NMDA-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide.

Abstract

The paraventricular nucleus (PVN) of the hypothalamus is an important site of integration in the central nervous system for sympathetic outflow. Both glutamate and nitric oxide (NO) play an important role in the regulation of sympathetic nerve activity. The purpose of the present study was to examine the interaction of NO and glutamate within the PVN in the regulation of renal sympathetic nerve activity in rats. Renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR) were measured in response to administration of N-methyl-D-aspartic acid (NMDA) and N(G)-monomethyl-L-arginine (L-NMMA) into the PVN. We found that microinjection of NMDA (25, 50, and 100 pmol) into the PVN increased RSND, BP, and HR in a dose-dependent manner, reaching 53 +/- 9%, 19 +/- 3 mmHg, and 32 +/- 12 beats/min, respectively, at the highest dose. These responses were significantly enhanced by prior microinjection of L-NMMA. On the other hand, inhibition of NO within the PVN by microinjection of L-NMMA also induced increases in RSND, BP, and HR in a dose-dependent manner, reaching 48 +/- 6.5%, 11 +/- 4 mmHg, and 55 +/- 16 beats/min, respectively, at the highest dose. This sympathoexcitatory response was eliminated by prior microinjection of DL-2-amino-5-phosphonovaleric acid, an antagonist of the NMDA receptor. Furthermore, with the use of the push-pull technique, perfusion of glutamate (0.5 micromol) or NMDA (0.1 nmol) into the PVN induced an increase in NO release. In conclusion, our data indicate that NMDA receptors within the PVN mediate an excitatory effect on renal sympathetic nerve activity, arterial BP, and HR. NO in the PVN, which is released by activation of the NMDA receptor, also inhibits NMDA-mediated increases in sympathetic nerve activity. This negative feedback of NO on the glutamate system within the PVN may play an important role in maintaining the overall balance and tone of sympathetic outflow in normal and pathophysiological conditions known to have increased sympathetic tone.