Prevention by NMDA receptor antagonists of the centrally‐evoked increases of cardiac inotropic responses in rabbits

Abstract

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 ftg kg-', 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-', 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-') and ifenprodil (1 mg kg-'), 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.

Inhibition of the centrally induced increases in myocardial oxygen demand in rabbits by chronic treatment with baclofen, a selective GABAB agonist

“…The heart rate is the single cardiovascular parameter that was not significantly increased; the activation of the baroreceptor reflex elicited by the marked rises in arterial pressure may have masked the potential tachycardic effect of central glutamate administration. These effects were of the same magnitude as those observed upon electrical or pharmacological stimulation of the PVN (Tibiriga et al, 1993;Monassier et al, 1994). Indeed, the sharp rises of the triple product, which is closely related to directly measured myocardial oxygen consumption (Baller et al, 1979), reached the maximum of more than 70% above baseline levels.…”

“…The inhibitory effect of baclofen could be explained by its well-known ability to decrease the presynaptic release of excitatory neurotransmitters like glutamate, which is mediated by hyperpolarization of the neurones via increased K+ conductance (Bowery et al, 1980;Lanthorn & Cotman, 1981;Raiteri et al, 1989;Otero-Losada & Acosta, 1992). Indeed, in a recent study we showed that the pretreatment of the animals with four different glutamate antagonists acting on different binding sites of the NMDA receptor/ channel complex also dose-dependently blunts the excitatory haemodynamic effects elicited by central stimulation (Monassier et al, 1994). Thus, we suggested that drugs modulating the activity of the GABAergic and/or glutamatergic systems of neurotransmission could be useful centrally acting cardioprotective drugs (Tibiriga' et al, 1993;Monassier et al, 1994).…”

“…Indeed, in a recent study we showed that the pretreatment of the animals with four different glutamate antagonists acting on different binding sites of the NMDA receptor/ channel complex also dose-dependently blunts the excitatory haemodynamic effects elicited by central stimulation (Monassier et al, 1994). Thus, we suggested that drugs modulating the activity of the GABAergic and/or glutamatergic systems of neurotransmission could be useful centrally acting cardioprotective drugs (Tibiriga' et al, 1993;Monassier et al, 1994).…”

σ2-Receptor Ligand-Mediated Inhibition of Inwardly Rectifying K+ Channels in the Heart

“…The animals were tracheotomized, immobilized with pancuronium bromide (0.3 mg/kg i.v. ), and artificially ventilated as described previously (Monassier et al, 1994). During the surgical procedure, the depth of anesthesia was regularly assessed by pinching the ear and checking whether there was any blood pressure response or any modification of the heart rate.…”

“…The right femoral vein was catheterized to permit i.v. injections, and instantaneous arterial pressure was continuously monitored through an arterial femoral catheter placed in the abdominal aorta via the right femoral artery as described previously (Monassier et al, 1994).…”