2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and 1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole

The bed nucleus of the stria terminalis (BST) plays a tonic role modulating the baroreflex bradycardiac response. In the present study, we verified whether local BST glutamatergic receptors and nitric oxide (NO) system modulate baroreflex bradycardiac responses. Bilateral BST- N-methyl-D-aspartate (NMDA) receptor inhibition by treatment with the selective NMDA receptor antagonist LY235959 increased bradycardiac response to mean arterial pressure increases. Treatment with the selective non-NMDA antagonist NBQX did not affect reflex bradycardia. These results suggest an involvement of local NMDA receptors in the BST-related tonic inhibitory modulation of baroreflex bradycardiac response. BST treatment with the nonselective NO synthase (NOS) inhibitor L-NAME or the selective neuronal NOS (nNOS) inhibitor N(omega)-propyl-L-arginine increased bradycardiac response, indicating that NO generated by nNOS activation modulates baroreflex. The NO involvement was further reinforced by observation that BST treatment with the NO scavenger carboxy-PTIO caused an effect similar to that observed after NMDA receptor blockade or treatment with NOS inhibitors. Additionally, it was observed that LY235959 effects on baroreflex bradycardiac response were reverted by BST treatment with the NO-donor sodium nitroprusside, suggesting an NMDA receptor-NO interaction. Baroreflex bradycardiac responses observed before and after BST treatment with LY235959 or N(omega)-propyl-L-arginine were no longer different when animals were pretreated intravenously with the anticholinergic drug homatropine methyl bromide. These results indicate that parasympathetic activation accounts for the effects observed after BST pharmacological manipulation. In conclusion, our data point out that local NMDA and nNOS interaction mediates the tonic inhibitory influence of the BST on the baroreflex bradycardiac response, modulating the parasympathetic cardiac activity.

Topics: Animals; Arginine; Baroreflex; Benzoates; Blood Pressure; Cardiac Output; Cholinergic Antagonists; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Imidazoles; Isoquinolines; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Nitroprusside; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Septal Nuclei; Tropanes

The ventral portion of medial prefrontal cortex (vMPFC) is involved in contextual fear-conditioning expression in rats. In the present study, we investigated the role of local N-methyl-D-aspartic acid (NMDA) glutamate receptors and nitric oxide (NO) in vMPFC on the behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats exposed to a context fear conditioning. The results showed that both freezing and cardiovascular responses to contextual fear conditioning were reduced by bilateral administration of NMDA receptor antagonist LY235959 (4 nmol/200 nL) into the vMPFC before reexposition to conditioned chamber. Bilateral inhibition of neuronal NO synthase (nNOS) by local vMPFC administration of the N omega-propyl-L-arginine (N-propyl, 0.04 nmol/200 nL) or the NO scavenger carboxy-PTIO (1 nmol/200 nL) caused similar results, inhibiting the fear responses. We also investigated the effects of inhibiting glutamate- and NO-mediated neurotransmission in the vMPFC at the time of aversive context exposure on reexposure to the same context. It was observed that the 1st exposure results in a significant attenuation of the fear responses on reexposure in vehicle-treated animals, which was not modified by the drugs. The present results suggest that a vMPFC NMDA-NO pathway may play an important role on expression of contextual fear conditioning.

Topics: Animals; Arginine; Benzoates; Blood Pressure; Conditioning, Psychological; Excitatory Amino Acid Antagonists; Fear; Freezing Reaction, Cataleptic; Glutamic Acid; Heart Rate; Imidazoles; Isoquinolines; Male; Nitric Oxide; Prefrontal Cortex; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

In a previous study, we reported depressor and bradycardiac responses after L-glutamate (L-glu) microinjection into the diagonal band of Broca (dbB) in anesthetized rats. Here, we report the glutamatergic-receptor subtype mediating the cardiovascular effects evoked by L-glu injection into the dbB and the involvement of local nitric oxide (NO) mechanisms as well as peripheral effectors. Microinjections of 100 nL of L-glu (1, 27, 81, 130 or 200 nmol) into the dbB of urethane-anesthetized rats caused short-lasting depressor and bradycardiac responses. Responses were dose-related, with an ED(50) of approximately 81 nmol. This dose was used in later experiments. The cardiovascular responses to L-glu in the dbB were abolished by local pretreatment (100 nL) with the selective N-methyl-D-aspartic acid (NMDA) receptor antagonist LY235959 (4 nmol) but were not affected by pretreatment with the selective non-NMDA receptor antagonist NBQX (4 nmol). Responses to L-glu in the dbB were blocked by local pretreatment with the selective neuronal NO-synthase (nNOS) inhibitor N(omega)-propyl-L-arginine (NPLA, 0.04 nmol); the NO scavenger carboxy-PTIO (C-PTIO, 1 nmol) or the guanylate cyclase inhibitor ODQ (1 nmol). These results suggest that the microinjection of L-glu into the dbB of urethane-anesthetized rats causes dose-related depressor and bradycardiac responses through the NMDA receptor-NO-guanylate cyclase pathway.

Topics: Anesthesia; Animals; Arginine; Benzoates; Blood Pressure; Diagonal Band of Broca; Dose-Response Relationship, Drug; Glutamic Acid; Heart Rate; Imidazoles; Isoquinolines; Male; Microinjections; Nitrergic Neurons; Oxadiazoles; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate