Prevention by NMDA receptor antagonists of the centrally-evoked increases of cardiac inotropic responses in rabbits.
1. The purpose of this study was to investigate further the role of the excitatory amino acid (EAA) system of neurotransmission, particularly of the NMDA receptor, in the central regulation of cardiac function. 2. Electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN) in pentobarbitone anaesthetized rabbits induced a cardiovascular response mainly characterized by a positive inotropic effect, hypertension and a marked increase in the myocardial oxygen demand index. 3. The intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of different EAA antagonists acting on different sites of the NMDA receptor/channel complex dose-dependently blunted the excitatory cardiovascular effects of PVN stimulation. 4. 5,7 Dichlorokynurenic acid was used as a specific glycine site antagonist and 2-amino-5-phosphonovaleric acid was used to block the agonist recognition site; ketamine was used as a channel blocker site antagonist and ifenprodil as a blocker of the polyamine binding site. 5. 5,7 Dichlorokynurenic acid (125 and 250 micrograms kg-1, i.c.v.) virtually abolished the cardiovascular responses, inducing only haemodynamic depression at the highest dose used. 2-Amino-5-phosphonovaleric acid (0.1 to 1.0 mg kg-1, i.c.v.) elicited a reduction of the peak values observed during PVN stimulation which was accompanied by a decrease of the basal cardiovascular parameters. Ketamine (2.5 and 10 mg kg-1) and ifenprodil (1 mg kg-1), injected intravenously, blocked the haemodynamic response induced by PVN stimulation without marked reduction of the basal haemodynamics. 6. It is concluded that glutamate neurotransmission is not only involved in vasomotor tone control but also in the central control of cardiac function and can therefore modulate the myocardial oxygen demand.
Monassier
L
L
Laboratoire de Pharmacologie Cardiovasculaire et Rénale, CNRS URA 589, Faculté de Médecine, Université Louis Pasteurs, Strasbourg, France.
Tibiriça
E
E
Roegel
J C
JC
Mettauer
B
B
Feldman
J
J
Bousquet
P
P
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004558:Electric Stimulation; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007649:Ketamine / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010286:Paraventricular Hypothalamic Nucleus / Q000502:physiology*; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid