title: EP₃ receptors mediate PGE₂-induced hypothalamic paraventricular nucleus excitation and sympathetic activation.
abstract: 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 EP(1), EP(2), EP(3), and EP(4). 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 EP(1), EP(3), and EP(4). 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 EP(3) receptor antagonist; the EP(1) and EP(4) 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 EP(3) receptor antagonist. Real-time PCR detected EP(3) receptor mRNA in PVN, and immunohistochemical studies revealed sparsely distributed EP(3) 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 EP(3) receptor antagonist. These data suggest that EP(3) receptors mediate the central excitatory effects of PGE(2) on PVN neurons and sympathetic discharge.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D055724:Electrophysiological Phenomena; D005455:Fluorescent Antibody Technique; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007668:Kidney / Q000187:drug effects / Q000294:innervation; D008297:Male; D008833:Microcirculation / Q000502:physiology; D016595:Misoprostol / Q000008:administration & dosage / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000098:blood supply / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013564:Sympathetic Nervous System / Q000187:drug effects*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016595:Misoprostol; C016767:sulprostone; D051546:Cyclooxygenase 2; D015232:Dinoprostone