EFFECTS OF ANGIOTENSINOGEN ANTISENSE OLIGONUCLEOTIDES ON FLUID INTAKEIN RESPONSE TO DIFFERENT DIPSOGENIC STIMULI IN THE RAT

The role of centrally synthesised angiotensinogen in neural mechanisms subserving water drinking in rats was investigated by injecting antis ense oligonucleotides complementary to rat angiotensinogen mRNA into t he brain with the aim of inhibiting cerebral angiotensinogen synthesis . Phosphorothioate antisense oligonucleotides (18 mer) encompassing th e translation start codon were injected into the lateral ventricle of rats and their responses to a number of dipsogenic stimuli tested. The se were: intracerebroventricular (icy) renin, icy angiotensin II, icy carbachol, subcutaneous isoproterenol, intravenous hypertonic saline, water deprivation for 24 h or subcutaneous injection of polyethylene g lycol. Antisense treatment significantly reduced (by approximately 50% ) the volume of water drunk in response to icy injection of renin or s ubcutaneous isoproterenol, but did not reduce water intake elicited by the other dipsogenic stimuli. The icy administration of mismatch, scr ambled or sense oligonucleotides did not inhibit water intake. These d ata suggest that centrally produced angiotensinogen may have a role in neural pathways subserving isoproterenol-induced drinking. (C) 1997 E lsevier Science B.V.