Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-"ouabain" pathway.
An increase in plasma ANG II causes neuronal activation in hypothalamic nuclei and a slow pressor response, presumably by increasing sympathetic drive. We evaluated whether the activation of a neuromodulatory pathway, involving aldosterone and "ouabain," is involved in these responses. In Wistar rats, the subcutaneous infusion of ANG II at 150 and 500 ng x kg(-1) x min(-1) gradually increased blood pressure up to 60 mmHg at the highest dose. ANG II at 500 ng x kg(-1) x min(-1) increased plasma ANG II by 4-fold, plasma aldosterone by 25-fold, and hypothalamic aldosterone by 3-fold. The intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevented the ANG II-induced increase in hypothalamic aldosterone without affecting the increase in plasma aldosterone. Neuronal activity, as assessed by Fra-like immunoreactivity, increased transiently in the subfornical organ (SFO) but progressively in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). The central infusion of the AS inhibitor or a mineralocorticoid receptor blocker markedly attenuated the ANG II-induced neuronal activation in the PVN but not in the SON. Pressor responses to ANG II at 150 ng x kg(-1) x min(-1) were abolished by an intracerebroventricular infusion of the AS inhibitor. Pressor responses to ANG II at 500 ng x kg(-1) x min(-1) were attenuated by the central infusion of the AS inhibitor or the mineralocorticoid receptor blocker by 70-80% and by Digibind (to bind "ouabain") by 50%. These results suggest a novel central nervous system mechanism for the ANG II-induced slow pressor response, i.e., circulating ANG II activates the SFO, leading to the direct activation of the PVN and SON, and, in addition, via aldosterone-dependent amplifying mechanisms, causes sustained activation of the PVN and thereby hypertension.
Hypertension Unit, Univ. of Ottawa Heart Institute, H3228, 40 Ruskin St., Ottawa, ON, Canada K1Y 4W7.
Bing S
BS
Huang
Sara
S
Ahmadi
Monir
M
Ahmad
Roselyn A
RA
White
Frans H H
FH
Leenen
D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002298:Cardenolides / Q000378:metabolism*; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D017316:Fadrozole; D006339:Heart Rate; D007031:Hypothalamus / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D055104:Infusions, Subcutaneous; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects; D012503:Saponins / Q000378:metabolism*; D013148:Spironolactone / Q000008:administration & dosage; D013356:Subfornical Organ / Q000378:metabolism; D013686:Telemetry; D013997:Time Factors
D002298:Cardenolides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007140:Immunoglobulin Fab Fragments; D000451:Mineralocorticoid Receptor Antagonists; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012503:Saponins; C050199:digoxin antibodies Fab fragments; C034504:digoxin-like factors; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole