Leptin Signaling in the Nucleus of the Solitary Tract Alters the Cardiovascular Responses to Activation of the Chemoreceptor Reflex By

Circulating levels of leptin are elevated in individuals suffering from chronic intermittent hypoxia (CIH). Systemic and central administration of leptin elicits increases in sympathetic nervous activity (SNA), arterial pressure (AP) and heart rate (HR), and attenuates the baroreceptor reflex, cardiovascular responses that are similar to those observed during CIH as a result of activation of chemoreceptors by the systemic hypoxia. Therefore, experiments were done in anesthetized Wistar rats to investigate the effects of leptin in nucleus of the solitary tract (NTS) on AP and HR responses, and renal SNA (RSNA) responses during activation of NTS neurons and the chemoreceptor reflex. Microinjection of leptin (5-100 ng; 20 nL) into caudal NTS pressor sites (L-glutamate; L-Glu; 0.25 M; 10 nL) elicited dose-related increases in AP, HR and RSNA. Leptin microinjections (5 ng; 20 nL) into these sites potentiated the increase in AP and HR elicited by L-Glu. Additionally, bilateral injections of leptin (5 ng; 100 nL) into NTS potentiated the increase in AP and attenuated the bradycardia to systemic activation of the chemoreflex. In the Zucker obese rat, leptin injections into NTS neither elicited cardiovascular responses, nor altered the cardiovascular responses to activation of the chemoreflex. Taken together, these data indicate that leptin exerts a modulatory effect on neuronal circuits within NTS that control cardiovascular responses elicited during the reflex activation of arterial chemoreceptors, and suggest that increased AP and SNA 3 observed in individuals with CIH may be due in part by leptin effects on the chemoreflex at the level of NTS. LIST OF ABBREVIATIONS 4V 4 th ventricle 12 n hypoglossal nucleus ANS autonomic nervous system AP arterial pressure ap area postrema cc central canal CIH chronic intermittent hypoxia com commissural subnucleus of the NTS complex cu fasciculus cuneatus CUN cuneate nucleus DMV dorsal motor nucleus of the vagus gr fasciculus gracilis GRN nucleus gracilis Hex hexamethonium bromide HR heart rate Int RSNA integrated renal sympathetic nerve activity KCN potassium cyanide Lep leptin L-Glu L-glutamate MAP mean arterial pressure NTS nucleus of the solitary tract RSNA renal sympathetic nerve activity Sc central subnucleus of the NTS complex Sg nucleus gelatinosa (sub-postremal area) of the NTS complex Sl lateral subnucleus of the NTS complex Sm medial subnuleus of the NTS complex Sni interstitial nucleus of the NTS complex SNA sympathetic nervous activity St solitary tract 4 INTRODUCTION