Leptin signaling in the nucleus of the solitary tract alters the cardiovascular responses to activation of the chemoreceptor reflex

Abstract

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 it 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 observed in individuals with CIH may be due, in part, by leptin's effects on the chemoreflex at the level of NTS.

Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats

“…Similar transient depressor responses to angiotensin II injection within the NTS have been observed, in part due to glutamate and substance P release (12,16). While our collective findings suggest that leptin does not play a role in modulation of cardiac vagal chemosensitive fibers, this hormone has been shown to modulate neuronal circuits within the NTS controlling respi- ratory and cardiovascular responses to arterial chemoreflex activation (9,19). Endogenous leptin tone for baroreflex suppression during aging.…”

“…In contrast, higher doses of leptin within the NTS can evoke pressor and sympathoexcitatory responses in younger rats (9,29). The finding that leptin transiently decreased blood pressure in older SD rats, an action not seen in the younger rats in the previous study, may suggest that the neural pathways activated by exogenous leptin within the NTS are altered with aging.…”

Leptin dependent changes in the expression of tropomyosin receptor kinase B protein in nucleus of the solitary tract to acute intermittent hypoxia

“…Reduction in synaptophysin has been reported in a number of central sites under pathophysiological conditions [42,49]. Although leptin does not appear to be involved in the reduction in synaptophysin during exposure to IH, leptin does play an important role in mediating chemoreceptor reflex responses as injections of leptin into the caudal medial NTS potentiates the cardiovascular and sympathetic reflex responses to activation of the chemoreceptor reflex [11]. Furthermore, the response of NTS neurons to chemoreceptor reflex activation has been shown to be facilitated by leptin [12].…”

“…Changes in circulatory levels of leptin have been reported to not only exacerbate the effects of chemoreceptor reflex activation on the cardiovascular system, but also potentiate the neuronal responses in NTS to chemoreflex activation [12] while inhibiting the neuronal responses to baroreflex activation [9]. These affects are not observed in leptin receptor deficient Zucker obese rats [9,11]. Additionally, administration of leptin directly into the caudal medial NTS of Sprague-Dawley rats potentiated the cardiovascular and sympathetic responses to activation of the chemoreceptor reflex [10].…”

Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat

“…Of interest, several studies have reported that systemic administration of leptin increases the expression of the c-fos gene within caudal NTS (Elmquist et al, 1997(Elmquist et al, , 1998Elias et al, 2000;Grill et al, 2002), regions that are known to receive cardiovascular afferent projections (Ciriello, 1983;Erickson and Millhorn, 1991;Finley and Katz, 1992;Mifflin, 1992;Chitravanshi et al, 1994;Ciriello et al, 1994;Chitravanshi and Sapru, 1995;Spyer et al, 1997;Dampney et al, 2003;Spyer and Gourine, 2009). In addition, administration of leptin into the caudal NTS has been reported to elicit increases in arterial pressure and renal sympathetic nerve activity (Mark et al, 2009;Ciriello and Moreau, 2012). Furthermore, leptin injections into the NTS have been shown to attenuate the cardiovagal component of the baroreceptor reflex (Arnold et al, 2009), while potentiating the sympathoexcitatory responses to activation of the chemoreflex .…”