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1.
Pflugers Arch ; 470(10): 1521-1542, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29845313

RESUMO

The ventral medial prefrontal cortex (vMPFC) facilitates the cardiac baroreflex response through N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) formation by neuronal NO synthase (nNOS) and soluble guanylate cyclase (sGC) triggering. Glutamatergic transmission is modulated by the cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid type 1 (TRPV1) receptors, which may inhibit or stimulate glutamate release in the brain, respectively. Interestingly, vMPFC CB1 receptors decrease cardiac baroreflex responses, while TRPV1 channels facilitate them. Therefore, the hypothesis of the present study is that the vMPFC NMDA/NO pathway is regulated by both CB1 and TRPV1 receptors in the modulation of cardiac baroreflex activity. In order to test this assumption, we used male Wistar rats that had stainless steel guide cannulae bilaterally implanted in the vMPFC. Subsequently, a catheter was inserted into the femoral artery, for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. The increase in tachycardic and bradycardic responses observed after the microinjection of a CB1 receptors antagonist into the vMPFC was prevented by an NMDA antagonist as well as by the nNOS and sGC inhibition. NO extracellular scavenging also abolished these responses. These same pharmacological manipulations inhibited cardiac reflex enhancement induced by TRPV1 agonist injection into the area. Based on these results, we conclude that vMPFC CB1 and TRPV1 receptors inhibit or facilitate the cardiac baroreflex activity by stimulating or blocking the NMDA activation and NO synthesis.


Assuntos
Barorreflexo , Coração/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Frequência Cardíaca , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Canais de Cátion TRPV/agonistas
2.
Eur J Neurosci ; 44(11): 2877-2884, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27646556

RESUMO

Baroreflex activity is a neural mechanism responsible for short-term adjustments in blood pressure (BP). Several supramedullary areas, which send projections to the medulla, are able to control this reflex. In this context, the ventrolateral part of the periaqueductal grey matter (vlPAG), which is a mesencephalic structure, has been suggested to regulate the cardiovascular system. However, its involvement in baroreflex control has never been addressed. Therefore, our hypothesis is that the vlPAG neurotransmission is involved in baroreflex cardiac activity. Male Wistar rats had stainless steel guide cannulae unilaterally or bilaterally implanted in the vlPAG. Afterward, a catheter was inserted into the femoral artery for BP and HR recording. A second catheter was implanted into the femoral vein for baroreflex activation. When the nonselective synaptic blocker cobalt chloride (CoCl2 ) was unilaterally injected into the vlPAG, in either the left or the right hemisphere, it increased the tachycardic response to baroreflex activation. However, when CoCl2 was bilaterally microinjected into the vlPAG it decreased the tachycardic response to baroreflex stimulation. This work shows that vlPAG neurotransmission is involved in modulation of the tachycardic response of the baroreflex. Moreover, we suggest that the interconnections between the vlPAG of both hemispheres are activated during baroreflex stimulation. In this way, our work helps to improve the understanding about brain-heart circuitry control, emphasizing the role of the autonomic nervous system in such modulation.


Assuntos
Barorreflexo , Coração/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Transmissão Sináptica , Animais , Pressão Sanguínea , Coração/inervação , Frequência Cardíaca , Masculino , Ratos , Ratos Wistar
3.
J Neurosci Res ; 91(10): 1338-48, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23913674

RESUMO

Neural reflex mechanisms, such as the baroreflex, are involved in regulating cardiovascular system activity. Previous results showed that the ventral portion of the medial prefrontal cortex (vMPFC) is involved in modulation only of the cardiac baroreflex bradycardic component. Moreover, vMPFC N-methyl-D-aspartate (NMDA) receptors modulate the bradycardia baroreflex, but the baroreflex tachycardic component has not been investigated. Furthermore, glutamatergic neurotransmission into the vMPFC is involved in activation of the cardiac sympathetic and parasympathetic nervous system. Finally, it has been demonstrated that glutamatergic neurotransmission into the vMPFC can be modulated by the endocannabinoid system and that activation of the CB1 cannabinoid receptor by anandamide, an endocannabinoid, can decrease both cardiac baroreflex bradycardic and tachycardic responses. Thus, there is the possibility that glutamatergic neurotransmission into the vMPFC does not modulate only the cardiac bradycardic component of the baroreflex. Therefore, the present study investigated whether glutamatergic neurotransmission into the vMPFC modulates both cardiac baroreflex bradycardic and tachycardic responses. We found that vMPFC bilateral microinjection of the NMDA receptor antagonist AP7 (4 nmol/200 nl), of a selective inhibitor of neuronal nitric oxide (NO) synthase N-propyl (0.08 nmol/200 nl), of the NO scavenger carboxy-PTIO (2 nmol/200 nl), or of the NO-sensitive guanylate cyclase ODQ (2 nmol/200 nl) decreased the baroreflex activity in unanesthetized rats. Therefore, our results demonstrate the participation of NMDA receptors, production of NO, and activation of guanylate cyclase in the vMPFC in the modulation of both cardiac baroreflex bradycardic and tachycardic responses.


Assuntos
Barorreflexo/fisiologia , Bradicardia/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Taquicardia/metabolismo , Animais , Sistema Nervoso Autônomo/fisiologia , GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia
4.
Exp Physiol ; 98(10): 1411-21, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23733521

RESUMO

We hypothesize that a local ATP-NO-NMDA glutamate receptor interaction in the paraventricular nucleus (PVN) modulates the baseline mean arterial pressure and heart rate in unanaesthetized rats. The microinjection of α,ß-methylene ATP [methyl ATP; 0.06, 0.12 and 1.2 nmol (100 nl)(-1)] into the PVN caused pressor and tachycardiac responses. Cardiovascular responses evoked by methyl ATP [0.12 nmol (100 nl)(-1)] in the PVN were blocked by pretreatment with the ganglion blocker pentolinium (5 mg kg(-1) i.v.). Also, responses to the injection of methyl ATP [0.12 nmol (100 nl)(-1)] into the PVN were reduced by pretreatment with the selective P2 purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid [0.5 nmol (100 nl)(-1)], the neuronal NO synthase inhibitor N(ω)-propyl-l-arginine [0.04 nmol (100 nl)(-1)] or the selective NMDA glutamate receptor antagonist LY235959 [2 nmol (100 nl)(-1)]. In addition, an injection of the NO donor sodium nitroprusside [27 nmol (100 nl)(-1)] into the PVN caused similar cardiovascular responses to those observed after methyl ATP, which were blocked by local pretreatment with LY235959. Therefore, the present results suggest that cardiovascular responses evoked by methyl ATP in the PVN involve a local production of NO, which promotes local glutamate release and activation of NMDA receptors that are probably located in pre-autonomic parvocellular neurons, leading to sympathetic nervous system stimulation.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Óxido Nítrico/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções , Óxido Nítrico/biossíntese , Nitroprussiato/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Quinazolinonas , Ratos , Ratos Wistar , Vigília
5.
Am J Physiol Regul Integr Comp Physiol ; 302(7): R876-85, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22204950

RESUMO

Neural reflex mechanisms, such as the baroreflex, are involved in the regulation of cardiovascular system activity. Previous results from our group (Resstel LB, Correa FM. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Eur J Neurosci 23: 481-488, 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB(1) receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB(1) receptors modulate baroreflex activity. We found that bilateral microinjection of the CB(1) receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB(1) receptors, which modulate local glutamate release.


Assuntos
Barorreflexo/fisiologia , Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Córtex Pré-Frontal/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/farmacologia , Barorreflexo/efeitos dos fármacos , Benzamidas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/farmacologia , Ácido Glutâmico/metabolismo , Masculino , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores
6.
Braz J Psychiatry ; 42(2): 218-224, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31314869

RESUMO

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.


Assuntos
Canabidiol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Animais , Estudos Clínicos como Assunto , Modelos Animais de Doenças , Humanos
7.
Brain Res ; 1747: 147037, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738232

RESUMO

Insular cortex is a brain structure involved in the modulation of autonomic activity and cardiovascular function. The nitric oxide/cyclic guanosine-3',5'-monophosphate pathway is a prominent signaling mechanism in the central nervous system, controlling behavioral and physiological responses. Nevertheless, despite evidence regarding the presence of nitric oxide-synthesizing neurons in the insular cortex, its role in the control of autonomic and cardiovascular function has never been reported. Thus, the present study aimed to investigate the involvement of nitric oxide/cyclic guanosine-3',5'-monophosphate pathway mediated by neuronal nitric oxide synthase (nNOS) activation within the insular cortex in the modulation of baroreflex responses in unanesthetized rats. For this, we evaluated the effect of bilateral microinjection of either the nitric oxide scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase inhibitor Nω-Propyl-l-arginine or the soluble guanylate cyclase inhibitor ODQ into the insular cortex on the bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and the tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of either NPLA or carboxy-PTIO into the insular cortex increased the reflex bradycardic response, whereas the reflex tachycardia was decreased by these treatments. Bilateral microinjection of the soluble guanylate cyclase inhibitor into the insular cortex did not affect any parameter of baroreflex function evaluated. Overall, our findings provide evidence that insular cortex nitrergic signaling, acting via neuronal nitric oxide synthase, plays a prominent role in control of baroreflex function. However, control of reflex responses seems to be independent of soluble guanylate cyclase activation.


Assuntos
Barorreflexo/fisiologia , Córtex Cerebral/metabolismo , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
8.
Physiol Rep ; 7(13): e14107, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31264387

RESUMO

GABAergic inhibitory input within the paraventricular hypothalamic nucleus (PVN) plays a key role in restraining sympathetic outflow. Although experimental evidence has shown depressed GABAA receptor function plus sympathoexcitation in hypertension and augmented GABA levels with reduced sympathetic activity after exercise training (T), the mechanisms underlying T-induced effects remain unclear. Here we investigated in T and sedentary (S) SHR and WKY: (1) time-course changes of hemodynamic parameters and PVN glutamic acid decarboxylase (GAD) isoforms' expression; (2) arterial pressure (AP) and heart rate (HR) responses, sympathetic/parasympathetic modulation of heart and vessels and baroreflex sensitivity to GABAA receptor blockade within the PVN. SHR-S versus WKY-S exhibited higher AP and HR, increased sympathetic reduced parasympathetic modulation, smaller baroreflex sensitivity, and reduced PVN GAD65 immunoreactivity. SHR-T and WKY-T showed prompt maintained increase (2-8 weeks) in GAD65 expression (responsible for GABA vesicular pool synthesis), which occurred simultaneously with HR reduction in SHR-T and preceded MAP fall in SHR-T and resting bradycardia in WKY-T. There was no change in GAD67 expression (mainly involved with GABA metabolic pool). Resting HR in both groups and basal MAP in SHR were negatively correlated with PVN GAD65 expression. Normalized baroreflex sensitivity and autonomic control observed only in SHR-T were due to recovery of GABAA receptor function into the PVN since bicuculline administration abolished these effects. Data indicated that training augments in both groups the expression/activity of GABAergic neurotransmission within presympathetic PVN neurons and restores GABAA receptors' function specifically in the SHR, therefore strengthening GABAergic modulation of sympathetic outflow in hypertension.


Assuntos
Glutamato Descarboxilase/genética , Hipertensão/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Esforço Físico , Receptores de GABA-A/metabolismo , Animais , Barorreflexo , Pressão Sanguínea , Glutamato Descarboxilase/metabolismo , Hipertensão/fisiopatologia , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologia
9.
Toxicology ; 398-399: 13-22, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471072

RESUMO

Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex. Adult male Wistar rats were injected intraperitoneally with a single dose of CPF (30 mg/kg) or saline (0.9%). 24 h after injections, cardiovascular reflexes were tested in awake rats. Potassium cyanide (KCN) and phenylbiguanide (PBG) were injected intravenously to activate the chemoreflex and the Bezold-Jarisch reflex, respectively. The baroreflex was activated by phenylephrine and sodium nitroprusside infusions. Blood samples were taken for measurements of butyrylcholinesterase (BChE) activity while acetylcholinesterase (AChE) activity was measured in brainstem samples. Animals treated with CPF presented signs of intoxication such as ataxia, tremor, lacrimation, salivation, tetany, urination and defecation. The hypertensive and the bradycardic responses of the chemoreflex as well as the hypotensive and bradycardic responses of the Bezold-Jarisch reflex were attenuated in CPF treated animals (P < 0.05). Concerning the baroreflex responses, CPF treatment reduced the bradycardia plateau, the range and the gain of the reflex (P < 0.05). Plasma BChE and brainstem AChE were both reduced significantly after CPF treatment (P < 0.05). Our results showed that acute sub-lethal exposure to CPF impairs the cardiovascular responses of homeostatic and defensive cardiovascular reflexes. These effects are associated with a marked inhibition of plasma BChE and brainstem AChE.


Assuntos
Barorreflexo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Clorpirifos/toxicidade , Acetilcolinesterase/sangue , Acetilcolinesterase/metabolismo , Animais , Tronco Encefálico/enzimologia , Butirilcolinesterase/sangue , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Inseticidas/toxicidade , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Testes de Toxicidade Aguda
10.
Front Mol Neurosci ; 10: 411, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29311804

RESUMO

Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia. The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function. Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus. Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes. Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels. Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.

11.
Braz. J. Psychiatry (São Paulo, 1999, Impr.) ; Braz. J. Psychiatry (São Paulo, 1999, Impr.);42(2): 218-224, Mar.-Apr. 2020.
Artigo em Inglês | LILACS | ID: biblio-1089257

RESUMO

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.


Assuntos
Humanos , Animais , Doença de Parkinson/tratamento farmacológico , Canabidiol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de Doenças , Estudos Clínicos como Assunto
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