leptin and Tachycardia

This study was designed to determine the role of changes in adrenergic activity in mediating the chronic cardiovascular, renal, and metabolic actions of leptin. Male Sprague-Dawley rats were implanted with catheters for mean arterial pressure (MAP) and heart rate (HR) measurements and IV infusions of either vehicle (n= 7) or alpha- and beta-adrenergic receptor antagonists, terazosin and propranolol (10 mg/kg/d; n= 8) throughout the study. After control measurements, murine leptin was infused IV (1.0 microg/kg/min) for 7 days along with vehicle or adrenergic antagonists, followed by a 7-day recovery period. Leptin infusion significantly reduced food intake in control rats from 22.6 +/- 0.8 to 10.6 +/- 0.4 g/d and, in adrenergic blockade rats, from 22.6 +/- 0.8 to 13.2 +/- 0.8 g/d. Fasting plasma insulin decreased from 48 +/- 10 to 5 +/- 2 microU/mL in control rats and from 51+/- 9 to 9 +/- 2 microU/mL in adrenergic blockade rats during leptin infusion. Leptin infusion did not significantly alter glomerular filtration rate in either group. MAP and HR increased by 6 +/- 1 mm Hg and 23 +/- 7 bpm after 7 days of leptin infusion in control rats. However, in adrenergic blockade rats, leptin infusion did not significantly alter MAP (-1 +/- 1 mm Hg) and decreased, rather than increased, HR (-23 +/- 8 bpm). These results indicate that leptin-induced increases in blood pressure and tachycardia are mediated by increased adrenergic activity and support the concept that leptin may be an important link between obesity, increased sympathetic activity, and hypertension. However, the chronic effects of leptin on insulin and glucose regulation do not appear to be altered by alpha- and beta-adrenergic receptor blockade.

Topics: Adrenergic Agonists; Adrenergic Antagonists; Animals; Blood Pressure; Disease Models, Animal; Drug Interactions; Eating; Heart Rate; Hormones; Kidney; Kidney Function Tests; Leptin; Male; Pressoreceptors; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Tachycardia

Acute studies suggest that leptin has pressor and depressor actions, including stimulation of sympathetic activity as well as increased release of NO from the vascular endothelium. The goal of this study was to examine the role of NO in modulating the chronic blood pressure, heart rate, and renal responses to hyperleptinemia, comparable to that found in obesity-induced hypertension. Male Sprague-Dawley rats were implanted with arterial and venous catheters, and mean arterial pressure and heart rate were monitored continuously 24 h/d. After a 4-day control period, the rats were infused with isotonic saline vehicle (n=6) or N(G)-nitro-L-arginine methyl ester (L-NAME, 10 microgram/kg per minute; n=9) to inhibit NO synthesis for 7 days. After 7 days of vehicle or L-NAME administration, leptin was infused intravenously for 7 days at a rate of 0.5 microgram/kg per minute, followed by a leptin infusion at 1.0 microgram/kg per minute for 7 days, along with vehicle or L-NAME. A 21-day infusion of L-NAME alone (n=6) served as a control for the L-NAME+leptin rats. Although the low dose of leptin alone did not significantly elevate arterial pressure, it raised the heart rate by 18+/-3 bpm. The higher leptin infusion rate raised arterial pressure from 96+/-3 to 104+/-3 mm Hg but did not increase the heart rate further. L-NAME+leptin increased arterial pressure by 40+/-6 mm Hg and heart rate by 79+/-19 bpm compared with pretreatment levels. In control L-NAME rats, mean arterial pressure increased by 31+/-4 mm Hg, whereas the heart rate was not altered significantly compared with pretreatment levels. Neither chronic leptin infusion alone nor L-NAME alone altered the glomerular filtration rate or renal plasma flow significantly, but L-NAME+leptin reduced glomerular filtration rate by 27+/-11% and renal plasma flow by 47+/-9%. These results indicate that impaired NO synthesis mildly enhances the chronic renal hemodynamic and hypertensive effects of leptin but markedly amplifies the tachycardia caused by hyperleptinemia.

Topics: Animals; Blood Pressure; Cardiovascular System; Drinking; Eating; Glomerular Filtration Rate; Heart Rate; Infusions, Intravenous; Kidney; Leptin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Potassium; Rats; Rats, Sprague-Dawley; Renal Plasma Flow; Sodium; Tachycardia

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.

Topics: Animals; Blood Pressure; Body Weight; Central Nervous System; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Eating; Heart Rate; Injections, Intraventricular; Leptin; Male; Rats; Rats, Sprague-Dawley; Sodium Chloride; Stress, Physiological; Tachycardia; Telemetry