Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension.
In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.
Rahmouni
Kamal
K
Institut de Pharmacologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France. kamal-rahmouni@uiowa.edu
Sibug
Rosana M
RM
De Kloet
E Ronald
ER
Barthelmebs
Mariette
M
Grima
Michèle
M
Imbs
Jean Louis
JL
De Jong
Wybren
W
D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000652:urine; D003900:Desoxycorticosterone / Q000008:administration & dosage; D004231:Diuresis / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007276:Injections, Intraventricular; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology; D012964:Sodium / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic
D002712:Chlorides; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000808:Angiotensinogen; D013148:Spironolactone; D003900:Desoxycorticosterone; C041006:RU 28318; D009320:Atrial Natriuretic Factor; D012964:Sodium; D011188:Potassium