leptin and Bradycardia

The hypothalamic-pituitary-adrenal (HPA) axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5) were instrumented with telemetry probes for determination of mean arterial pressure (MAP) and heart rate (HR) 24-hrs/day and an intracerebroventricular (ICV) cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group), diabetes was induced by single injection of streptozotocin (50 mg/kg, IP). Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm), with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl) compared to controls. Chronic ICV leptin infusion (7 days, 0.62 μg/hr) in non-diabetic rats reduced caloric intake and body weight (-10%) in Hypo and control rats and markedly increased HR in control rats (~25 bpm) while causing only modest HR increases in Hypo rats (8 bpm). In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl), respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin's effect on HR regulation without altering leptin's ability to suppress appetite or normalize glucose levels in diabetes.

Topics: Animals; Blood Glucose; Blood Pressure; Bradycardia; Central Nervous System; Diabetes Mellitus, Experimental; Energy Intake; Heart Rate; Hyperglycemia; Hyperphagia; Hypophysectomy; Infusions, Intraventricular; Insulin; Leptin; Male; Pituitary Gland; Rats; Rats, Sprague-Dawley; Streptozocin

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.

Topics: Analysis of Variance; Animals; Baroreflex; Bradycardia; Disease Models, Animal; Heart Rate; Leptin; Male; Microinjections; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reference Values; RNA, Messenger; Sensitivity and Specificity; Solitary Nucleus; Sympathetic Nervous System

Caloric restriction of mammals leads to decreases in blood pressure and heart rate. Although relevant clinically, the mechanisms involved, in terms of hormones and signaling pathways invoked, are currently not known. Circumstantial evidence suggests that leptin signaling may be involved with the bradycardia and hypotension associated with caloric restriction. This hypothesis was specifically tested using leptin-deficient mice (ob/ob) or leptin-receptor rats (Koletsky). Ob/ob mice were hypertensive during the light cycle relative to littermate controls (108 +/- 2 vs. 100 +/- 2 mmHg, respectively). Both ob/ob mice and wild-type mice exhibited hypotension and bradycardia on initiation of a 50% caloric restriction regime, suggesting that the loss of leptin during caloric restriction is not required to explain the cardiovascular effects. Blood pressure in Koletsky rats did not drop in response to caloric restriction during the light cycle, whereas blood pressure in littermate control rats significantly dropped. These data suggest that at least two pathways are involved with cardiovascular effects of caloric restriction: one dependent on leptin signaling and the other independent of the leptin axis.

Topics: Animals; Blood Pressure; Bradycardia; Energy Intake; Female; Gene Expression; Heart Rate; Hypertension; Hypotension; Leptin; Mice; Mice, Obese; Myosin Heavy Chains; Photoperiod; Rats; Rats, Inbred Strains; RNA, Messenger; Signal Transduction