title: Adrenomedullin acts in the lateral parabrachial nucleus to increase arterial blood pressure through mechanisms mediated by glutamate and nitric oxide.
abstract: Adrenomedullin (ADM) acts in a site-specific manner within autonomic centers of the brain to modulate mean arterial pressure (MAP). To determine the role of ADM in the pontine autonomic center, the lateral parabrachial nucleus (LPBN), we used urethane-anesthetized adult Sprague-Dawley male rats to test the hypothesis that ADM increases MAP at this site through glutamate- and nitric oxide (NO)-dependent mechanisms. ADM microinjected into the LPBN increased MAP in a dose-dependent manner. The pressor effect of ADM (0.01 pmol) had a peak value of 11.9 +/- 1.9 mmHg at 2 min and lasted for 7 min. We demonstrated that ADM's effect is receptor mediated by blocking the effect with the ADM receptor antagonist, ADM22-52. We showed that glutamate mediates ADM's pressor response, as this response was blocked using coinjections of ADM with dizolcipine hydrogen maleate or 6-cyano-7-nitroquinoxaline-2,3-dione, N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists, respectively. We tested the roles of NO with coinjections of ADM with either N5-(1-iminoethyl)-L-ornithine or 7-nitroindazole monosodium salt, nonspecific and neuronal NO synthase (NOS) inhibitors, respectively; both inhibitors blocked ADM's pressor effect. Finally, we studied the role of calcium influx in ADM's pressor effect, as intracellular calcium is important in both glutamate and NO neurotransmission. ADM's effect was blocked when nifedipine, an L-type calcium channel blocker, was coinjected with ADM into the LPBN. This study is the first to show that ADM acts in the LPBN to increase MAP through mechanisms dependent on activation of ionotropic glutamate receptors, neuronal and endothelial NOS-mediated NO synthesis, and L-type calcium channel activation.
authors.affiliation: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Geambasu
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Krukoff
mesh_terms: D053607:Adrenomedullin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D009569:Nitric Oxide; D018698:Glutamic Acid; D019001:Nitric Oxide Synthase