Human essential hypertension (HTN) causes end organ damage, cardiovascular disease and premature death. While increased sympathetic nerve activity (SNA) is a principal risk factor for the development of HTN, the central mechanisms that drive high sympathetic outflow remain unclear. Increased SNA and blood pressure (BP) can be triggered by high salt intake (2% NaCl) and the hormone angiotensin II (AngII). Our lab has extensively studied a rat model of HTN caused by these two factors in combination (AngII-salt HTN), and have shown that SNA contributes to the HTN and blocking whole-body eicosanoid (prostaglandin, thromboxane, lipoxygenase) synthesis with cyclooxygenase (COX) inhibitors attenuated both the increased SNA and HTN development. My project was to determine how eicosanoid products contribute to AngII-salt HTN. In initial experiments, I showed that whole-body COX inhibition failed to reverse established AngII-salt HTN in rats (similar to human hypertensives). In contrast, COX inhibition only during the first several days of 14-day AngII-salt treatment successfully prevented subsequent HTN development and sympathetic support of BP (i.e. neurogenic pressor activity). I concluded that COX products exert important physiological effects only during the early phase. I next investigated the roles of the two isoforms of COX and found that COX-1 specific products drive the development of AngII-salt HTN. Because most eicosanoid products in peripheral tissues (blood vessel, kidney) lower BP, I decided to test if central (i.e. brain) eicosanoids, acting early in the process of AngII-salt HTN development, cause a long-lived increase in SNA and BP. I chronically administered the COX inhibitor into the brain at a dose designed to block COX in the brain, and showed that this prevented increase in SNA and HTN development. I concluded that one or more COX-1 products in the brain contribute to HTN development. I also performed PCR and Western blot analysis of COX pathway-associated gene and protein expression in known cardio-regulatory regions of the brain. This revealed only modest changes for the most part, but I observed significant changes in the prostaglandin D2 (PGD2) pathway (downstream from COX) in the OVLT (cardio-regulatory brain region), choroid plexus (CP) and cerebrospinal fluid (CSF). Importantly, I showed increased lipocalin-prostaglandin D synthase (L-PGDS) expression in the CP and CSF, the main sites of L-PGDS synthesis and secretion, respectively. These findings were the first ever to implicate brain PGD2 in HTN. Thus, to investigate this finding in more detail, I measure brain levels of PGD2 with mass spectrometry and found high levels in CSF and rostral ventrolateral medulla (RVLM) of HTN rats. PGD2 in the brain binds mainly to the G-protein coupled receptor DP1R. Immunofluorescence staining revealed down-regulation of DP1R in the RVLM during the early phase of AngII-salt HTN; perhaps predictable in the presence of increased agonist concentration. Finally, blockade of L-PGDS prevented the increase in PGD2 levels in the RVLM during the early phase of AngII-salt treatment and attenuated subsequent HTN development. In conclusion, the results of my studies suggest a novel mechanism for neurogenic HTN development: PGD2 generated in the brain from L-PGDS acts on DP1R in the RVLM, which ultimately leads to increased SNA, neurogenic pressor activity and HTN.
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