Prostaglandin D2‐DP1 receptor signaling inhibits sympathetic nerve activity and development of angiotensin II‐salt hypertension (874.11)

Abstract

Cerebrospinal fluid levels of lipocalin‐prostaglandin D synthase protein (L‐PGDS) and the lipid mediator prostaglandin D2 (PGD2) are increased in early stages of AngII‐salt hypertension (AngII‐HS‐HTN) in rats. Because L‐PGDS inhibition reduces neurogenic AngII‐HS‐HTN development and its product PGD2 acts on central DP‐1 receptors (DP‐1Rs), we hypothesized that PGD2 acting through DP1‐Rs mediated AngII‐HS‐HTN development.Method: Two sets of studies were performed. First, anesthetized rats received an injection of PGD2 (50µg/5µl) intracerebroventricularly (icv). PGD2 caused a maximum 22±6 mmHg increase in BP. In other anesthetized rats the DP1‐R antagonist BW A868C (78ng/5µl) was injected icv followed by PGD2 injection; BW A868C blocked PGD2 mediated increases in BP. In the second study we tested the effect of chronic DP1‐R blockade on AngII‐salt HTN. Continuous radio‐telemetric recording of BP was used. After control BP recording, rats on 2% NaCl diet were pretreated with vehicle (n=4) or BW A868C (425nM/h, sc, n=5). All rats then received AngII (150ng/kg/min, sc) for 14 days. Ganglionic blockade with hexamethonium (30mg/kg, ip) was performed on day 10 of AngII administration to assess neurogenic pressor activity. Finally, PGD2 (50µg/5µl) was injected acutely into lateral ventricles to test if central DP‐1Rs were inhibited.Result: Compared to the control period, AngII infusion increased mean arterial pressure (MAP, mmHg) from 95±2 to143±10 (31±10 increase) in vehicle, and from 109±7 to140±1 (56±3 increase) in BW A868C treated rats (p<0.05). Neurogenic pressor activity (mmHg) was significantly higher in BW A868 (86±10) than vehicle (46±11) treated rats. Finally, central PGD2 injection failed to elicit a BP response in BW A868C treated rats confirming central DP1‐R inhibition.Conclusion: Acute icv PGD2 induced increases in BP are mediated via DP‐1R. However, chronic PGD2 signaling through central DP1‐R inhibits AngII‐HS‐HTN development and causes sympathoinhibition.Grant Funding Source: “Supported by” RO1 HL 076312 and RCO HL 060363