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The periaqueductal gray area (PAG) is a mesencephalic area involved in cardiovascular modulation. Glutamate (L-Glu) is an abundant excitatory amino acid in the central nervous system (CNS) and is present in the rat PAG. Moreover, data in the literature indicate its involvement in central blood pressure control. Here we report on the cardiovascular effects caused by microinjection of L-Glu into the dorsomedial PAG (dmPAG) of rats and the glutamatergic receptors as well as the peripheral mechanism involved in their mediation. The microinjection of L-Glu into the dmPAG of unanesthetized rats evoked dose-related pressor and bradycardiac responses. The cardiovascular response was significantly reduced by pretreatment of the dmPAG with a glutamatergic M-methyl-D-aspartate (NMDA) receptor antagonist (LY235959) and was not affected by pretreatment with a non-NMDA receptor antagonist (NBQX), suggesting a mediation of that response by the activation of NMDA receptors. Furthermore, the pressor response was blocked by pretreatment with the ganglion blocker pentolinium (5 mg/kg, intravenously), suggesting an involvement of the sympathetic nervous system in this response. Our results indicate that the microinjection of L-Glu into the dmPAG causes sympathetic-mediated pressor responses in unanesthetized rats, which are mediated by glutamatergic NMDA receptors in the dmPAG., (Copyright © 2012 Wiley Periodicals, Inc.)

It has been reported that L-glutamate (L-glu) microinjection into the hypothalamic paraventricular nucleus (PVN) evokes pressor and tachycardiac responses in unanesthetized rats. In the present study the hypothesis was tested that a local nitric oxide (NO)-guanylate cyclase interaction mediates cardiovascular effects of L-glu microinjection into the PVN of rats. The cardiovascular responses evoked by 10 nmol/100 nL of L-glu microinjected into the PVN were measured before and 10 min after PVN treatment with vehicle, the selective neuronal NO-synthase (nNOS) inhibitor N(omega)-Propyl-L-arginine (N-Propyl, 0.04 nmol or 4 nmol/100 nL), the NO scavenger carboxy-PTIO (C-PTIO, 1 nmol/100 nL) or the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolol [4,3-a]quinoxalin-1-one (ODQ, 1 nmol/100 nL). In a final experiment, different doses of the NO donor sodium nitroprusside (SNP; 9, 27 or 45 nmol/100 nL) were microinjected into the PVN. Cardiovascular responses evoked by L-glu microinjection into the PVN were abolished by local pretreatment with N-Propyl in both anesthetized and unanesthetized rats. PVN treatment with either C-PTIO or ODQ also reduced L-glu cardiovascular responses. The microinjection of SNP into the PVN caused pressor and tachycardiac responses in unanesthetized rats, whereas depressor and bradycardiac responses were observed in anesthetized rats. The present results suggest that cardiovascular responses evoked by L-glu microinjection into the PVN involve a local production of NO and activation of guanylate cyclase., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

We report on the cardiovascular effects of L-glutamate (L-glu) microinjection into the hypothalamic paraventricular nucleus (PVN) as well as the mechanisms involved in their mediation. L-glu microinjection into the PVN caused dose-related pressor and tachycardiac responses in unanesthetized rats. These responses were blocked by intravenous (i.v.) pretreatment with the ganglion blocker pentolinium (PE; 5 mg/kg), suggesting sympathetic mediation. Responses to L-glu were not affected by local microinjection of the selective non-NMDA receptor antagonist NBQX (2 nmol) or by local microinjection of the selective NMDA receptor antagonist LY235959 (LY; 2 nmol). However, the tachycardiac response was changed to a bradycardiac response after treatment with LY235959, suggesting that NMDA receptors are involved in the L-glu heart rate response. Local pretreatment with LY235959 associated with systemic PE or dTyr(CH(2))(5)(Me)AVP (50 microg/kg) respectively potentiated or blocked the response to L-glu, suggesting that L-glu responses observed after LY235959 are vasopressin mediated. The increased pressor and bradycardiac responses observed after LY + PE was blocked by subsequent i.v. treatment with the V(1)-vasopressin receptor antagonist dTyr(CH(2))(5)(Me)AVP, suggesting vasopressin mediation. The pressor and bradycardiac response to L-glu microinjection into the PVN observed in animals pretreated with LY + PE was progressively inhibited and even blocked by additional pretreatment with increasing doses of NBQX (2, 10, and 20 nmol) microinjected into the PVN, suggesting its mediation by local non-NMDA receptors. In conclusion, results suggest the existence of two glutamatergic pressor pathways in the PVN: one sympathetic pathway that is mediated by NMDA receptors and a vasopressinergic pathway that is mediated by non-NMDA receptors., ((c) 2009 Wiley-Liss, Inc.)

Microinjection of l-glutamate (l-glu: 1, 3, 10 and 30nmol/100nL) into the lateral hypothalamus (LH) caused dose-related depressor and bradycardiac responses. The cardiovascular response to l-glu stimulation of the LH was blocked by pretreatment of the ventrolateral portion of the periaqueductal gray matter (vlPAG) with CoCl2 (1mM/100nL), indicating the existence of a synaptic relay of the hypotensive pathway in that area. Furthermore, the response to l-glu was blocked by pretreatment of the vlPAG with 2nmol/100nL of the selective NMDA-receptor antagonist LY235959 and was not affected by pretreatment with 2nmol/100nL of the selective non-NMDA-receptor antagonist NBQX, suggesting a mediation of the hypotensive response by NMDA receptors in the vlPAG. In conclusion, our results indicate that the hypotensive pathway activated by microinjection of l-glu into the LH involves a NMDA synaptic relay in the vlPAG.

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.

We report on the cardiovascular effects of L-glutamate (L-glu) microinjection in the hypothalamic supraoptic nucleus (SON) as well as possible receptor and mechanisms involved. Microinjection of L-glu in 100 nL in the SON caused dose-related pressor and bradycardic responses in unanesthetized rats. Responses were markedly reduced in urethane-anesthetized rats. The response to L-glu 10 nmol was blocked by local pretreatment with 2 nmol of the non-NMDA-receptors antagonist NBQX and not affected by 2 nmol of the selective NMDA-receptor antagonist LY 235959, suggesting that non-NMDA receptors mediate these responses. The pressor and bradycardic response to L-glu was potentiated by intravenous pretreatment with the ganglion blocker pentolinium and was blocked by intravenous pretreatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP, suggesting involvement of circulating vasopressin in this response. Additionally L-glu microinjection into the SON increased plasma vasopressin levels (control: 1.3 +/- 0.2 pg/mL, n = 6; L-glu: 14.7+/-2.3 pg/mL, n=6). In conclusion the results suggest that pressor responses to SON microinjection of L-glu are caused by activation of non-NMDA glutamate receptors and mediated by vasopressin release into systemic circulation.

The lateral hypothalamus (LH) is involved in cardiovascular control. L-glutamate (L-glu) stimulation of the LH of unanesthetized rats evoked hypotensive responses without significant heart rate changes. The neuronal pathway that mediates this response is unknown. There is evidence that the periaqueductal gray (PAG) is involved in the mediation of hypotensive responses evoked by electrical stimulation of the LH. In the present study, we attempted to verify the effect of an acute and reversible pharmacological ablation of the PAG with lidocaine or CoCl(2) on the hypotensive response caused by L-glu injection in the LH of unanesthetized rats. Microinjection of the local anesthetic lidocaine or the unspecific synaptic blocker CoCl(2) in the PAG significantly attenuated the hypotensive effects of L-glu stimulation of the LH, indicating the involvement of local synapses within the PAG in the hypotensive pathway activated by LH glutamatergic receptors. Microinjection of the neuronal tracer biotinylated dextran amine (BDA) in the PAG labeled neuronal cell bodies in the LH, indicating the existence of direct connections between these areas. In conclusion, the present results indicate that the hypotensive response evoked by L-glu stimulation of LH may involve a synaptic relay in the dorsal PAG.

The diagonal band of Broca (dbB) is involved in central cardiovascular control. In the present study we compared the effects of microinjections of L-glutamate into the dbB of unanesthetized rats with those observed after the injection of L-glutamate into the same area in urethane-anesthetized rats. The microinjection of L-glutamate (10, 30, 100 or 200 nmol/200 nl) into the dbB of urethane-anesthetized rats caused dose-related short-lasting depressor responses The depressor responses to L-glutamate were accompanied by dose-related heart rate reduction. The cardiovascular response to the injection of L-glutamate (10, 30 or 100 nmol/200 nl) into the dbB of unanesthetized rats was characterized as a long-lasting pressor response without consistent heart rate changes. The pressor response was dose-related and presented an ED(50) of approximately 30 nmol/200 nl. The fact that the chemical stimulation of the dbB with L-glutamate caused only dose-related pressor responses in unanesthetized rats suggests that under normal conditions the dbB is predominantly a pressor area. After the characterization of the pressor response to L-glutamate microinjected into the dbB of unanesthetized rats we studied the mechanisms involved in the mediation of these responses. The pressor response to L-glutamate (30 nmol/200 nl) into the dbB was blocked by intravenous pretreatment with the vasopressin antagonist dTyr(CH(2))(5)(Me)AVP (50 microg/kg), suggesting the involvement of circulating vasopressin in this response. Further evidence of the involvement of the endocrine vasopressin system in the pressor response to L-glutamate injected into the dbB was provided by hypophysectomy since L-glutamate (30 nmol/200 nl) microinjection into the dbB of hypophysectomized rats caused only depressor responses. We presently report that chemical stimulation of the dbB with L-glutamate caused only pressor responses in unanesthetized rats that were mediated by vasopressin release into the systemic circulation. Additionally, the results confirmed the existence of an L-glutamate-sensitive depressor system in the dbB, which is predominant in urethane-anesthetized rats or may be evidenced in unanesthetized hypophysectomized rats.