prostaglandin-d2 and Flushing

Systemic mastocytosis is characterized by an abnormal proliferation of tissue mast cells. Symptoms of mastocytosis are primarily attributed to the release of mast cell mediators during episodes of systemic activation of the excessive numbers of mast cells. Thus, biochemical evidence for the release of increased quantities of mast cell secretory products can suggest or confirm, depending on the clinical situation, a diagnosis of systemic mastocytosis. A major advantage of the biochemical approach to the diagnosis of systemic mast cell disease is that it has allowed the recognition of a class of patients in whom episodes of systemic mastocyte activation can be unequivocally documented biochemically but in whom clear-cut evidence of abnormal mast cell proliferation is lacking by current histologic criteria. Although the release of increased quantities of mast cell mediators can be demonstrated during episodes of mast cell activation in such patients, mediator levels are usually normal at quiescent times. By contrast, patients with proliferative mast cell disease (mastocytosis) usually exhibit chronic overproduction of mast cell mediators. Mast cell secretory products that can be measured in an attempt to obtain biochemical evidence of systemic mast cell activation include histamine, prostaglandin D2, tryptase, and heparin. The analytical approaches to assessing release of those individual mast cell products are evaluated. In general, the diagnosis and investigation of patients with systemic mast cell activation can best be accomplished by concerted use of histologic examination of key tissues together with analysis of chemical markers of the mast cell.

Topics: Flushing; Heparin; Histamine; Humans; Mastocytosis, Systemic; Prostaglandin D2; Tryptases

Topics: Bayes Theorem; Cardiovascular Diseases; Delayed-Action Preparations; Dyslipidemias; Flushing; Humans; Indoles; Lipid Regulating Agents; Niacin; Prostaglandin D2; Risk Assessment

Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30-40%. Thus, the aim of the present study was to investigate the mechanisms of niacin-induced flushing, with and without aspirin, in normal, healthy individuals.. Niacin-induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9α,11β-prostaglandin (PG) F(2) was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST).. After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36-53% of participants still had some degree of symptoms, even though aspirin completely blocked 11β-PGF(2) synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF(2) and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R(2) = 40%).. The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD(2) , may play an important role in niacin-induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin-induced flushing.

Topics: Adult; Aged; Aged, 80 and over; Autonomic Nervous System; Female; Flushing; Humans; Male; Middle Aged; Niacin; Prostaglandin D2; Reference Values

The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids prostaglandin D2 (PGD2) and prostaglandin E2 from arachidonic acid metabolism through the cyclooxygenase pathway. Arachidonic acid is also metabolized by the cytochrome P450 system, which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH).. These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing.. Niacin-induced flushing was reduced from 506 ± 126% to 213 ± 39% in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose-dependent manner, with maximal reduction to 143% ± 15% of baseline flow using a concentration of 1 mg/kg TPAU (1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation, which was not changed by either pharmacologic sEH inhibition or sEH gene deletion.. Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans.

Topics: Animals; Arachidonic Acid; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Epoxide Hydrolases; Flushing; Gene Deletion; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Niacin; Phenylurea Compounds; Piperidines; Prostaglandin D2; Vasodilation; Vasodilator Agents

Niacin lowers serum cholesterol, low-density lipoprotein, and triglycerides, and it raises high-density lipoprotein. However, most patients experience cutaneous warmth and vasodilation (flush). Acetylsalicylic acid (ASA) can reduce this flush, presumably by decreasing prostaglandin D(2) (PGD(2)) release from macrophages. Here, we show that methylnicotinate induces significant PGD(2) release from human mast cells and serotonin from human platelets. Intradermal injection of methylnicotinate induces rat skin vasodilation and vascular permeability. Niacin increases plasma PGD(2) and serotonin in a rat model of flush. The phenothiazine prochlorperazine, the H(1), serotonin receptor antagonist cyproheptadine, and the specific serotonin receptor-2A antagonist ketanserin inhibit niacin-induced temperature increase by 90% (n = 5, p < 0.05), 90 and 50% (n = 3, p < 0.05), and 85% (n = 6, p = 0.0008), respectively, in this animal model. These results indicate that niacin-induced flush involves both PGD(2) and serotonin, suggesting that drugs other than ASA are required to effectively inhibit niacin-induced flush.

Topics: Animals; Blood Platelets; Capillary Permeability; Flushing; Humans; Mast Cells; Models, Animal; Niacin; Prostaglandin D2; Rats; Serotonin; Skin; Vasodilation

Sustained release niacin effectively lowers serum cholesterol, LDL and triglycerides, while raising HDL. However, 75% of patients experience cutaneous warmth and itching known as flush, leading to discontinuation. Acetylsalicylic acid (aspirin) reduces this flush only by about 30%, presumably through decreasing prostaglandin D2 (PGD2). We investigated whether niacin-induced flush in a rat model involves PGD2 and 5-HT, and the effect of certain flavonoids.. Three skin temperature measurements from each ear were recorded with an infrared pyrometer for each time point immediately before i.p. injection with either niacin or a flavonoid. The temperature was then measured every 10 min for 60 min.. Niacin (7.5 mg per rat, equivalent to a human dose of 1750 mg per 80 kg) maximally increased ear temperature to 1.9+/-0.2 degrees C at 45 min. Quercetin and luteolin (4.3 mg per rat; 1000 mg per human), administered i.p. 45 min prior to niacin, inhibited the niacin effect by 96 and 88%, respectively. Aspirin (1.22 mg per rat; 325 mg per human) inhibited the niacin effect by only 30%. Niacin almost doubled plasma PGD2 and 5-HT, but aspirin reduced only PGD2 by 86%. In contrast, luteolin inhibited both plasma PGD2 and 5-HT levels by 100 and 67%, respectively. CONCLUSIONS AND IMPLICATIONS. Niacin-induced skin temperature increase is associated with PGD2 and 5-HT elevations in rats; luteolin may be a better inhibitor of niacin-induced flush because it blocks the rise in both mediators.

Topics: Animals; Aspirin; Body Temperature; Disease Models, Animal; Flushing; Hypolipidemic Agents; Luteolin; Male; Niacin; Prostaglandin D2; Quercetin; Random Allocation; Rats; Rats, Sprague-Dawley; Serotonin; Skin

Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D2 (PGD2) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD2 secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD2 secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1-3 mM) induced PGD2 secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD2 secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD2 secretion. Pre-incubation of the cells with aspirin (100 microM) entirely prevented the nicotinic acid effects on PGD2 secretion. The PGD2 secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6 microM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect.

Topics: Aspirin; Calcimycin; Calcium; Flushing; Humans; Macrophages; Models, Biological; Niacin; Nicotinic Acids; Prostaglandin D2; Tumor Cells, Cultured

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.

Topics: Adolescent; Adult; Animals; Aspirin; Female; Flushing; Humans; Hydantoins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Niacin; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Receptors, Immunologic; Receptors, Prostaglandin; Vasodilation

Nicotinic acid, used for atherosclerosis treatment, has an adverse effect of skin flushing. The flushing mechanism, thought to be caused by the release of prostaglandin D(2) (PGD(2)), is not well understood. We aimed to identify which cells mediate the flushing effect. Nicotinic acid receptor (GPR109A) gene expression was assessed in various tissues and cell lines. Cells expressing GPR109A mRNA were further assayed for PGD(2) release in response to nicotinic acid. Of all samples, only skin was able to release PGD(2) upon stimulation with nicotinic acid. The responsive cells were localized to the epidermis, and immunocytochemical studies revealed the presence of GPR109A on epidermal Langerhans cells. CD34+ cells isolated from human blood and differentiated into Langerhans cells (hLC-L) also showed GPR109A expression. IFNgamma treatment increased both mRNA and plasma membrane expression of GPR109A. IFNgamma-stimulated hLC-Ls released PGD(2) in response to nicotinic acid in a dose-dependant manner (effector concentration for half-maximum response=1.2 mM+/-0.7). Acifran, a structurally distinct GPR109A ligand, also increased PGD(2) release, whereas isonicotinic acid, a nicotinic acid analog with low affinity for GPR109A, had no effect. These results suggest that nicotinic acid mediates its flushing side effect by interacting with GPR109A on skin Langerhans cells, resulting in release of PGD(2).

Topics: Animals; Cells, Cultured; Flushing; Humans; Hypolipidemic Agents; In Vitro Techniques; Langerhans Cells; Male; Mice; Mice, Inbred C57BL; Niacin; Oligonucleotide Array Sequence Analysis; Prostaglandin D2; Receptors, G-Protein-Coupled; Receptors, Nicotinic; RNA, Messenger; Skin; Tissue Distribution

The aim of this pilot study was to evaluate a potential skin test for schizophrenia based on the effect of aqueous methyl nicotinate (AMN) on the production of prostaglandin D2 (PGD2) from skin macrophages and the resultant cutaneous capillary vasodilatation. Four concentrations of AMN were applied topically to the forearm skin in patients and controls, and any resulting vasodilatation was rated as redness after 5 min. The test was carried out on 38 patients with schizophrenia diagnosed according to DSM-III-R criteria, and 22 normal control subjects. At all concentrations of AMN, the schizophrenics were highly significantly different from the controls. One concentration gave the greatest degree of differentiation: at this concentration at 5 min, 83% of schizophrenics but only 23% of controls had a zero or minimal response to AMN. The skin flushing seen after oral administration of nicotinic acid is due to the same reaction, and this has been normal in those with affective illness and neurosis; cyclo-oxygenase inhibitors, e.g., aspirin, give a false-positive result (failure of vasodilatation). This result is consistent with the concept of reduced membrane arachidonic acid levels in schizophrenia. This test may contribute to the reliable diagnosis of schizophrenia.

Topics: Adult; Arachidonic Acid; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Erythrocyte Membrane; Feasibility Studies; Female; Flushing; Humans; Male; Middle Aged; Nicotinic Acids; Pilot Projects; Prostaglandin D2; Psychiatric Status Rating Scales; Reference Values; Schizophrenia; Sensitivity and Specificity; Skin; Vasodilation

Nicotinic acid (niacin) is a B vitamin which is also a potent hypolipidemic agent. However, intense flushing occurs following ingestion of pharmacologic doses of niacin which greatly limits its usefulness in treating hyperlipidemias. Previous studies have demonstrated that niacin-induced flushing can be substantially attenuated by pre-treatment with cyclooxygenase inhibitors, suggesting that the vasodilation is mediated by a prostaglandin. However, the prostaglandin that presumably mediates the flush has not been conclusively determined. In this study we report the finding that ingestion of niacin evokes the release of markedly increased quantities of PGD2 in vivo in humans. PGD2 release was assessed by quantification of the PGD2 metabolite, 9 alpha, 11 beta-PGF2, in plasma by gas chromatography mass spectrometry. Following ingestion of 500 mg of niacin in three normal volunteers, intense flushing occurred and plasma levels of 9 alpha, 11 beta-PGF2 were found to increase dramatically by 800, 430, and 535-fold. Levels of 9 alpha, 11 beta-PGF2 reached a maximum between 12 and 45 min. after ingesting niacin and subsequently declined to near normal levels by 2-4 hours. Levels of 9 alpha, 11 beta-PGF2 in plasma correlated with the intensity and duration of flushing that occurred in the 3 volunteers. Release of PGD2 was not accompanied by a release of histamine which was assessed by quantification of plasma levels of the histamine metabolite, N tau-methylhistamine. This suggests that the origin of the PGD2 release is not the mast cell. Only a modest increase (approximately 2-fold) in the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-PGF1 alpha, occurred following ingestion of niacin and no increase in the excretion of the major urinary metabolite of PGE2 was found. These results indicate that the major vasodilatory PG released following ingestion of niacin is PGD2. The fact that markedly increased quantities of PGD2 are released suggests that PGD2 is the mediator of niacin-induced vasodilation in humans.

Topics: Adult; Chromatography, Ion Exchange; Dinoprost; Dinoprostone; Epoprostenol; Flushing; Histamine; Histamine Release; Humans; Niacin; Prostaglandin D2; Time Factors

Prostaglandin D2 (PGD2) was infused intravenously into normal male volunteers. Seven subjects received infusions of 16, 32, 64 ng/kg/min and six of these a further dose of 128 ng/kg/min. Each individual's maximum dose was limited by discomfort caused by intense facial flushing and nasal congestion. At these doses there was no significant effect on systolic or diastolic blood pressure nor on spirometric measurements. There was a small but statistically significant tachycardia at 64 and 128 ng/kg/min. Collagen- and adenosine diphosphate (ADP)-induced platelet aggregation ex vivo was not affected at any of the infusion rates. Infused PGD2 is unlikely to be a useful antithrombotic agent.

Topics: Adenosine Diphosphate; Adult; Airway Obstruction; Blood Pressure; Collagen; Flushing; Heart Rate; Humans; Infusions, Parenteral; Male; Platelet Aggregation; Prostaglandin D2; Prostaglandins D; Tachycardia