Hypotensive and prophylactic effects of angiotensin II subtype 1 receptor antagonist, irbesartan, in stroke-prone spontaneously hypertensive rats.
We determined the acute hypotensive effect of a single administration and the prophylactic effect of chronic treatment with Irbesartan, an angiotensin II receptor antagonist, on the development of end-organ damage in stroke-prone spontaneously hypertensive rats (SHRSP). The acute hypotensive effect was determined by a telemetrical method in SHRSP fed a normal diet. The prophylactic effect was examined by biochemical, histopathological and immunohistochemical methods in SHRSP fed a high-salt and low-protein diet. Irbesartan (3, 10, 30 and 100 mg/kg) reduced blood pressure in a dose-dependent manner without affecting heart rate. Irbesartan (3, 10 and 30 mg/kg) increased the survival rate in SHRSP fed a high-salt and low-protein diet. Furthermore, Irbesartan ameliorated the appearance of stroke symptoms in dose-dependent manner showing association with the prevention of microscopic lesions. Irbesartan ameliorated the increases in urinary protein excretion and N-acetyl-D-glucosamidase activity by preventing nephrosclerosis, as judged by microscopic observations, and ameliorated the increases in the expression of collagen IV and fibronectin in the kidney. These findings demonstrate that Irbesartan is a potent antihypertensive drug offering a protective effect on the development of hypertension-induced end-organ damages in SHRSP. Thus, Irbesartan is useful for the therapy of hypertension with end-organ damage.
Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan. toshitake.shimamura@shionogi.co.jp
Toshitake
T
Shimamura
Masao
M
Masui
Mikinori
M
Torii
Masatoshi
M
Nakajima
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D000077405:Irbesartan; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000008:administration & dosage*; D020521:Stroke / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D016019:Survival Analysis; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000008:administration & dosage*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D015415:Biomarkers; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000077405:Irbesartan