Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension

Abstract

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.