Abstract P391: Local Ionotropic Glutamate Receptors Contribute to the Sympathoexcitatory Effects of Leptin in the Paraventricular Nucleus

Abstract

In male rats, intracerebroventricular infusion of leptin increases sympathetic nerve activity (SNA), and this response can be partially reversed by nanoinjections of the ionotropic glutamate receptor (iGluR) blocker, kynurenate (KYN), and also the melanocortin type 3/4 receptor (MC3/4R) antagonist, SHU9119, into the hypothalamic paraventricular nucleus (PVN). These results suggest that leptin increases SNA in part via activation of PVN iGluR and MC3/4R. More recently, we found that injection of leptin directly into the PVN also dose-dependently increases SNA. However, the role of PVN iGluR or MC3/4R in this response is unknown. Therefore, we determined if PVN KYN (2.7 nmol in 60 nL) or SHU9119 (30 pmol) reverses the increases in lumbar SNA (LSNA), mean arterial pressure (MAP), and heart rate (HR) evoked by bilateral PVN nanoinjections of leptin (30 ng in 60 nL; n=6) or, as a control, of artificial cerebrospinal fluid (aCSF; n=4). After ninety min, PVN leptin increased (all P<0.05) LSNA to 164±10 % of control, MAP from 106±5 to 118±5 mmHg, and HR from 360±12 to 399±16 bpm. Then, PVN injections of KYN decreased (all P<0.05) LSNA to 133±8 % control, MAP to 108±4 mmHg, and HR to 379±16 bpm. On the other hand, neither PVN aCSF injections (LSNA, to 105±3 % control; MAP, from 107±8 to 109±7 mmHg; and HR, from 363±31 to 367±20 bpm) nor subsequent PVN KYN injections (LSNA, to 102±5 % control; MAP, to 108±6 mmHg; and HR, to 373±17 bpm) significantly altered these variables. In a second set of animals, while PVN leptin (n=4) elicited similar increases (all P<0.05) in LSNA (to 158±8 % control), MAP (from 101±6 to 113±4 mmHg), and HR (from 367±19 to 405±11 bpm), subsequent SHU9119 had no effects (LSNA, to 151±7 % control; MAP, to 108±5 mmHg; and HR, to 400±14 bpm). Again, no changes in these variables were observed in response to PVN injections of aCSF (n=4), even when followed by SHU9119 (LSNA, to 114±11 and then 110±13 % control; MAP, from 107±7 to 109±8 and then 106±9 mmHg; and HR, 357±31 to 355±24 and then 354± 25 bpm). In conclusion, activation of local iGluR, but not MC3/4R, contribute to the increases in LSNA, MAP, and HR in response to PVN leptin.