The role of the central nervous system (CNS) in the control of hydrosaline homeostasis has been strikingly demonstrated by several studies. Growing evidence suggests that insulin may exert an influence in the modulation of many brain functions. However, there are no available data examining the CNS effect of insulin injection on renal sodium handling. Also, to examine the influence of renal nerve activity during i.c.v. administration of insulin, unanesthetized, unrestrained rats were randomly assigned to one of nine separated groups: (a) sham-operated i.c.v. 0.15 M NaCl-injected (Co, pooled data, n = 37) and sham-operated i.c.v. 0.42 ng.mul(-1) (n = 12), 4.2 ng.mul(-1) (n = 10) and 42.0 ng.mul(-1) (n = 11) insulin-injected rats (In);, (b) renal-denervated i.c.v. 0.15 M NaCl (Co-Dx, n = 5), and insulin-injected rats (In-Dx, n = 5); and (c) subcutaneously insulin-injected rats (SC, n = 5). We showed that centrally administered insulin produced dose-related increased urinary output of sodium [Co: 855 +/- 85 Delta% min, 0.42 ng.mul(-1)In 1189 +/- 308 Delta% min, 4.2 ng.mul(-1)In: 1461 +/- 594 Delta% min (p = 0.048), and 42.0 ng.mul(-1)In: 2055 +/- 411 Delta% min (p = 0.0001)], and dose-independently increased potassium excretion [Co: 460 +/- 28 Delta% min, 0.42 ng.mul(-1)In: 649 +/- 100 Delta% min (p = 0.016), 4.2 ng.mul(-1)In: 671 +/- 175 +/- min (p = 0.003), and 42.0 ng.mul(-1)In: 669 +/- 70 Delta% min (p = 0.002)] compared to control. The urinary sodium excretion response to i.c.v. 42 ng.mul(-1) insulin injections were abolished by bilateral renal denervation. In addition, we showed that insulin-induced natriuresis occurred by increasing postproximal tubule sodium rejection (FEPPNa), and changed glomerular filtration rate (C-Cr) at 42.0 ng.mul(-1) (p = 0.023) i.c.v. insulin microinjection but not at smaller insulin dose. The current data suggests that a blunted efferent insulin-sensitive nerve activity from periventricular region may contribute to the inability of renal tubules to handle the hydroelectrolyte balance. (C) 2002 Elsevier Science Inc.575613618