivo. Urinary prostaglandin (PG) E2(1), PGF2 alpha, thromboxane B2 (TxB2), 6-keto-PGF1 alpha, and the major urinary metabolites of the E and F PGs, PGE-M and PGF-M, respectively, were determined by radioimmunoassay and by GC-MS. Administration of pharmacological doses of dexamethasone to rabbits failed to inhibit urinary excretion rates of PGE2, TxB2, 6-keto-PGF1 alpha and that of PGE-M and PGF-M. In contrast, urinary PGF2 alpha was slightly reduced by dexamethasone. In further experiments the effect of dexamethasone was studied in humans. Urinary excretion rates of PGE2, PGE-M, PGF-M, 2,3-dinor TxB2 and 2,3-dinor 6-keto-PGF1 alpha were not suppressed by dexamethasone. Collagen-induced platelet TxB2 formation and platelet aggregation was also unaltered. To test one possible explanation for the apparent discrepancy between in vitro and in vivo effects of glucocorticoids on arachidonic acid metabolites we investigated the effects of dexamethasone in vivo on basal and on antidiuretic hormone-stimulated renal PG synthesis. Dexamethasone treatment failed to inhibit both basal and antidiuretic hormone-stimulated PGE2 and PGF2 alpha production. We conclude that glucocorticoids in vivo do not decrease the basal rate of total body, kidney and platelet prostanoid synthesis, and that dexamethasone does not inhibit renal PG production when it is elevated by antidiuretic hormone, a physiological stimulus. Thus, a differential effect of glucocorticoids on basal vs stimulated PG synthesis cannot account for the discrepancy between in vivo and in vitro effects.

Animals↗
PubMed1988

Mechanisms of action of lipoxygenase and cytochrome P-450-mono-oxygenase inhibitors in blocking endothelium-dependent vasodilatation.

1. Acetylcholine, ionophore A23187 and melittin induced endothelium-dependent relaxations of preconstricted strips of rabbit aorta. These relaxations are likely to be mediated by endothelium-derived relaxing factor (EDRF). 2. Relaxations in response to acetylcholine (1 microM) were inhibited by the following lipoxygenase inhibitors, with the approximate IC50 values indicated in parentheses: gossypol (1.5 microM), nordihydroguairetic acid (NDGA, 5 microM), AA 861 (20 microM), phenidone (30 microM), quercetin (40 microM), BW 755C (300 microM), and piriprost (500 microM); with cirsiliol 50% inhibition was not achieved. Acetylcholine-induced relaxations were also blocked by the cytochrome P-450-mono-oxygenase inhibitors proadifen (SKF 525A, 4 microM), metyrapone (300 microM), and cimetidine (300 microM); 7,8 benzoflavone had no effect up to 100 microM. 3. The more potent inhibitors were also tested against relaxations induced by A23187 (0.1 microM) and melittin (1 microM) and produced partial inhibition of these relaxations. 4. The mechanism of action of the more potent inhibitors was investigated in a bioassay system. EDRF was produced in columns filled with cultured human endothelial cells. The factor was bioassayed with endothelium denuded segments of rabbit femoral artery. When added to effluent of the column, NDGA, AA861, proadifen and metyrapone inhibited the EDRF-induced vasodilatation, whereas gossypol had no effect. Gossypol, however, blocked EDRF production when infused through the column. 5. The more potent inhibitors were also tested to determine their effect on purified soluble guanylate cyclase. While gossypol, NDGA and proadifen had no appreciable effects, basal and nitroprusside (50 microM)-stimulated guanylate cyclase activity was inhibited by AA861 and metyrapone. 6. These data suggest that many of the above compounds inhibit EDRF by mechanisms other than lipoxygenase- or cytochrome P-450-mono-oxygenase inhibition.

Acetylcholine↗