Leptin impairs cardiovagal baroreflex function at the level of the solitary tract nucleus

Abstract

Circulating leptin is elevated in some forms of obesity-related hypertension, associated with impaired baroreflex function. Leptin receptors are present on vagal afferent fibers and neurons within the solitary tract nucleus, providing an anatomic distribution consistent with baroreflex modulation. Although solitary tract nucleus microinjection of 144 fmol/60 nL of leptin had no significant effect on baroreflex sensitivity for control of the heart rate in urethane/chloralose-anesthetized Sprague-Dawley rats, 500 fmol of leptin impaired baroreflex sensitivity for bradycardia in response to increases in pressure (1.15+/-0.04 versus 0.52+/-0.12 ms/mm Hg; P<0.01). Transgenic ASrAOGEN rats with low brain angiotensinogen have an upregulation of the leptin receptor and p85 alpha mRNA in the dorsal medulla relative to Sprague-Dawley rats. Consistent with these observations, the response to leptin was enhanced in ASrAOGEN rats, because both the 144-fmol (1.46+/-0.08 versus 0.75+/-0.10 ms/mm Hg; P<0.001) and 500-fmol (1.36+/-0.32 versus 0.44+/-0.06 ms/mm Hg; P<0.05) leptin microinjections impaired baroreflex sensitivity. At these doses, leptin microinjection had no effect on resting pressure, heart rate, or the tachycardic response to decreases in pressure in Sprague-Dawley or ASrAOGEN rats. Thus, exogenous leptin at sites within the solitary tract nucleus impairs the baroreflex sensitivity for bradycardia induced by increases in arterial pressure, consistent with a permissive role in mediating increases in arterial pressure. Baroreflex inhibition was enhanced in animals with evidence of increased leptin receptor and relevant signaling pathway mRNA.

Figure 1. Effect of NTS leptin microinjection on BRS for control of HR evoked by PE in SD rats

NTS microinjection of 144 fmol leptin impaired BRS by 22% in SD rats, an effect that did not reach significance (A; n = 4). In contrast, 500 fmol leptin injection impaired BRS by ~ 63% (B; n = 5). In SD rats, the BRS was impaired at 10 and 60 min with evidence of recovery at 120 min after NTS microinjection of 500 fmol leptin (C; n = 3). The slope of the relationship between the increases in MAP produced by phenylephrine and the corresponding reflex bradycardia [expressed as pulse interval] shows graded reductions in the linear regression slope with increasing doses of leptin [1.05 ± 0.14 msec/mm Hg baseline; 0.91 ± 0.27 msec/mm Hg after 144 fmol leptin; 0.38 ± 0.10 msec/mm Hg after 500 fmol leptin (r = 0.48 – 0.60)] in data from pooled SD rats. SD = Sprague-Dawley, MAP = mean arterial pressure, PI = pulse interval * p < 0.05 versus baseline, † p < 0.01 versus baseline

Figure 2. Effect of NTS leptin microinjection on BRS for control of HR evoked by PE in ASrAOGEN rats

In ASrAOGEN rats, NTS microinjection of 144 (A; n = 8) and 500 fmol (B; n = 4) leptin significantly impaired BRS by 50% and 68%, respectively. The BRS was impaired at 10, 60 and 120 min after NTS microinjection of 500 fmol leptin (C; n = 3). In ASrAOGEN rats (D), the 144 and 500 fmol leptin doses produced equivalent reductions in the slope of the regression line [1.11 ± 0.10 msec/mm Hg baseline; 0.45 ± 0.19 msec/mm Hg after 144 fmol leptin; 0.53 ± 0.08 msec/mm Hg after 500 fmol leptin (r = 0.61 – 0.89)]. AS = ASrAOGEN, MAP = mean arterial pressure; PI = pulse interval * p < 0.05 versus baseline; ‡ = p < 0.001;

Figure 3. Leptin receptor and PI3K p85 alpha mRNA in dorsal medulla of SD and ASrAOGEN rats

Relative gene expression of leptin receptor and PI3K regulatory p85 alpha was higher in dorsal medullary tissue of 15-week old ASrAOGEN (n = 7) relative to SD (n = 9) rats. SD = Sprague-Dawley, AS = ASrAOGEN * p < 0.05 versus SD; † p < 0.01 versus SD