6-cyano-7-nitroquinoxaline-2-3-dione and Hypertension

The paraventricular nucleus (PVN) of the hypothalamus is critical to the regulation of sympathetic output. The PVN hyperactivity is known to cause increased sympathetic nerve activity in spontaneously hypertensive rats (SHRs). The purpose of this study was to determine whether glutamatergic input to the PVN contributes to heightened sympathetic outflow in hypertension. Lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate were recorded from anesthetized SHRs and Wistar-Kyoto (WKY) rats. Bilateral microinjection of an N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonopentanoic acid, or a non-N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, into the PVN dose-dependently decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Bilateral microinjection of kynurenic acid into the PVN also significantly decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Furthermore, microinjection of gabazine, a specific GABA(A) receptor antagonist, into the PVN increased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in both SHRs and WKY rats. Notably, this response was significantly attenuated in SHRs compared with that in WKY rats. In addition, kynurenic acid abolished the sympathoexcitatory and pressor responses to microinjection of gabazine into the PVN in both SHRs and WKY rats. Thus, this study provides new functional evidence that resting sympathetic vasomotor tone is maintained by tonic glutamatergic input in the PVN in SHRs. Removal of GABAergic inhibition results in augmented glutamatergic input in the PVN, which probably constitutes an important source of excitatory drive to the brain stem vasomotor neurons in hypertension.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Blood Pressure; Excitatory Amino Acid Antagonists; GABA Antagonists; Glutamic Acid; Heart Rate; Hypertension; Kynurenic Acid; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Pyridazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; Vasomotor System

Spontaneously hypertensive rats (SHR) are used as a model for attention-deficit hyperactivity disorder (ADHD) since SHR display the major symptoms of ADHD (hyperactivity, impulsivity, inablity to sustain attention during behavioral tasks). We previously showed that electrical and/or K+-stimulated release of dopamine (DA) from nerve terminals in the prefrontal cortex, nucleus accumbens, and caudate-putamen of SHR was significantly lower than that of Wistar-Kyoto (WKY) control rats. The aim of the present investigation was to determine whether glutamate-stimulated release of DA from nucleus accumbens core and shell of SHR was significantly different from that of WKY. Using an in vitro superfusion technique, we showed that glutamate-stimulated release of [3H]DA from striatal slices is mediated by glutamate activation of AMPA receptors and that glutamate-stimulated release of [3H]DA from nucleus accumbens core and shell of 4-6-week-old SHR and WKY is not significantly different. Glutamate-stimulated release of [3H]DA from SHR shell is significantly lower than SHR core and there is also a tendency for glutamate-stimulated [3H]DA release from SHR shell to be lower than release from WKY shell.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dopamine; Excitatory Amino Acid Antagonists; Glutamic Acid; Hypertension; In Vitro Techniques; Nucleus Accumbens; Perfusion; Quinoxalines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, AMPA

The microinjection of L-glutamate (1-6 nmol/rat) and N-methyl-D-aspartate (NMDA 1-10 nmol/rat), ionotropic glutamate receptor (iGluR) agonists, into the nucleus raphe obscurus caused a concentration -dependent increase of arterial blood pressure. In contrast, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD, 14-42 nmol/rat), a metabotropic glutamate receptor (mGluRs) agonist, caused a concentration-dependent decrease in blood pressure. Pretreatment with D,L-2-amino-phosphono valeric acid (2-APV, 5 nmol/rat) a selective NMDA iGluR antagonist, and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b] cyclohepten-5,10-imine hydrogen maleate (MK801, 0.9 nmol/rat), a noncompetitive NMDA iGluR antagonist, blocked both the glutamate and NMDA pressor responses, while pretreatment with (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 0.05 nmol/rat), a mGluR1 antagonist, increased the glutamate-induced pressor effects and blocked the fall in blood pressure induced by t-ACPD. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX, 0.4 nmol/rat) a non-NMDA iGluR antagonist, did not affected the glutamate-induced hypertension. These observations indicate opposing roles for ionotropic and metabotropic receptors in the glutamate-induced blood pressure changes elicited from the nucleus raphe obscurus. Moreover, we suggest that the glutamate-induced hypertension may be due to the activation of NMDA ionotropic receptor subtypes and the metabotropic receptors may influence this activation through a reduction of excitability at level of synapses.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Benzoates; Blood Pressure; Cycloleucine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Hypertension; Male; Microinjections; N-Methylaspartate; Neurotoxins; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Structure-Activity Relationship; Valine