EP3 receptors mediate PGE2-induced hypothalamic paraventricular nucleus excitation and sympathetic activation

Abstract

Prostaglandin E₂ (PGE₂), an important mediator of the inflammatory response, acts centrally to elicit sympathetic excitation. PGE₂ acts on at least four E-class prostanoid (EP) receptors known as EP₁, EP₂, EP₃, and EP₄. Since PGE₂ production within the brain is ubiquitous, the different functions of PGE₂ depend on the expression of these prostanoid receptors in specific brain areas. The type(s) and location(s) of the EP receptors that mediate sympathetic responses to central PGE₂ remain unknown. We examined this question using PGE₂, the relatively selective EP receptor agonists misoprostol and sulprostone, and the available selective antagonists for EP₁, EP₃, and EP₄. In urethane-anesthetized rats, intracerebroventricular (ICV) administration of PGE₂, sulprostone or misoprostol increased renal sympathetic nerve activity, blood pressure, and heart rate. These responses were significantly reduced by ICV pretreatment with the EP₃ receptor antagonist; the EP₁ and EP₄ receptor antagonists had little or no effect. ICV PGE₂ or misoprostol increased the discharge of neurons in the hypothalamic paraventricular nucleus (PVN). ICV misoprostol increased the c-Fos immunoreactivity of PVN neurons, an effect that was substantially reduced by the EP₃ receptor antagonist. Real-time PCR detected EP₃ receptor mRNA in PVN, and immunohistochemical studies revealed sparsely distributed EP₃ receptors localized in GABAergic terminals and on a few PVN neurons. Direct bilateral PVN microinjections of PGE₂ or sulprostone elicited sympathoexcitatory responses that were significantly reduced by the EP₃ receptor antagonist. These data suggest that EP₃ receptors mediate the central excitatory effects of PGE₂ on PVN neurons and sympathetic discharge.