Pressor response to CSF sodium in mice: mediation by a ouabain-like substance and renin-angiotensin system in the brain.
Intracerebroventricular (i.c.v.) infusion of sodium in rats increases cerebrospinal fluid (CSF) [Na], mimicking the effects of a high salt diet in salt-sensitive strains and causing sympathetic hyperactivity and a pressor response that are mediated via both an endogenous brain ouabainlike substance (OLS) and the brain renin-angiotensin system (RAS). However, the concept that CSF sodium activates both the brain OLS and brain RAS to increase blood pressure has not been tested in any other species besides the rat. In the current study, it was established that continuous i.c.v. infusion of NaCl causes sustained increases in blood pressure and heart rate in both outbred (Swiss Webster, SW) and inbred (C57Bl/6) mouse strains. Subsequently, the mechanisms of the pressor effects were explored. In both SW and C57Bl/6, the i.c.v. administration of Fab fragments of an antibody with high affinity for ouabain and the OLS (Fab) abolished the pressor and tachycardic responses to i.c.v. sodium, as did the angiotensin II AT1 receptor antagonist losartan given i.c.v. In contrast, doses of NaCl, Fab and losartan that were effective i.c.v. were ineffective when given i.v. I.c.v. ouabain also caused the pressor and tachycardic responses, which were abolished by losartan (i.c.v.). In the reciprocal study, i.c.v. Fab had no effect on similar responses to i.c.v. angiotensin II. These studies demonstrate that the sustained blood pressure and heart rate responses caused by increases in CSF [Na] are mediated via both a brain OLS and the brain RAS. The RAS activation occurs downstream of the OLS effect.
Van Huysse
James W
JW
Hypertension Unit, University of Ottawa Heart Institute, Room H-347, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7. jvanhuysse@ottawaheart.ca
Hou
Xiaohong
X
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007276:Injections, Intraventricular; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D010042:Ouabain / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D012964:Sodium / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000494:pharmacology; D012965:Sodium Chloride / Q000008:administration & dosage*
D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D007140:Immunoglobulin Fab Fragments; D000804:Angiotensin II; D012965:Sodium Chloride; D010042:Ouabain; D012964:Sodium; D019808:Losartan