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: Kang Cheng, Tsuei-Ju Wu, Kenneth K Wu, Claudio Sturino, Kathleen Metters, Keith Gottesdiener, Samuel D Wright, Zhaoyin Wang, Gary O'Neill, Eseng Lai, M Gerard Waters
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 17 Pg. 6682-7 (Apr 25 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16617107 (Publication Type: Journal Article)

Chemical References

• Hydantoins
• Receptors, Immunologic
• Receptors, Prostaglandin
• Niacin
• 13,14-dihydro-15-ketoprostaglandin D2
• BW 245C
• Prostaglandin-Endoperoxide Synthases
• Aspirin
• Prostaglandin D2
• prostaglandin D2 receptor

Topics

• Adolescent
• Adult
• Animals
• Aspirin (pharmacology)
• Female
• Flushing (drug therapy, physiopathology)
• Humans
• Hydantoins (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Niacin (pharmacology)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Prostaglandin-Endoperoxide Synthases (physiology)
• Receptors, Immunologic (agonists, antagonists & inhibitors, deficiency, genetics)
• Receptors, Prostaglandin (agonists, antagonists & inhibitors, deficiency, genetics)
• Vasodilation (drug effects, physiology)