Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats.
OBJECTIVE
To study the effects of blockade of the renin-angiotensin system on the development of hypertension and end-organ damage in hyporeninaemic deoxycorticosterone acetate (DOCA)-salt hypertensive rats, using an angiotensin II (Ang II) receptor antagonist (TCV-116) or an angiotensin converting enzyme (ACE) inhibitor (enalapril).


METHODS
DOCA-salt hypertensive rats were produced by uninephrectomy, implantation with DOCA pellets and 1% NaCl loading. TCV-116 (0.1 or 1 mg/kg) or enalapril (10 mg/kg) was given orally once a day from 3 to 6 weeks after the operation. Body weight, blood pressure, plasma renin and creatinine, urinary protein and blood urea nitrogen were measured. After 3 weeks' treatment, oedema and omega 3-subtype benzodiazepine receptor binding in the brain were measured.


RESULTS
Three weeks after the operation the blood pressure in the DOCA-salt hypertensive rats was approximately 200 mmHg, and the plasma renin concentration was lower than in sham-operated rats. However, after a further 3 weeks the renin concentration was slightly above the normal level, and this increase was accompanied by a decrease in body weight and increases in blood urea nitrogen, plasma creatinine, urinary protein and omega 3-subtype benzodiazepine receptor binding in the cerebral cortex, and by brain oedema. Treatment with TCV-116 or enalapril prevented renal damage and decrease in body weight with little effect on blood pressure. Enalapril prevented brain oedema and the increase in benzodiazepine binding in the brain cortex, and 1 mg/kg TCV-116 prevented them markedly.


CONCLUSIONS
Although the hypertension in DOCA-salt hypertensive rats is independent of the renin-angiotensin system, the degree of cerebral and renal damage is associated with the activity of the renin-angiotensin system and has little relationship with the blood pressure level.
Wada
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan.
Kanagawa
R
R
Ishimura
Y
Y
Inada
Y
Y
Nishikawa
K
K
D000284:Administration, Oral; D000804:Angiotensin II / Q000187:drug effects / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D012965:Sodium Chloride; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011963:Receptors, GABA-A; D013777:Tetrazoles; D000804:Angiotensin II; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D004656:Enalapril; C077793:candesartan cilexetil