Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension.
The sympathetic nerve activity is elevated in cardiovascular diseases such as hypertension. Enhanced glutamatergic inputs in the paraventricular nucleus (PVN) of the hypothalamus contribute to heightened sympathetic outflow in spontaneously hypertensive rats (SHR). We determined the role of group I metabotropic glutamate receptors (mGluR) in the PVN in the control of sympathetic vasomotor tone in hypertension. Lumbar sympathetic nerve activity (LSNA), arterial blood pressure (ABP), and heart rate (HR) were recorded in anesthetized SHR and Wistar-Kyoto (WKY) rats. Bilateral microinjection of 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGluR5 receptor antagonist, or (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), a selective mGluR1 receptor antagonist, into the PVN had no significant effect on LSNA and ABP in WKY rats. Strikingly, MPEP and LY367385 dose dependently decreased LSNA, ABP, and HR in SHR. The MPEP-induced decreases in LSNA and ABP were significantly greater than those inhibited by LY367385 in SHR. Furthermore, bilateral microinjection of (S)-3,5-dihydroxyphenylglycine (S-DHPG), a selective group I mGluR agonist, into the PVN caused a similar dose-dependent increase in LSNA, ABP, and HR in both groups. S-DHPG-induced responses were attenuated by MPEP or LY367385 alone and were abolished by a combination of MPEP and LY367385 in WKY rats and SHR. In addition, microinjection of the NMDA receptor antagonist attenuated the sympathoexcitatory responses induced by S-DHPG in both WKY rats and SHR. Collectively, this study provides important new evidence that the resting sympathetic vasomotor tone is maintained by tonic activation of group I mGluRs in the PVN in hypertension. Activation of NMDA receptors are involved in the sympathoexcitatory effect of group I mGluRs in the PVN.
Dept. of Critical Care, The Univ. of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 110, Houston, TX 77030, USA. dpli@mdanderson.org
De-Pei
DP
Li
Hui-Lin
HL
Pan
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D015854:Up-Regulation; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1