Proceedings of The Physiological Society
Trinity College Dublin (2003) J Physiol 551P, C49
Modulation of the autonomic control of the kidney by leptin acting in the brain of anaesthetised rats
Chunhua Huang*, Aoife McMahon and Edward J. Johns
*Department of Physiology, University College London , London, UK and Department of Physiology, University College Cork, Ireland
A complex neural network exists in the hypothalamus determining food intake and thermogenesis to ensure energy balance and to maintain body fat levels. A number of neuromodulators are involved which control the degree of sympathetic nervous activity to various organs, including the kidney, to ensure metabolic rate is optimised against food intake. The afferent limb of this complex reflex is leptin, which is a peptide hormone released from white adipocytes that activates receptors in the hypothalamus. Central administration of leptin has been shown to cause a slowly developing stimulation of the sympathetic nervous system. The question addressed in this study was whether leptin within the brain might modify cardiovascular reflex regulation of sympathetic outflow. To this end, cardiopulmonary receptors were stimulated and the responses in renal sympathetic nerve activity (RSNA) and nerve-dependent function evaluated normally and following I.C.V. leptin administration.
Male Wistar rats, 310 ± 7 g, were anaesthetised (32/450 mg kg-1 chloralose/urethane, I.V.). Blood pressure (BP) and heart rate (HR) were monitored from a femoral artery and saline (150 mM NaCl) was infused via a femoral vein at 3 ml h-1. A cannula was placed into the right cerebroventricle to infuse saline or leptin (5 µg bolus plus 5, 10 or 20 µg at 7.7 µl h-1). The left kidney was exposed via a flank incision and either the renal sympathetic nerves were isolated and sealed on to recording electrodes or the right and left ureters were cannulated, the left kidney was denervated and a flow probe was placed on its artery. Inulin was infused to allow measurement of glomerular filtration rate (GFR). After a 2 h recovery period, 15 min clearances were taken, two before and two during either saline or leptin I.C.V. infusion and two after 20 min of phenylbiguanide (PBG) infusion I.V. at 32 µg min-1 to stimulate the cardiopulmonary receptors. The animals were killed with an overdose of anaesthetic. Data are means ± S.E.M. and were tested using ANOVA and Student's paired t test with significance at P < 0.05.
Infusion of saline I.C.V. (n = 6) had no effect on any variable, but leptin (5+20 µg h-1) I.C.V. (n = 6) increased RSNA by 11 % to 11.0 ± 2.6 µV s-1 (P < 0.05) without change in BP, 99 ± 2 mmHg, or HR, 6.6 ± 0.4 Hz. When PBG was given I.V. with saline I.C.V., BP was unchanged, HR increased by 15 % (P < 0.05) while RSNA decreased by 50 % (P < 0.05), but PBG infusion with leptin I.C.V. decreased RSNA by only 18 % (P < 0.05), less than that with saline I.C.V. (P < 0.05). In the functional studies, during saline I.C.V. (n = 9) PBG had no effect on fractional sodium excretion (FENa) in the denervated (DNX) kidneys at 1.51 ± 0.36 %, but it was increased some 3-fold in the innervated (INN) kidney, from 0.54 ± 0.14 to 1.70 ± 0.52 (P < 0.05). During infusion of leptin I.C.V. (n = 9, 5+20 µg h-1), PBG had no effect on FENa<
Where applicable, experiments conform with Society ethical requirements