Effects of angiotensin II type 1 receptor antagonist on nitric oxide synthase expression and myocardial remodeling in Goldblatt hypertensive rats.
We evaluated the effects of long-term treatment with TCV-116, an angiotensin II type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein expression in the left ventricle and its relation to myocardial remodeling in Goldblatt hypertensive rats. Two-kidney, one-clip Goldblatt hypertensive rats (RHR) were assigned either to a TCV-116 treatment group (RHR-TCV, n = 8, 3 mg/kg/day, subdepressor dose) or to a group without treatment (RHR-V, n = 7) after their kidneys had been clipped for 4 weeks. TCV-116 was administered to rats in the treatment group for 6 weeks, and age-matched sham-operated rats (ShC, n = 7) served as a control group. Blood pressure in RHR-V and RHR-TCV was similar and significantly higher than that in ShC. The eNOS mRNA and protein levels and NOS activity in the left ventricle was significantly decreased in RHR-V compared with ShC, and significantly increased in RHR-TCV compared with ShC and RHR-V. RHR-V demonstrated a significant increase in fibrosis factor (type I collagen) mRNA expression, perivascular fibrosis, and myocardial fibrosis. These parameters in the microvasculature were improved significantly by TCV-116. Subdepressor dose of TCV- 116 improved pathological myocardial changes in RHR, which may be due in part to an increased eNOS mRNA and protein expression and NOS activity in the left ventricle.
Higashi
T
T
Department of Medicine, Institute for Medical Science, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Kobayashi
N
N
Hara
K
K
Shirataki
H
H
Matsuoka
H
H
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009573:Nitrites; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D003094:Collagen; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C077793:candesartan cilexetil