Leptin increases lumbar sympathetic nerve activity (LSNA) in part via excitatory amino acid inputs into the hypothalamic paraventricular nucleus (PVN)

Intracerebroventricular (ICV) leptin increases LSNA and LSNA baroreflex gain (BRG). Previously, we demonstrated that the PVN is required, since PVN inhibition with muscimol completely reversed the effects of leptin. Inhibition of PVN melanocortin 3/4 receptors with SHU9119 only partially reversed leptin's effects, suggesting that another excitatory input into PVN also contributes. Therefore, we tested the hypothesis that leptin enhances baroreflex control of LSNA in part via increased PVN excitatory amino acid drive. In α ‐chloralose anesthetized male SD rats, basal LSNA and LSNA BRG were assessed at baseline, 1 hr after ICV leptin (3 μg) or aCSF, and then again 30 min later after microinjection of 60 nL of aCSF (n=5) or kynurenate (Kyn; 2.7 nmol; n=6). After 60 min, leptin increased (P<0.05) basal LSNA (to 158±9%) and LSNA BRG (from 3.2±0.4 to 5.7±0.2 %/mmHg). After PVN aCSF, LSNA (to 186±21%) and LSNA BRG (to 7.2±0.6 %/mmHg) continued to rise (P<0.05). In contrast, PVN Kyn prevented further increases such that LSNA [to 144±7% (leptin) then 137±7% (Kyn)] and LSNA BRG [in %/mmHg: from 3.4±0.3 to 5.3±0.2 (leptin) then 5.1±0.2 (Kyn)] were decreased (P<0.05) compared to PVN aCSF. However, both LSNA and LSNA BRG remained elevated (P<0.05) versus baseline. No change in LSNA was observed following PVN microinjection of Kyn after ICV aCSF infusion. In conclusion, excitatory amino acid inputs into the PVN contribute to the sympathoexcitatory effects of leptin. Supported by HL088552 and AHA.