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

Zhang ZH, Yu Y, Wei SG, Nakamura Y, Nakamura K, Felder RB. EP3 receptors mediate PGE(2)-induced hypothalamic paraventricular nucleus excitation and sympathetic activation. Am J Physiol Heart Circ Physiol 301: H1559-H1569, 2011. First published July 29, 2011; doi:10.1152/ajpheart.00262.2011.-Prostaglandin E-2 (PGE(2)), an important mediator of the inflammatory response, acts centrally to elicit sympathetic excitation. PGE(2) acts on at least four E-class prostanoid (EP) receptors known as EP1, EP2, EP3, and EP4. Since PGE(2) production within the brain is ubiquitous, the different functions of PGE(2) 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 PGE(2) remain unknown. We examined this question using PGE(2), 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 PGE(2), 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 PGE(2) 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 PGE(2) 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 PGE(2) on PVN neurons and sympathetic discharge.