Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats.

Abstract

Whereas few studies have dealt with the central sympathoexcitatory action of the inflammatory prostanoid prostaglandin E2 (PGE2), there is no information on the expression and cardiovascular function of different PGE2 (EP) receptors in one of the major cardiovascular-regulating nuclei, the rostral ventrolateral medulla (RVLM). The current study aimed at filling this knowledge gap as well as elucidating the implicated molecular mechanisms. To achieve these goals, we showed the expression of EP2, EP3, and EP4 receptors in the RVLM and investigated their cardiovascular roles in conscious rats, ex vivo as well as in cultured PC12 cells. Intra-RVLM PGE2 significantly increased blood pressure and sympathetic dominance (spectral analysis). Studies with selective EP receptor subtype agonists and antagonists showed that these PGE2-evoked responses were only replicated by intra-RVLM activation of the EP3 receptor with its agonist sulprostone. The RVLM of PGE2-treated rats exhibited increases in c-Fos expression and extracellular signal-regulated kinase 1/2 and neuronal nitric oxide synthase phosphorylation along with oxidative stress, and PGE2 increased l-glutamate release in PC12 cells (surrogates of RVLM neurons). Abrogation of the PGE2-evoked pressor and biochemical responses only occurred following EP3 receptor blockade (N-[(5-Bromo-2-methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl)phenyl]-2-propenamide, L-798106). These findings suggest the dependence of RVLM PGE2-mediated sympathoexcitation/pressor response on local EP3 receptor signaling in conscious rats, and highlight central EP3 receptor blockade as a potential therapeutic modality for hypertension management.