Suppression of Niacin-induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1

Lai, Eseng; Lepeleire, Inge De; Crumley, TM; Liu, Fang; Wenning, LA; Michiels, Nicole; Vets, Eva; O’Neill, Gary P.; Ja, Wagner; Gottesdiener, K.

doi:10.1038/sj.clpt.6100180

Cited by 134 publications

(86 citation statements)

References 44 publications

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“…Nicotinic acid-mediated stimulation of GPR109A receptors expressed on Langerhans cells in the skin leads to activation of cytosolic phospholipase A 2 (cPLA 2 ) and subsequent production and secretion of prostaglandin D 2 (PGD 2 ), which, through activation of its own 7TMR, leads to cutaneous flushing (7,8). This cutaneous flushing response can be attenuated by inhibiting PGD 2 synthesis with aspirin or by blocking PGD 2 receptor with an antagonist (9)(10)(11). Neither of the above strategies is ideal, because they both involve administration of additional drugs.…”

Section: Introductionmentioning

confidence: 99%

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

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Nicotinic acid is one of the most effective agents for both lowering triglycerides and raising HDL. However, the side effect of cutaneous flushing severely limits patient compliance. As nicotinic acid stimulates the GPCR GPR109A and G i /G o proteins, here we dissected the roles of G proteins and the adaptor proteins, β-arrestins, in nicotinic acid-induced signaling and physiological responses. In a human cell line-based signaling assay, nicotinic acid stimulation led to pertussis toxin-sensitive lowering of cAMP, recruitment of β-arrestins to the cell membrane, an activating conformational change in β-arrestin, and β-arrestin-dependent signaling to ERK MAPK. In addition, we found that nicotinic acid promoted the binding of β-arrestin1 to activated cytosolic phospholipase A 2 as well as β-arrestin1-dependent activation of cytosolic phospholipase A 2 and release of arachidonate, the precursor of prostaglandin D 2 and the vasodilator responsible for the flushing response. Moreover, β-arrestin1-null mice displayed reduced cutaneous flushing in response to nicotinic acid, although the improvement in serum free fatty acid levels was similar to that observed in wild-type mice. These data suggest that the adverse side effect of cutaneous flushing is mediated by β-arrestin1, but lowering of serum free fatty acid levels is not. Furthermore, G protein-biased ligands that activate GPR109A in a β-arrestin-independent fashion may represent an improved therapeutic option for the treatment of dyslipidemia.

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Section: Introductionmentioning

confidence: 99%

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Walters¹,

Shukla²,

Kovacs³

et al. 2009

J. Clin. Invest.

207

174

View full text Add to dashboard Cite

show abstract

“…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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“…Reductions in patient-rated flushing correlated significantly with decreases in malar blood flow (r=0.64-0.68; P<.001). 137 In multiple-dose studies, 200 mg of adjunctive laropiprant reduced time-weighted average flushing scores by 65% (vs 1.5 g of extended-release niacin alone) on day 1 and by 52% on day 3. 137 In a phase 1 study (study 044), coadministration of 325 mg of aspirin did not confer significant incremental benefits in reducing the incidence and severity of residual flushing associated with 40 mg of laropiprant and 2.0 g of extended-release niacin.…”

mentioning

confidence: 99%

“…137 In multiple-dose studies, 200 mg of adjunctive laropiprant reduced time-weighted average flushing scores by 65% (vs 1.5 g of extended-release niacin alone) on day 1 and by 52% on day 3. 137 In a phase 1 study (study 044), coadministration of 325 mg of aspirin did not confer significant incremental benefits in reducing the incidence and severity of residual flushing associated with 40 mg of laropiprant and 2.0 g of extended-release niacin. 138 In a phase 2, dose-ranging study, adjunctive laropiprant (18.75 to 150 mg [pooled]) resulted in lower proportions of patients reporting moderate or greater flushing during the first week of treatment with 1.0 g of extended-release niacin (vs 1.0 g of extended-release niacin alone).…”

mentioning

confidence: 99%

“…136 In a single-dose study, adjunctive (concomitant) laropiprant significantly reduced flushing associated with 1.5 g of extended-release niacin: by 47% for a 30-mg dose of laropiprant, by 67% for a 100-mg dose, and by 74% for a 300-mg dose. 137 Coadministration of extended-release niacin with either 30 mg or 100 mg of laropiprant decreased peak malar (cheek) skin blood flow (objective measure of vasodilation) by 50% and 70%, respectively. Reductions in patient-rated flushing correlated significantly with decreases in malar blood flow (r=0.64-0.68; P<.001).…”

mentioning

confidence: 99%

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A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

Jacobson

2010

Mayo Clinic Proceedings

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Niacin is the most effective lipid-modifying agent for raising highdensity lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 19851, , through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptormediated, mainly prostaglandin D 2 -driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events. Proc. 2010;85(4):365-379 GPR = G i protein-coupled receptor; HDL-C = high-density lipoprotein cholesterol; NSAID = nonsteroidal anti-inflammatory drug; PG = prostaglandin; RCT = randomized controlled trial R educing low-density lipoprotein cholesterol levels is the primary treatment for preventing cardiovascular disease, largely because of robust evidence from randomized controlled trials (RCTs) involving statins. Mayo Clin

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Suppression of Niacin-induced Vasodilation with an Antagonist to Prostaglandin D2 Receptor Subtype 1

Cited by 134 publications

References 44 publications

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

β-Arrestin1 mediates nicotinic acid–induced flushing, but not its antilipolytic effect, in mice

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

A “Hot” Topic in Dyslipidemia Management—“How to Beat a Flush”: Optimizing Niacin Tolerability to Promote Long-term Treatment Adherence and Coronary Disease Prevention

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