Leptin increases baroreflex gain: role of melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus

Abstract

Intracerebroventricular (ICV) leptin increases lumbar sympathetic nerve activity (LSNA) and LSNA baroreflex gain (BRG), but the sites and neuronal pathways are unknown. To test the role of the paraventricular nucleus (PVN), baroreflex function was assessed in α‐chloralose anesthetized male SD rats at baseline and 1 hr after ICV leptin (3 μg), using a 4 parameter sigmoidal fit of LSNA responses to slow ramp (3–5 min) changes in arterial pressure, induced by iv infusion of nitroprusside and phenylephrine. Then, 90 min after ICV leptin, 60 nL of muscimol (mus; 1 mM/L; n=3), the melanocortin 3/4 receptor (MC3/4R) inhibitor SHU9119 (0.5 mM/L; n=6), or the aCSF vehicle (n=5) was microinjected bilaterally into the PVN. Leptin increased (P<0.05) LSNA (158±9%) and LSNA BRG (from 3.2±0.4 to 5.7±0.2 %/mmHg). In control experiments (after PVN aCSF), further increases (P<0.05) in LSNA (186±21%) and LSNA BRG (7.2±0.6 %/mmHg) were observed. In contrast, PVN inhibition with mus completely reversed (P<0.05) the effects of leptin to increase LSNA [to 160±9% (leptin) then 125±2% (mus)] and LSNA BRG [in %/mmHg: from 3.4±0.6 to 4.8±0.6 (leptin) then 3.6±0.4 (mus)]. PVN SHU9119 decreased (P<0.05) LSNA [to 169±9% (leptin) then 139±10% (SHU9119)] and LSNA BRG [in %/mmHg: from 3.1±0.4 to 4.8±0.7 (leptin) then 4.4±0.6 (SHU9119)] compared to aCSF; however, both LSNA and LSNA BRG remained elevated (P<0.05) versus baseline. In conclusion, the PVN contributes to the increases in LSNA and LSNA BRG induced by ICV leptin, in part via MC3/4R. Support: HL088552.