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R Neuwirth

Publications and source records attributed to R Neuwirth.

At least 19 recordsLinked to original sources
PubMed2006

[Idiopathic premature ventricular complexes--catheter ablation as a therapeutic alternative].

UNLABELLED: Frequent isolated ventricular premature complexes (VPCs) in patients without major structural heart disease are generally associated with benign prognosis, however can lead to serious symptoms and also to the development of left ventricular dysfunction. Purpose of this study is to present mapping findings and immediate results of catheter ablation of frequent idiopathic VPCs, and evaluation of long-term clinical outcome and the role of catheter ablation in clinical practice. METHODS: Twenty-seven patients, aged 48 +/- 14 years without major structural heart disease, presenting with frequent VPCs, were investigated electrophysiologically in 28 procedures. Twenty-five patients underwent catheter ablation. RESULTS: In 19 patients, the ectopic focus was found in the right ventricular outflow tract (RVOT) and could be reached from the endocardial approach. In these patients, VPCs were successfully eliminated by the ablation. Comparison of 24-hour Holter ECG recordings showed complete elimination of the target VPCs in all the cases [18,483 +/- 12,790 (2,152-48,820)/17 +/- 10 (3-42) % VPCs before ablation vs. 94 +/- 219 (0-763)/0.01 +/- 0.2 (0-0.7) % VPCs after ablation]. In 5 patients, mapping revealed epicardial localization of the ectopic focus in the OT. Ablation endocardially from the RVOT failed in 2 of the patients, cryoablation epicardially from the venous system was partially successful in 1 patient, and no ablation was attempted in 2 patients. In another 3 patients, ectopic foci were found in other parts of the ventricles and ablation was completely successful in one case. During the 14 +/- 9 (1-34) month follow-up period, full elimination of the target VPCs and elimination or significant reduction of symptoms was achieved in 20 (74%) patients. The procedures were accomplished without complications and with fluoroscopy time of 8,2 +/- 5,9 minutes. CONCLUSION: Catheter ablation of frequent idiopathic VPCs was performed effectively and safely, particularly, if the ectopic focus was localized on the endocardial aspect of the RVOT. Efficacy of catheter ablation ofVPCs arising from the epicardium of ventricular OT or other atypical sites is limited by inaccessibility or proximity to the conduction system. Indication to more aggressive mapping and ablation methods like intrapericardial approach or ablation from inside the venous system should be always critically considered with regard to the symptoms or other clinical risk factors.

Adult↗
PubMed2006

[Sustained monomorphic ventricular tachycardia in patients with structural heart disease. Different arrhythmogenic substrates, different options of palliative and curative treatment in the era of three-dimensional mapping].

UNLABELLED: Results of catheter ablation of sustained monomorphic ventricular tachycardia (SMVT) in patients with structural heart disease are presented. METHODS: Catheter ablation was performed in 34 patients (5 females), aged 63 +/- 11 years. One (3%) patient had a permanent SMVT resistant to electric cardioversion, 13 (38%) patients had incessant SMVT, 4 (12%) patients had SMVT at least once a day, 9 (26%) patients at least once a week, and 7 (21%) patients at least once a month. Twenty-nine (85%) patients were treated with amiodarone. Twenty-seven (79%) patients had a history of remote myocardial infarction, 2 (6%) patients presented with dilated cardimyopathy, 4 (12%) patients had arrhythmogenic right ventricular cardimyopathy, and 1 (3%) patient was after surgery for tetralogy of Fallot. Left ventricular ejection fraction was 35 +/- 13%. Ablation was mostly performed as a palliative approach with the purpose to eliminate clinically significant forms of SMVT leading to frequent ICD discharges, respectively to the worsening of heart failure. Less frequently, ablation was accomplished as a curative therapy. For the SMVT ablation, electroanatomic mapping was used, and, target or substrate mapping and ablation or their combinations were employed. RESULTS: Clinical form of SMVT was successfully eliminated in 33 (97%) patients, all inducible ventricular tachyarrhythmias were eliminated in 14 (41%) patients. Any ventricular tachycardia did not recur in 29 (85%) patients during 22 +/- 17 months follow-up. Twenty-three (68 %) patients had eventually implanted ICD. Ablation was performed as a curative procedure in 11 (32 %) patients. Average procedure duration was 213 +/- 56 minutes, fluoroscopy time was 18 +/- 9 minutes, and number of radiofrequency applications was 23 +/- 13. CONCLUSION: Catheter ablation in patients with structural heart disease offers a highly effective method in elimination of clinical forms of SMVT. In long-term perspective, it is associated with low recurrence of any ventricular tachyarrhythmia. Efficacy of the ablation in elimination of all inducible forms of ventricular tachyarrhythmia is lower and therefore it should be mostly viewed as a palliative method, particularly in patients with left ventricular dysfunction and incomplete revascularization.

Aged↗
PubMed2001

Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. METHODS: A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). RESULTS: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. CONCLUSIONS: The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Adolescent↗
PubMed1998

Pregnancy rates following hysteroscopic polypectomy, myomectomy, and a normal cavity in infertile patients.

Objective: To assess the reproductive benefits of hysteroscopic myomectomy and polypectomy for infertility when compared to infertile couples with a normal cavity at hysteroscopy.Material and Methods: All patients with a diagnosis of infertility who underwent hysteroscopic evaluation by a single surgeon between 1975 and 1996 were sent a questionnaire as routine follow-up regarding their reproductive history. All 100 subjects who were located responded to the questionnaire, and 78 subjects met the inclusion criteria; age <45 years, 12 months of infertility, and 18 months of follow-up with attempts to conceive including in vitro fertilization in patients with bilateral tubal occlusion.Results: Of the 78 subjects, 36 had undergone a myomectomy, 23 a polypectomy, and 19 had a normal cavity. Among the three groups there was no significant difference in their ages, types of infertility, length of infertility, or follow-up after the procedure. Using the Cox proportional hazard model, and adjusting for age, polypectomy patients had a significantly higher pregnancy rate (RR 3.89, P <.01) and a higher live birth rate (RR 2.42, P =.06) than patients with a normal cavity. Patients who had undergone a myomectomy also had a higher pregnancy rate (RR 2.02, P =.11) and live birth rate, but this did not achieve statistical significance. Pregnancy following a hysteroscopic myomectomy was associated with a larger fibroid resection (3.15 cm vs 2.5 cm P =.05). The spontaneous abortion rate following the myomectomy, polypectomy, or a normal study was equivalent, 28.1%, 23.1%, and 29.2%, respectively.Conclusions: Both hysteroscopic polypectomy and hysteroscopic myomectomy appear to enhance fertility when compared to infertile patients with a normal cavity. Despite concern that hysteroscopic resection of a large myoma may ablate a large surface area of the endometrial cavity, patients with larger myomas were more likely to conceive following resection.

Journal Article↗
PubMed1998

Uterine thermal balloon therapy for the treatment of menorrhagia: the first 300 patients from a multi-centre study. International Collaborative Uterine Thermal Balloon Working Group.

OBJECTIVE: To evaluate the safety and efficacy of thermal balloon therapy for menorrhagia. DESIGN: Prospective, observational study. SETTING: Fifteen centres in Canada and Europe. POPULATION: Two hundred and ninety-six eligible women for whom follow up data were available for three months or more. Eligible women included those for whom further fertility was not a concern, were not postmenopausal, suffered from intractable menorrhagia, had a normal uterine cavity, and who were fully informed regarding the investigational nature of uterine thermal balloon therapy. METHODS: Three hundred and twenty-one procedures of balloon endometrial ablation were performed using the same protocol between June 1994 and August 1996. Exclusion criteria included structural uterine abnormality or (pre) malignant lesions. Treatment entailed controlled heating of fluid in an intrauterine balloon. General anaesthesia was employed in the 61% of procedures while local anaesthesia with or without sedation was used in 39% of cases. ANALYSIS: Follow up data at 3 and/or 6, and/or 12 months were required for inclusion in the analysis. A paired t test, Wilcoxon signed-ranks test, and multiple and logistic regression analyses were used to evaluate the changes in bleeding and dysmenorrhoea patterns, and possible confounding variables, respectively. Success was defined as the subjective reduction of menses to eumenorrhoea or less. RESULTS: No intra-operative complications occurred, and post-operative morbidity was minimal. Success of the procedure was constant over the year (range 88%-91%). Treatment led to a significant decrease in the duration of menstrual flow and severity of pain (P < 0.0001). Increasing age, higher balloon pressure, smaller uterine cavity, and a lesser degree of pre-procedure menorrhagia were associated with significantly improved results. Pre-treatment with gonadotrophin releasing hormone agonists increased amenorrhoea and spotting rates (P = 0.03), but was only used in 5% of cases. CONCLUSION: Thermal balloon endometrial ablation appears to be safe, as well as effective in properly selected women with menorrhagia and is potentially an outpatient procedure.

Catheter Ablation↗
PubMed1994

[The chemotactic behavior of alveolar macrophages and blood monocytes after exposures to different NO2 concentrations].

The chemotaxis of alveolar macrophages (AM) and blood monocytes (BM) is important in the elimination of particles and microorganisms which have invaded the lung. The effect of nitrogen dioxide (NO2) on chemotaxis was tested on AM obtained by diagnostic bronchoscopy from five patients suspected of having bronchial carcinoma (four men, one woman; mean age 59 +/- 10 years). Blood monocytes were also studied with blood from seven healthy subjects (five men, two women; mean age 32 +/- 10 years). These cells were placed on polycarbonate membranes for 15 min each, exposed to NO2 concentrations between 1.0 and 5.0 parts per million (ppm), and then incubated with complement component C5a as chemotactically active agent. The number of AM or BM which actively migrated through the polycarbonate membrane under the influence of C5a was measured by means of a light microscope. The migration rate of AM (compared to air exposure) was reduced by 33% with 1.0 ppm NO2 and by 61% with 5.0 ppm. The migration rate of BM in similar conditions was reduced by as much as 55%. There was no significant cytotoxic effect of NO2 exposure at 1.0 and 3.0 ppm. With 5.0 ppm 13.0 +/- 3.0 cells were no longer viable. These results indicate that NO2 concentrations relevant to indoor conditions affect the chemotaxis of AM and BM after short-time NO2 exposures. The data further suggest that NO2 exposures of these cells depressed chemotactic mechanisms without relevant cytotoxicity.

Aged↗
PubMed1994

Preliminary clinical experience with a thermal balloon endometrial ablation method to treat menorrhagia.

OBJECTIVE: To evaluate the clinical effectiveness and safety of a thermal balloon system to ablate the endometrium. METHODS: All 18 patients were candidates for hysteroscopic endometrial ablation or hysterectomy for menorrhagia and consented to a trial of the balloon technique of ablation. All procedures were done in the operating room under general anesthesia, except in one patient who had regional and another who had local anesthesia with analgesia. Follow-up of 6-34 months is reported. RESULTS: Fifteen subjects (83%) reported significant reduction in bleeding or amenorrhea. Two patients underwent subsequent hysterectomy and one a follow-up hysteroscopic examination with biopsy. Histology in these three cases showed areas of scar as well as areas of normal endometrial histology. In one uterus, the entire cavity and the endometrium were normal. The others had endometrial bands of scar and some contraction of the cavity. CONCLUSIONS: Based on follow-up results, the frequency of successful reduction of bleeding and/or amenorrhea in this small series is comparable to hysteroscopic methods of endometrial ablation. There were no complications. A larger trial is warranted to compare this method to hysteroscopic endometrial ablation.

Catheter Ablation↗
PubMed1992

Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group.

OBJECTIVE: To evaluate the contribution of mild to moderate hypertension to progressive loss of renal function by analysis of renal function data from the Multiple Risk Factor Intervention Trial. DESIGN: The cohort of men with mild to moderate hypertension (baseline diastolic blood pressure > or = 90 mm Hg), randomized to a special intervention (SI) group or usual care (UC) group, were examined for change in renal function based on individual reciprocal creatinine slopes over an average of 7 years' follow-up as the outcome measure. Contribution of blood pressure control during follow-up, age, race, and blood pressure at entry were assessed. PARTICIPANTS: The cohort of 5524 (463 black, 5061 nonblack) hypertensive men receiving no therapy at entry provided the data for the present analysis. RESULTS: Blood pressure control was similar for black and white participants, but significant decline in reciprocal creatinine slope was found for black men (mean slope, -0.0090 +/- 0.0013 dL/mg/y) compared with white men (+0.0018 +/- 0.0004 dL/mg/y) (P < .001 for difference between blacks and whites). Decline in renal function was also greater among individuals with elevated systolic (P < .001) as well as diastolic blood pressure (P < .001), and older individuals (P < .001). No difference between the SI and UC groups was seen in reciprocal creatinine slopes, but in both groups combined, treatment that maintained diastolic blood pressure below an average value of 95 mm Hg was associated with stable or improving renal function, whereas participants whose blood pressure remained 95 mm Hg or greater continued to decline at -0.0013 +/- 0.0009 dL/mg/y (P = .007 for difference). Separate examination of the subset of black men (n = 463) failed to show such a difference. CONCLUSIONS: Effective blood pressure control was associated with stable or improving renal function in nonblacks but not in blacks. These findings emphasize the importance of blood pressure control to maintain adequate renal function in hypertensive white men and raise important questions about the relationship of pressure reduction and renal function change in blacks.

Adult↗
PubMed1990

Effects of fish oil on glomerular function in rats with diabetes mellitus.

The mechanisms responsible for hyperfiltration in diabetes mellitus (DM) as well as for the initiation and progression of diabetic nephropathy are not fully elucidated. Enhanced prostaglandin E2 (PGE2) production has been invoked in the former and thromboxane (TXB2) and hyperlipidemia in the latter. Fish oil (FO)-enriched diets can favorably alter eicosanoid synthesis and serum lipid profiles. We therefore examined the effects of a FO-enriched diet on glomerular filtration (GFR), proteinuria, glomerular eicosanoid production, and serum lipids in rats with streptozotocin-induced DM (STZ-DM). Groups of 5-8 rats with STZ-DM were maintained on low insulin and then pair-fed with isocaloric diets enriched with either FO (20% w/w) or beef tallow (BT; 20% w/w). GFR was determined in the same animals at onset of diet and after 8 and 20 weeks on the respective diets by [14C]inulin clearance using implanted osmotic minipumps each time. Significant hyperfiltration was present initially and GFR did not change on either diet for 20 weeks, in spite of a significant and greater than 50% decrease in all prostaglandins (PGE2, TXB2, PGF2 alpha, 6-keto, PGF1 alpha) produced by glomeruli isolated from DM/FO as compared to DM/BT or control rats. FO diet completely corrected the hypertriglyceridemia of diabetes and significantly reduced the mild and early proteinuria of DM. The decrease in proteinuria and the correction of hyperlipidemia of DM by a FO-enriched diet may be beneficial in the long term not only for the development of diabetic glomerulopathy, but also for the accelerated atherosclerosis of DM.

Animals↗
PubMed1989

Eicosapentaenoic and dihomo gamma linolenic acid metabolism by cultured rat mesangial cells.

To better understand the effects of dietary fatty acid manipulations on glomerular function, we compared mesangial incorporation, release, and metabolism of arachidonic (AA), eicosapentaenoic (EPA), and dihomo gamma linolenic (DHG) acids. We found marked differences in mesangial handling of these fatty acids. AA was incorporated into lipids of mesangial cells much more rapidly than EPA or DHG. Ionophore-induced stimulation of fatty acid release from mesangial cells prelabeled with [14C]AA, [14C]EPA, or [14C]DHG caused a release of labeled AA greater than DHG much less than EPA, respectively. Preloading mesangial cells with DHG or EPA for 24 h reduced subsequent basal, ionophore-, and hormone-stimulated prostaglandin E2 (PGE2) synthesis. Finally, unlike AA, neither EPA nor DHG was converted to a significant extent by mesangial cyclooxygenase or lipoxygenase. Thus the mesangial metabolism of DHG and EPA differs both quantitatively and qualitatively from that of AA. Furthermore, EPA and DHG inhibit metabolism of AA at the level of mesangial cyclooxygenase.

8,11,14-Eicosatrienoic Acid↗
PubMed1989

Extra- and intracellular metabolism of platelet-activating factor by cultured mesangial cells.

Metabolism of platelet-activating factor (PAF) was examined in cultured mesangial cells from human and rat glomeruli. Human mesangial cells, similar to those from rat, generated PAF after A23187. Both human and rat mesangial cells rapidly hydrolyzed [3H]PAF to lyso-[3H]PAF, and reacylated it into 1-alkyl-2-acyl glycerophosphocholine. Extra- and intracellular metabolism of PAF was then analyzed separately. The majority of [3H]PAF metabolism occurred extracellularly and generated Lyso-[3H]PAF. Intracellularly generated lyso-PAF was rapidly converted to 1-alkyl-2-acyl glycerophosphocholine. Cells prelabeled with [3H]PAF released some [3H]PAF within minutes and then rapidly converted it to lyso-PAF extracellularly. Under control conditions no acetylhydrolase activity was released from cells into the buffer. Acetylhydrolase activity could, however, be released from cell surface into buffer by limited trypsinization, supporting its location on the outer cell membrane. The acetylhydrolase activity was different from phospholipase A2, since phosphatidylcholine was not a substrate for the enzyme. In summary our results show that both rat and human mesangial cells can generate and metabolize PAF. Acetylhydrolase for PAF is present intracellularly, but also and predominantly on the outer cell surface of cells. This ectoenzymatic acetylhydrolase activity may be important in the rapid inactivation of PAF presented to cells, thus protecting cells from deleterious effects of PAF.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1989

Angiotensin II causes formation of platelet activating factor in cultured rat mesangial cells.

Angiotensin II may contribute to the progression of renal glomerular diseases. Beneficial effects of converting enzyme inhibition in models of renal disease are, however, not always explicable by hemodynamic consequences of angiotensin II inhibition. Angiotensin increases intracellular calcium in glomerular mesangial cells and activates phospholipase A2, factors required for the formation of the lipid mediator of inflammation platelet activating factor (PAF). We therefore examined whether angiotensin II could stimulate PAF production in cultured rat mesangial cells. During a 15-minute incubation angiotensin II caused formation of PAF in a dose-dependent manner with a threshold around 10(-9) M. In four experiments PAF formation in response to angiotensin II (10(-8) M) occurred within 5 minutes and was 29 +/- 8 pmol PAF/mg protein. The amount of PAF detected then declined to 9 +/- 2 and 13 +/- 3 pmol after 15 and 30 minutes of incubation with angiotensin II. More than 90% of the PAF remained cell-associated. The PAF formation was confirmed by negative ion chemical ionization mode of mass spectrometry. A single species of PAF was detected and identified as hexadecyl PAF. We speculate that part of the detrimental effects of angiotensin II in progressive renal disease may relate to PAF formation. The PAF generated may in turn influence glomerular function, platelets, and eicosanoid synthesis, all factors implicated in renal disease. Furthermore, we speculate that angiotensin II-induced PAF formation may contribute to microvasculature pathology in general.

Angiotensin II↗
PubMed1988

Evidence for immunoglobulin Fc receptor-mediated prostaglandin2 and platelet-activating factor formation by cultured rat mesangial cells.

The possibility of Fc-dependent uptake of IgG immune complexes was examined in subcultured rat mesangial cells free of monocytes. 195Au-labeled colloidal gold particles were coated either with BSA only or with BSA followed by rabbit anti-BSA-IgG or the F(ab')2 fragment of the IgG. Mesangial cells preferentially took up 195Au particles covered with BSA-anti-BSA-IgG over those covered with BSA or the F(ab')2 fragment. This uptake was a time-dependent and saturable process inhibitable by sodium azide or cytochalasin B. Using phase-contrast microscopy in the light reflectance mode, it was established that essentially all mesangial cells took up IgG-coated gold particles. By electron microscopy the process was shown to consist of vesicular uptake with delivery to endosomes. Mesangial binding-uptake of the IgG-covered particles was associated with stimulation of PGE2 synthesis and production of platelet-activating factor, a lipid mediator of inflammation. To characterize the potential Fc receptor for IgG we used the rosetting technique with sheep red blood cells coated with IgG subclass-specific mouse monoclonal antibodies. 50% of mesangial cells exhibited rosetting with red cells coated with mouse IgG2a, whereas negligible rosetting was observed with IgG2b or IgG1. Competition experiments confirmed the specificity of IgG2a binding. We conclude that cultured rat mesangial cells exhibit specific receptors for IgG and that occupancy of Fc receptors results in endocytosis and is associated with generation of PGE2 and platelet-activating factor. These observations may be of significance for immune-mediated glomerular diseases.

Animals↗
PubMed1987

Effect of platelet activating factor antagonists on cultured rat mesangial cells.

Platelet activating factor (PAF; 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a lipid mediator of inflammation produced by inflammatory cells and also by renal glomerular mesangial cells. PAF may play a role in glomerular function and disease. Previously the authors reported that glomerular mesangial cells respond to PAF by increasing prostaglandin E2 (PGE2) synthesis and by cell contraction. This paper examines the specificity of BN52021, SRI 63-072 and kadsurenone on the effects of PAF on cultured rat glomerular mesangial cells. Both BN52021 and SRI 63-072 specifically decreased PAF (1 X 10(-6) M)-stimulated PGE2 production in a dose-dependent fashion (10(-7)-10(-5) M) without affecting the stimulation by angiotensin II (AII) or the calcium ionophore A23187. Kadsurenone also decreased PAF-stimulated PGE2 production, but in a less specific manner, as it also decreased AII- and A23187-stimulated PGE2 production. In order to examine the site of antagonism of PAF-induced PGE2 synthesis by BN52021 and SRI 63-072, the authors prelabeled cells with [14C]arachidonic acid. Both agents diminished the release of [14C]arachidonate from these prelabeled cells in response to PAF in a dose-dependent fashion, though not decreasing release in response to AII or A23187, indicating that they blocked the effect of PAF on phospholipase activation, consistent with receptor blocking activity. BN52021 and SRI 63-072 also inhibited PAF-induced contraction of cultured mesangial cells without an effect on basal tone of the cells or the contractile response to AII.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells.

Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) results in contraction of isolated glomeruli and cultured mesangial cells and concomitantly causes release of arachidonic acid and prostaglandin E2 (PGE2) formation. The kidney and isolated glomeruli can also generate material that has PAF bioactivity. We therefore examined the capacity of isolated renal glomeruli and cultured glomerular mesangial cells from rats to form PAF. Both isolated glomeruli and cultured mesangial cells transformed 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine ([3H]lyso-PAF) into a labeled product comigrating both on thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC) with authentic PAF. Using rabbit platelet aggregation as bioassay for PAF, we found that isolated glomeruli produced 4 +/- 2 pmol/mg glomerular protein of PAF-like material, and mesangial cells produced 30 +/- 8 pmol/mg cell protein when stimulated with A23187 (10(-5) M) for 30 min. The major species of the PAF material produced by mesangial cells was identified as 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine after HPLC separation, followed by fast atom bombardment and gas chromatography-mass spectrometry. These results show that glomerular mesangial cells can produce PAF, which could contribute locally to the regulation of glomerular function.

Animals↗
PubMed1986

Platelet-activating factor and the kidney.

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.

Acetylation↗