Cardiovascular response to a group III mGluR agonist in NTS requires NMDA receptors.
Previous studies have demonstrated that microinjection of the putative group III metabotropic glutamate receptor (mGluR) agonist, l(+)-2-amino-4-phosphonobutyric acid (L-AP4), into the nucleus tractus solitarius (NTS) produces depressor and sympathoinhibitory responses. These responses are significantly attenuated by a group III mGluR antagonist and may involve ionotropic glutamatergic transmission. Alternatively, a previous report in vitro suggests that preparations of L-AP4 may nonspecifically activate NMDA channels due to glycine contamination (Contractor A, Gereau RW, Green T, and Heinemann SF. Proc Natl Acad Sci USA 95: 8969-8974, 1998). Therefore, the present study tested whether responses to L-AP4 specifically require the N-methyl-D-aspartate (NMDA) receptor and whether they are due to actions at the glycine site on the NMDA channel. To test these possibilities in vivo, we performed unilateral microinjections of L-AP4, glycine, and selective antagonists into the NTS of urethane-anesthetized rats. L-AP4 (10 mM, 30 nl) produced sympathoinhibitory responses that were abolished by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (AP-5, 10 mM) but were unaffected by the non-NMDA antagonist 6-nitro-7-sulfamobenzoquinoxaline-2,3-dione (NBQX, 2 mM). Microinjection of glycine (0.02-20 mM) failed to mimic sympathoinhibitory responses to L-AP4, even in the presence of the inhibitory glycine antagonist, strychnine (3 mM). Strychnine blocked pressor and sympathoexcitatory actions of glycine (20 mM) but failed to reveal a sympathoinhibitory component due to presumed activation of NMDA receptors. The results of these experiments suggest that responses to L-AP4 require NMDA receptors and are independent of non-NMDA receptors. Furthermore, although it is possible that glycine contamination or other nonspecific actions are responsible for the sympathoinhibitory actions of L-AP4, our data and data in the literature argue against this possibility. Thus we conclude that responses to L-AP4 in the NTS are mediated by an interaction between group III mGluRs and NMDA receptors. Finally, we also caution that nonselective actions of L-AP4 should be considered in future studies.
Mueller
Patrick J
PJ
Department of Biomedical Sciences, Dalton Cardiovascular Research Center, 134 Research Park, University of Missouri, Columbia, MO 65211-3300, USA.
Foley
C Michael
CM
Vogl
Helen W
HW
Hay
Meredith
M
Hasser
Eileen M
EM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000502:physiology; D013331:Strychnine / Q000494:pharmacology
D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D018684:Glycine Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D015763:2-Amino-5-phosphonovalerate; C012729:2-amino-4-phosphonobutyric acid; D013331:Strychnine; D005998:Glycine