From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru (N.A.-J.).
Department of Pharmacology and Toxicology (N.A.-J., R.B., G.D.F.), Michigan State University, East Lansing.
Hypertension. 2019 Dec;74(6):1499-1506. doi: 10.1161/HYPERTENSIONAHA.119.13175. Epub 2019 Oct 7.
This study tested whether brain L-PGDS (lipocalin-type prostaglandin [PG] D synthase), through prostanoid signaling, might increase neurogenic pressor activity and thereby cause hypertension. Sprague Dawley rats on high-salt diet received either vehicle or Ang II (angiotensin II) infusion. On day 4, the developmental stage of hypertension, brains from different sets of control and Ang II-treated rats were collected for measuring L-PGDS expression, PGD2 levels, and DP1R (type 1 PGD2 receptor) expression. In a different set of 14-day Ang II-salt-treated rats, mini-osmotic pumps were used to infuse either a nonselective COX (cyclooxygenase) inhibitor ketorolac, L-PGDS inhibitor AT56, or DP1R inhibitor BWA868C to test the role of brain COX-PGD2-DP1R signaling in Ang II-salt hypertension. The acute depressor response to ganglion blockade with hexamethonium was used to quantify neurogenic pressor activity. During the developmental stage of Ang II-salt hypertension, L-PGDS expression was higher in cerebrospinal fluid, and PGD2 levels were increased in the choroid plexus, cerebrospinal fluid, and the cardioregulatory brain region rostral ventrolateral medulla. DP1R expression was decreased in rostral ventrolateral medulla. Both brain COX inhibition with ketorolac and L-PGDS inhibition with AT56 lowered mean arterial pressure by altering neurogenic pressor activity compared with vehicle controls. Blockade of DP1R with BWA868C, however, increased the magnitude of Ang II-salt hypertension and significantly increased neurogenic pressor activity. In summary, we establish that the development of Ang II-salt hypertension requires increased COX- and L-PGDS-derived PGD2 production in the brain, making L-PGDS a possible target for treating neurogenic hypertension.
本研究旨在测试脑 L-PGDS（脂氧素型前列腺素[PG] D 合酶）是否通过前列腺素信号转导增加神经源性升压活性，从而导致高血压。高盐饮食的 Sprague Dawley 大鼠接受载体或 Ang II（血管紧张素 II）输注。在第 4 天，即高血压的发育阶段，从不同的对照组和 Ang II 处理组大鼠收集大脑以测量 L-PGDS 表达、PGD2 水平和 DP1R（1 型 PGD2 受体）表达。在另一组 14 天 Ang II-盐处理的大鼠中，使用微型渗透泵输注非选择性 COX（环氧化酶）抑制剂酮咯酸、L-PGDS 抑制剂 AT56 或 DP1R 抑制剂 BWA868C，以测试脑 COX-PGD2-DP1R 信号在 Ang II-盐高血压中的作用。用六烃季铵阻断神经节来检测神经源性升压活性的急性降压反应。在 Ang II-盐高血压的发育阶段，脑脊液中 L-PGDS 表达升高，脉络丛、脑脊液和心脏调节脑区延髓头端腹外侧区的 PGD2 水平升高。DP1R 表达在延髓头端腹外侧区降低。与载体对照组相比，脑 COX 抑制（用酮咯酸）和 L-PGDS 抑制（用 AT56）均降低平均动脉压，通过改变神经源性升压活性。然而，用 BWA868C 阻断 DP1R 增加了 Ang II-盐高血压的幅度，并显著增加了神经源性升压活性。总之，我们证实 Ang II-盐高血压的发展需要脑内 COX 和 L-PGDS 衍生的 PGD2 产生增加，使 L-PGDS 成为治疗神经源性高血压的一个可能靶点。
