Submitted on March 6, 2008
Accepted on May 14, 2008
Adrenomedullin acts in the lateral parabrachial nucleus to increase arterial blood pressure through mechanisms mediated by glutamate and nitric oxide
Adrian Geambasu1 and Teresa L Krukoff2*
1 Cell Biology, University of Alberta, Edmonton, Canada
2 Cell Biology, University of Alberta, Edmonton, Canada; Cell Biology, University of Alberta, Faculty of Med. and Dentistry, Edmonton, AB, Canada
* To whom correspondence should be addressed. E-mail: teresa.krukoff{at}ualberta.ca.
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-anesthetised adult Sprague-Dawley male rats to test the hypothesis that ADM increases MAP at this site through glutamate- and 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 minutes and lasted for 7 minutes. 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 co-injections 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 co-injections of ADM with either N5-(1-iminoethyl)-L-ornithine or 7-nitroindazole monosodium salt, non-specific 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 co-injected 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.
