title: Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.
abstract: 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.
authors.affiliation: Department of Cardiovascular Diseases, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. kang_cheng@merck.com
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Tsuei-Ju
authors.initials: TJ
authors.lastname: Wu
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Claudio
authors.initials: C
authors.lastname: Sturino
authors.forename: Kathleen
authors.initials: K
authors.lastname: Metters
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: O'Neill
authors.forename: Eseng
authors.initials: E
authors.lastname: Lai
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D005260:Female; D005483:Flushing / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009525:Niacin / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology*
chemical_list: D006827:Hydantoins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D009525:Niacin; C034832:13,14-dihydro-15-ketoprostaglandin D2; C030669:BW 245C; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor