Morrow J D, Parsons W G, Roberts L J
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
Prostaglandins. 1989 Aug;38(2):263-74. doi: 10.1016/0090-6980(89)90088-9.
Nicotinic acid (niacin) is a B vitamin which is also a potent hypolipidemic agent. However, intense flushing occurs following ingestion of pharmacologic doses of niacin which greatly limits its usefulness in treating hyperlipidemias. Previous studies have demonstrated that niacin-induced flushing can be substantially attenuated by pre-treatment with cyclooxygenase inhibitors, suggesting that the vasodilation is mediated by a prostaglandin. However, the prostaglandin that presumably mediates the flush has not been conclusively determined. In this study we report the finding that ingestion of niacin evokes the release of markedly increased quantities of PGD2 in vivo in humans. PGD2 release was assessed by quantification of the PGD2 metabolite, 9 alpha, 11 beta-PGF2, in plasma by gas chromatography mass spectrometry. Following ingestion of 500 mg of niacin in three normal volunteers, intense flushing occurred and plasma levels of 9 alpha, 11 beta-PGF2 were found to increase dramatically by 800, 430, and 535-fold. Levels of 9 alpha, 11 beta-PGF2 reached a maximum between 12 and 45 min. after ingesting niacin and subsequently declined to near normal levels by 2-4 hours. Levels of 9 alpha, 11 beta-PGF2 in plasma correlated with the intensity and duration of flushing that occurred in the 3 volunteers. Release of PGD2 was not accompanied by a release of histamine which was assessed by quantification of plasma levels of the histamine metabolite, N tau-methylhistamine. This suggests that the origin of the PGD2 release is not the mast cell. Only a modest increase (approximately 2-fold) in the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-PGF1 alpha, occurred following ingestion of niacin and no increase in the excretion of the major urinary metabolite of PGE2 was found. These results indicate that the major vasodilatory PG released following ingestion of niacin is PGD2. The fact that markedly increased quantities of PGD2 are released suggests that PGD2 is the mediator of niacin-induced vasodilation in humans.
烟酸是一种B族维生素，也是一种有效的降血脂药物。然而，摄入药理剂量的烟酸后会出现强烈的潮红，这极大地限制了其在治疗高脂血症中的应用。先前的研究表明，用环氧化酶抑制剂预处理可显著减轻烟酸引起的潮红，这表明血管舒张是由前列腺素介导的。然而，推测介导潮红的前列腺素尚未最终确定。在本研究中，我们报告了一项发现，即摄入烟酸会在人体内引起体内PGD2释放量显著增加。通过气相色谱-质谱法定量血浆中PGD2代谢物9α,11β-PGF2来评估PGD2的释放。在三名正常志愿者摄入500毫克烟酸后，出现了强烈的潮红，并且发现血浆中9α,11β-PGF2水平分别急剧增加了800倍、430倍和535倍。9α,11β-PGF2水平在摄入烟酸后12至45分钟达到峰值，随后在2至4小时内降至接近正常水平。血浆中9α,11β-PGF2水平与三名志愿者出现的潮红强度和持续时间相关。PGD2的释放并未伴随着组胺的释放，组胺的释放通过定量血浆中组胺代谢物Nτ-甲基组胺水平来评估。这表明PGD2释放的来源不是肥大细胞。摄入烟酸后，前列环素代谢物2,3-二去甲-6-酮-PGF1α的尿排泄仅出现适度增加（约2倍），并且未发现PGE2主要尿代谢物排泄增加。这些结果表明，摄入烟酸后释放的主要血管舒张性PG是PGD2。PGD2释放量显著增加这一事实表明，PGD2是人类烟酸诱导血管舒张的介质。
