Central mechanisms activated by leptin to modify hypercapnia‐induced ventilatory responses

Melanocortin 3/4 receptors (MC3/4R) play a pivotal role in mediated metabolic and cardiovascular actions of leptin. In this study, we evaluated the changes in pulmonary ventilation (V E ) to hypercapnia (7% CO 2 ) in rats treated with daily microinjections of leptin and SHU9119 (MC3/4R antagonist) alone or combined into the lateral ventricle (LV) for 7 days. Male Holtzman rats (n=6/group) with stainless steel cannula implanted into the LV were used. Ventilation was recorded by plethysmography. Leptin (5 μg/5μl/day) into the LV reduced body weight by ~17% and increased (P<0.05) the tidal volume (11.0±0.7 vs. saline: 7.8±0.7 ml.kg −1 ) and the ventilatory response to hypercapnia (1796±140 vs. saline: 1213±126 ml.min −1 .kg −1 ), without changing respiratory frequency. SHU (1 nmol/5μl/day) increased body weight by ~ 13%, without changing the increase in ventilation (1185±53 ml.min −1 .kg −1 )and in the tidal volume (6.8±0.7 ml.kg −1 ) produced by hypercapnia. Combined treatment with SHU+leptin also increased body weight (~9%), however, decreased tidal volume (5.2±0.3 ml.kg −1 ) and ventilatory response to hypercapnia (795±34 ml.min − 1 .kg −1 , P<0.05). The results suggest that leptin‐induced increase in ventilation depends on the activation of central MC3/4 receptors. In addition, it seems that leptin produces also a parallel secondary inhibitory action on ventilation independent on MC3/4R activation.