Release of markedly increased quantities of prostaglandin D2 in humans following the administration of nicotinic acid

Morrow, Jason D.; Parsons, Willis G.; Roberts, L. Jackson

doi:10.1016/0090-6980(89)90088-9

Cited by 191 publications

(127 citation statements)

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“…Although the mechanism of action of NA-induced flushing is not completely understood, the sensitivity to COX inhibitors suggests that prostanoids are involved. Indeed, it has been shown that NA greatly increases the plasma levels of prostaglandin (PG) D 2 (16), and that the skin is the major source of this vasodilatory prostanoid after NA treatment (17). These results led to the hypothesis that PGD 2 generation in the skin drives NA-induced flushing (17).…”

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confidence: 98%

“…These results led to the hypothesis that PGD 2 generation in the skin drives NA-induced flushing (17). However, because NA treatment also increases other prostanoids (16,(18)(19)(20) [for example, PGI 2 (16), which is also vasodilatory (21)], the prostanoid(s) responsible for flushing in humans remains to be unequivocally determined.Two G protein-coupled receptors for PGD 2 , PGD 2 receptor 1 (DP1) (22), also called DP; and PGD 2 receptor 2 (DP2) (23, 24), sometimes termed CRT H2 (chemoattractant receptorhomologous molecule expressed on T-helper 2 cells), have been identified. Activation of DP1 by PGD 2 leads to the stimulation of adenylate cyclase activity and increased intracellular cAMP levels (22).…”

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confidence: 99%

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Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Cheng¹,

Wu²,

Wu³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

188

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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.aspirin ͉ prostaglandin D2 receptor 1 antagonist ͉ MK-0524 ͉ niacin ͉ flushing N icotinic acid (NA), sometimes called niacin, is a watersoluble B vitamin that has been used to treat dyslipidemia for almost 50 years (1, 2). Used in high doses, it reduces plasma low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a) and increases high-density lipoprotein cholesterol and apolipoprotein A-I (3, 4). NA has been shown to have cardiovascular benefit when used alone or in combination with statins (hydroxymethylglutaryl-CoA reductase inhibitors) in several clinical trials (5-7).Despite these demonstrated beneficial effects, widespread use of NA for dyslipidemia has been limited by symptoms of flushing, which is associated with cutaneous vasodilation of the face, neck, and torso that occurs in nearly all patients (5, 8). Administration of cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, before ingestion of NA can attenuate the NA-induced cutaneous reactions in most patients (9-13) without affecting its plasma free fatty acid-lowering effect (14). However, doses of aspirin of 325 mg or higher are generally required to significantly block flushing (15), which compromises the utility of this approach for the chronic suppression of flushing. Although the mechanism of action of NA-induced flushi...

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confidence: 98%

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Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Cheng¹,

Wu²,

Wu³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

263

188

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“…Evidence favors PGD 2 as the predominant mediator of the flush response (Morrow et al, 1989). However PGE 2 levels also increase in response to niacin (Eklund et al, 1979;Kobza Black et al, 1982).…”

Section: Mediation Of Niacin Flush By Aa Metabolitesmentioning

confidence: 99%

“…Formation of AA is the rate-limiting step in the biosynthesis of the vasodilatory PGD 2 and E2 (PGE 2 ) (Murakami and Kudo 2004) These prostaglandins bind to specific prostanoid receptors on vascular smooth muscle within the skin. Activation of prostanoid receptors dilates cutaneous blood vessels (Lai et al, 2007), and a visible skin flush arises from the ensuing increased blood flow (Benyó et al, 2005;Maciejewski-Lenoir et al, 2006;Morrow et al, 1989Morrow et al, , 1992.…”

Section: Mechanism Of the Niacin Flush Responsementioning

confidence: 99%

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

Messamore

Yao

2015

OCL

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-This paper reviews the potential role of arachidonic acid in the pathophysiology of schizophrenia. We discuss how abnormal levels of arachidonic acid may arise, and how dysregulation of signaling molecules derived from it have the potential to disrupt not only dopamine signaling, but numerous other physiological processes associated with the illness. Pharmacological doses of niacin stimulate the release of arachidonic acid; and arachidonic acid-derived molecules in turn dilate blood vessels in the skin. A blunted skin flush response to niacin is reliably observed among patients with schizophrenia. The niacin response abnormality may thus serve as a biomarker to identify a physiological subtype of schizophrenia associated with defective arachidonic acid-derived signaling.Keywords: Phospholipids / arachidonic acid / eicosanoids / niacin-induced flushing, endophenotype marker / schizophrenia Résumé -Signalisation des phospholipides, de l'arachidonate et de l'écosanoïde dans la schizophrénie. Cet article examine le rôle potentiel de l'acide arachidonique dans la physiopathologie de la schizophrénie. Il est discuté comment des niveaux anormaux d'acide arachidonique peuvent survenir, et comment la dérégulation des molécules de signalisation qui en découle est capable de perturber non seulement la signalisation de la dopamine, mais aussi de nombreux autres processus physiologiques associés avec cette maladie. Des doses pharmacologiques de niacine stimulent la libération d'acide arachidonique ; des molécules dérivées de l'acide arachidonique dilatent à leur tour les vaisseaux sanguins dans la peau. Une brusque rougeur de la peau en réponse à la niacine est observée de manière constante parmi les patients atteints de schizophrénie. La réponse anormale à la niacine peut donc servir de biomarqueur afin d'identifier un sous-type physiologique de la schizophrénie, associé à un système défectueux de signalisation des dérivés de l'acide arachidonique.

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Urticaria Pigmentosa

et al. 1991

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Nine patients with adult-onset urticaria pigmentosa were studied for the incidence of extracutaneous mast cell involvement and the efficacy of potent topical corticosteroid therapy for cutaneous lesions. Seven of the nine patients had increased mast cells in the marrow biopsy specimens, and five patients had focal aggregates of mast cells. The bone scan was abnormal in one patient. Liver-spleen scans revealed a shift of colloid uptake from liver to spleen in four patients. No abnormal gastrointestinal tract roentgenograms were obtained. Urinary histamine metabolites correlated with nodular bone marrow involvement, but not with other parameters. Results of the psychoneurologic testing revealed significant deviation from the norm with a verbal memory deficit in all nine patients and abnormalities on the Minnesota Multiphasic Personality Inventory in four patients. All nine patients were treated with 0.05% betamethasone dipropionate ointment under occlusion over half of the body nightly for 6 weeks. Seven of nine patients treated responded with almost complete resolution of their lesions. Hypothalamic pituitary adrenal axis suppression was evaluated with intramuscular cosyntropin stimulation and metyrapone administration during treatment. Only two patients, both of whom used the medication improperly, developed transient abnormalities. Slow return of lesions was noted 6 months after completion of therapy. Remissions could be lengthened with single weekly applications of topical steroids. Systemic involvement is frequent in patients with cutaneous mast cell disease and it is best demonstrated by bone marrow biopsy. Mast cell lesions can be safely and effectively treated with topical steroids in motivated patients.

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Release of markedly increased quantities of prostaglandin D2 in humans following the administration of nicotinic acid

Cited by 191 publications

References 11 publications

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

Urticaria Pigmentosa

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Release of markedly increased quantities of prostaglandin D2 in humans following the administration of nicotinic acid

Cited by 191 publications

References 11 publications

Antagonism of the prostaglandin D 2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Antagonism of the prostaglandin D 2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

Urticaria Pigmentosa

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Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

Antagonism of the prostaglandin D ₂ receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans