Cheng Kang, Wu Tsuei-Ju, Wu Kenneth K, Sturino Claudio, Metters Kathleen, Gottesdiener Keith, Wright Samuel D, Wang Zhaoyin, O'Neill Gary, Lai Eseng, Waters M Gerard
Department of Cardiovascular Diseases, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6682-7. doi: 10.1073/pnas.0601574103. Epub 2006 Apr 14.
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.
烟酸（NA）常用于治疗血脂异常，但它会引发一种名为潮红的不良反应，其表现为皮肤血管扩张并伴有不适感。在小鼠中已建立了NA诱导潮红的动物模型。与人类情况一样，NA以剂量依赖的方式刺激血管扩张，与血浆中血管舒张性前列腺素（PG）D2的增加有关，并且可以通过阿司匹林预处理来阻断。已鉴定出两种PGD2受体：PGD2受体1（DP1，也称为DP）和PGD2受体2（DP2，有时称为CRTH2）。DP2不介导NA诱导的血管扩张；DP2特异性激动剂DK-PGD2（13,14-二氢-15-酮-PGD2）不会诱导皮肤血管扩张，并且DP2基因敲除小鼠对NA具有正常的血管舒张反应。相比之下，DP1选择性激动剂BW245C可诱导小鼠血管扩张，而DP1选择性拮抗剂MK-0524可阻断PGD2和NA诱导的血管扩张。还在DP1+/+、DP1+/-和DP1-/-小鼠中研究了NA诱导的血管扩张；尽管NA诱导的血管扩张在雌性小鼠中几乎完全依赖于DP1，但在雄性小鼠中仅部分依赖于DP1。雄性DP基因敲除小鼠中残留的NA诱导的血管扩张对阿司匹林敏感。因此，在小鼠中，DP1似乎是参与NA诱导血管扩张的重要组成部分，但其他环氧化酶依赖性机制也可能参与其中。一项针对健康男性和女性的临床研究表明，用MK-0524治疗可减轻潮红症状以及NA给药后皮肤灌注的增加。这些研究表明，DP1受体拮抗作用可能是抑制人类NA诱导潮红的有效手段。
