Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in 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.
Li
De-Pei
DP
Department of Critical Care, University of Texas MD Anderson Cancer Center, Houston 77030-4009, USA.
Pan
Hui-Lin
HL
D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology*; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D011724:Pyridazines; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; C049853:gabazine; D007736:Kynurenic Acid