Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans
Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans
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DOI：
10.1073/pnas.0601574103
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发表时间：
2006-04-25
影响因子：
11.1
通讯作者：
Waters, MG
中科院分区：
文献类型：
--
作者：
Cheng, K;Wu, TJ;Waters, MG
烟酸（NA）常用于治疗血脂异常，但它会引起称为潮红的不良反应，包括皮肤血管扩张和相关不适。在小鼠中建立了NA诱导的潮红动物模型。在人类中，NA刺激血管舒张的剂量依赖性的方式，与血管扩张的前列腺素（PG）D-2在血浆中的增加，并可以通过预先与阿司匹林阻断。已鉴定出两种PGD（2）受体：PGD（2）受体1（DP 1，也称为DP）和PGD（2）受体2（DP 2，有时称为CRTH 2）。DP 2不介导NA诱导的血管舒张; DP 2特异性激动剂DK-PGD（2）（13，14-dihydro-15-keto-PGD（2））不诱导皮肤血管舒张，DP 2（-/-）小鼠对NA有正常的血管舒张反应。相反，DP 1选择性激动剂BW 245 C诱导小鼠血管舒张，DP 1选择性拮抗剂MK-0524阻断PGD（2）和NA诱导的血管舒张。还在DP 1（+/+）、DP 1（+/-）和DP 1（-/-）小鼠中研究了NA诱导的血管舒张;尽管NA诱导的血管舒张在雌性小鼠中几乎完全依赖于DP 1，但在雄性小鼠中仅部分依赖于DP 1。在雄性DP-/-小鼠中，残余NA诱导的血管舒张是阿司匹林敏感的。因此，在小鼠中，DP 1似乎是参与NA-诱导的血管舒张的重要组分，但也可能涉及其他环加氧酶依赖性机制。在健康男性和女性中进行的一项临床研究表明，MK-0524治疗可减轻NA给药后的潮红症状和皮肤灌注增加。这些研究表明，DP 1受体拮抗剂可能是一种有效的手段来抑制NA诱导的人类潮红。
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) D-2 in plasma and could be blocked by pretreatment with aspirin. Two PGD(2) receptors have been identified: PGD(2) receptor 1 (DP1, also called DP) and PGD(2) receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD(2) (13,14-dihydro-15-keto-PGD(2)) 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 PGD(2)- and NA-incluced vasodilation. NA-incluced vasodilation was also studied in DP1(+/+), DP1(+/-), and DP1(-/-) mice; although NA-induced vasoclilation 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-incluced 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.